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How does a fungus protect itself from digestion by other fungi?

How does a fungus protect itself from digestion by other fungi?


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If a fungus releases its digestive enzymes outside its body, how does it protect itself from digestion? How do fungi growing nearby protect themselves?

I have tried searching this on google but couldn't get an answer.


In general fungal cell walls are resistant to whatever enzymes or compounds they are excreting to break material down for consumption. Conceptually, it is a little like your stomach lining being resistant to stomach acid. For a more detailed answer you may have to head over to your local university and find a Mycologist.

There is ongoing research on how fungi actually "eat." You can look up fungal endocytosis if you wish to research it more. There may be other mechanisms as Shigeta mentions.


How plants react to fungi

Plants are under constant pressure from fungi and other microorganisms. The air is full of fungal spores, which attach themselves to plant leaves and germinate, especially in warm and humid weather. Some fungi remain on the surface of the leaves. Others, such as downy mildew, penetrate the plants and proliferate, extracting important nutrients. These fungi can cause great damage in agriculture.

The entry ports for some of these dangerous fungi are small pores, the stomata, which are found in large numbers on the plant leaves. With the help of specialised guard cells, which flank each stomatal pore, plants can change the opening width of the pores and close them completely. In this way they regulate the exchange of water and carbon dioxide with the environment.

Chitin covering reveals the fungi

The guard cells also function in plant defense: they use special receptors to recognise attacking fungi. A recent discovery by researchers led by the plant scientist Professor Rainer Hedrich from Julius-Maximilians-Universität (JMU) Würzburg in Bavaria, Germany, has shed valuable light on the mechanics of this process.

"Fungi that try to penetrate the plant via open stomata betray themselves through their chitin covering," says Hedrich. Chitin is a carbohydrate. It plays a similar role in the cell walls of fungi as cellulose does in plants.

Molecular details revealed

The journal eLife describes in detail how the plant recognizes fungi and the molecular signalling chain via which the chitin triggers the closure of the stomata. In addition to Hedrich, the Munich professor Silke Robatzek from Ludwig-Maximilians-Universität was in charge of the publication. The molecular biologist Robatzek is specialized in plant pathogen defense systems, and the biophysicist Hedrich is an expert in the regulation of guard cells and stomata.

Put simply, chitin causes the following processes: if the chitin receptors are stimulated, they transmit a danger signal and thereby activate the ion channel SLAH3 in the guard cells. Subsequently, further channels open and allow ions to flow out of the guard cells. This causes the internal pressure of the cells to drop and the stomata close - blocking entry to the fungus and keeping it outside.

Practical applications in agricultural systems

The research team has demonstrated this process in the model plant Arabidopsis thaliana (thale cress). The next step is to transfer the findings from this model to crop plants. "The aim is to give plant breeders the tools they need to breed fungal-resistant varieties. If this succeeds, the usage of fungicides in agriculture could be massively reduced," said Rainer Hedrich.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.


Life Cycle of Taphrina (With Diagram) | Fungi

The genus Taphrina (old generic name Exoascus still in use by many authors) contains several’ species which are very important pathogens. They induce hyper­trophic malformations of buds, leaves, twigs, flowers and fruits producing diseases known as leaf curl, blister and fasciatiom. In woody twigs often unnatural, profuse, tufted branching “witches’ broom” is .developed.

Taphrina deformans causes peach leaf curl disease and T. cerasi causes witches’ broom of cherries.

The somatic mycelium grows intercellularly and forms a network under the epi­dermis, or the cuticle of the host tissue. Its cells are irregular in size and shape and are dikaryotic. The mycelium in most species of Taphrina is annual, but in some species it is perennial.

Asexual reproduction takes place by uninucleate, thin-walled spores which are referred to as conidia. The conidia are developed from the ascospores. The ascospores produce conidia by budding. The conidia themselves bud indefinitely pro­ducing secondary, tertiary, etc., conidia. They germinate by germ tubes which pene­trate through cuticle of young leaf and cause infection in the host tissue.

Sexual reproduction is accomplished by the development of palisade-like layer of rectangular asci which are produced from the dikaryotic cells of a compact mycelial layer. These cells are the ascogenous cells. The mycelial layer is one cell thick and is formed subcuticularly.

The ascogenous cells are ovoid, pyriform, or dome-shaped. During the development of an ascus the ascogenous cell elongates perpendicularly to the host surface. Its nuclei fuse forming a diploid nucleus.

The diploid nucleus then divides mitotically into two daughter nuclei of which one moves to the distal end of the elongated ascogenous cell and the other remains at the base. The elongated ascogenous cell now divides into two unequal cells by a transverse septum. The upper larger cell is the ascus mother cell and the lower smaller cell is the stalk cell.

The ascus mother cell now develops into an ascus. The protoplasmic contents of the ascus mother cell crowd the tip where the diploid nucleus divides reductionally into daughter nuclei which again divide mitotically to form eight haploid nuclei. Ultimately eight asco­spores are formed.

There is no development of ascocarp. Mature asci are exposed by the rupture of the cuticle or epidermis of the host tissue, when palisade-like asci become visible. The ascospores, soon after they are formed when already in the ascus, produce small, round or ovoid uninucleate blastospores (also known as conidia) by budding.

Copu­lation of conidia takes place establishing dikaryotic condition. The ascospores with adhering conidia forming spore balls are ejected forcibly from the asci. They may be carried by wind or splashed in raindrops.

On reaching host surface, the dikaryotic conidia germinate by germ tubes which infect the host and produce hyphae with dikaryotic cells. The hyphae grow intercellularly and conjugate division of the nuclei perpetuates the dikaryotic condition of the hyphal cells. Life cycle of the genus Taphrina is illustrated by T. deformans in Figure 223.

Some Indian species of Genus Taphrina:

Taphrina deformans (Berk.) Tul. T. maculans Butler T. purni Tul. T. rhomboidalis Syd. and Butler T. tubiforme (Rabenh.) Lagerh.


The main defense strategy of fungi is chemical defense

Fungi have evolved different strategies to increase their competitiveness for nutrient acquisition toward other microorganisms and to protect themselves from predation by animals. Similar to plants, the main defense strategy of fungi is chemical defense, i.e., the production of toxins impairing the growth, development, or viability of the antagonists by the fungus [4]. These defense effectors include secondary metabolites [5], peptides (ribosomally or nonribosomally synthesized) [6, 7], and proteins [8] and usually act by binding to specific target molecules of the antagonists (Table 1). It has been hypothesized that effectors against microbial competitors are secreted, whereas effectors against metazoan predators are usually stored within the fungal cells and are taken up during predation (Fig 1) [9]. Examples of fungal defense effectors in accordance with this hypothesis are the β-lactam antibiotic penicillin produced by some Penicillium species [10], the antifungal lipopeptide pneumocandin B0 produced by Glarea lozoyensis [11], and the cytotoxic, ribosomally synthesized octapeptide α-amanitin produced by some Amanita, Galerina, Conocybe, and Lepiota species [12]. Penicillin is secreted and binds and inhibits extracellular enzymes involved in peptidoglycan biosynthesis, an essential and conserved process in all bacteria [13]. Similarly, pneumocandin B0 is secreted and inhibits 1,3-β-D-glucan synthase, one of the main enzymes involved in fungal cell wall biosynthesis and is therefore called “penicillin of the antifungals” [11]. In contrast, α-amanitin is taken up from the fungal cell upon predation and enters epithelial cells of the digestive tract of animal predators where it binds and inactivates the essential and conserved nuclear enzyme RNA polymerase II [14]. Exceptions to the hypothesis are a number of secreted insecticidal and nematicidal secondary metabolites [15]. In addition to the action of toxins, fungi have more subtle ways of chemical defense, e.g., by the production of molecules interfering with bacterial and animal communication. Examples are intracellular lactonases of the coprophilous ink cap mushroom Coprinopsis cinerea acting as a sink for quorum sensing signals of gram-negative bacteria [16] and the production of insect juvenile hormones by the mold Aspergillus nidulans [17].

The fungus is represented by its vegetative mycelial network originating from a spore (black oval) and a fruiting body (mushroom) arising from that network. The circles show close ups on the competition between the fungal hyphae and bacteria (left) and predation by fungivorous nematodes (right) and the induction of respective fungal defense effectors fungal nuclei are represented by grey ovals, extracellular antibacterial defense effectors by red squares, and intracellular defense effectors against nematodes by green triangles. Specific examples of antibacterial and antinematode effectors and their properties are listed in Table 1. Fungal hyphae producing the two types of defense effectors are colored respectively. Autonomous and antagonist-dependent production of defense effectors is indicated by thin and thick hyphae, respectively. The indicated spatial restriction of antagonist-dependent defense effector production in the fungal mycelium is hypothetical.


Do Fungi Feast on Radiation?

Casadevall and his colleagues, however, have a theory. Based on experiments with three different types of fungi, they believe the melanin-containing breeds absorb the high levels of energy in ionizing radiation and somehow turn it into a biologically useful (and benign) form, akin to a dark and dangerous version of photosynthesis. "We were able to see significant growth of the black ones relative to the white ones in a radiation field," he says. "That is the observation. How you interpret it … is where the interesting speculations come in."

In a paper published online in PLoS One, Casadevall and his colleagues report that ionizing radiation changes the electron structure of the melanin molecule and that fungi with a natural melanin shell (the soil-dwelling Cladosporium sphaerospermum and yeastlike Wangiella dermatitidis varieties), which were deprived of other nutrients, grew better in the presence of radiation. They also report that fungi induced to produce a melanin shell (the human pathogen Cryptococcocus neoformans) grew well in such levels of radiation, unlike those sans pigment. Further, an albino mutant strain of W. dermatitidis failed to thrive as well as its black cousin when exposed to 500 times the normal amount of ionizing radiation (still well below the level of radiation necessary to kill tough fungal forms).

"The presumption has always been that we don't know why truffles and other fungi are black," Casadevall says. "If they have some primitive capacity to harvest sunlight or to harvest some kind of background radiation a lot of them would be using it."

Melanin drinks in ultraviolet rays, acting as a natural sunblock for human skin. "Melanin is very good at absorbing energy and then dissipating it as quickly as possible," says Jennifer Riesz, a biophysicist at the University of Queensland in Brisbane, Australia. "It does this by very efficiently changing the energy into heat."

But Casadevall and his colleague Ekaterina Dadachova, a nuclear chemist at Einstein, speculate that the melanin in this case acts like a step-down electric transformer, weakening the energy until it is useable by the fungi. "The energy becomes … low [at] a certain point where it can already be used by a fungus as chemical energy," Dadachova argues. "Protection doesn't play a role here. It is real energy conversion."

Mycologists and biophysicists find the notion both intriguing and potentially plausible. "Since melanin is used commonly by fungi&mdashand other organisms&mdashto protect themselves against UV radiation, it is perhaps not surprising that melanin would be affected by ionizing radiation,'' says Albert Torzilli, a mycologist at George Mason University in Virginia, adding that "the subsequent enhancement of growth, if true, is a novel response."

Riesz, for one, is skeptical. "It does not surprise me that fungi protected with higher levels of melanin might grow better when exposed to [ionizing radiation], since the nonprotected fungi are more likely to be harmed by the radiation," she says. "However, I find the claim that melanin is involved in energy capture and utilization to be unlikely."

More study is needed to confirm whether fungi will be able to add the ability to grow by harvesting radiation to their list of seeming superpowers, but it does raise the question of whether edible fungi&mdashlike mushrooms&mdashhave been harboring this function undiscovered for years. If true, melanin could be genetically engineered into photosynthetic plants to boost their productivity or melanin-bearing fungi could be used in clothing to shield workers from radiation or even farmed in space as astronaut food. The group plans further tests to see if fungi with melanin are converting other wavelengths of the electromagnetic spectrum into energy, as well.

"[Melanin] doesn't reflect any light it's all going into it. Is it all disappearing into a black pigment and has no use whatsoever? Biology is incredibly inventive," Casadevall argues. After all, extremophile microbes thrive in the heat and acid of hydrothermal vents below the sea or live off the radiation of decaying radioactive rocks deep inside Earth's crust. "It's not that outlandish," Casadevall says, for fungi to harvest the energy in ionizing radiation with the help of melanin. But it is unexpected and strange.


The hidden viruses of the fungal kingdom

There are countless examples of plant, animal and bacterial viruses that cause severe symptoms of disease, sometimes with considerable socio-economic consequences. Viruses of fungi, otherwise known as &lsquomycoviruses&rsquo, infect many medically and commercially important fungi, but often do not cause obvious signs of disease.

Mycoviruses may have evolved to minimise their burden upon fungi because their entire life cycle occurs exclusively within their host cell. Specifically, mycoviruses replicate within fungi but are never released from infected cells to the environment. Mycoviruses are transmitted to a new host by cell division or cell-to-cell fusion. Consequently, if a mycovirus were to cause severe disease, this would profoundly limit their own replication and spread, as their survival is inescapably linked to the success of their host. The apparent benign nature of mycoviruses may potentially explain their widespread distribution throughout fungi. However, fungi have not &lsquorolled out the welcome mat&rsquo, as they mount many potent antiviral defences to limit mycovirus replication and spread. Similarly, mycoviruses can subvert fungal antiviral defences through a variety of fascinating mechanisms. The study of mycoviruses offers many unique scientific and commercial opportunities, including the use of mycoviruses and their toxins to control pathogenic fungi, and as a model system to study the fundamental principles of virus&ndashhost interactions.

Mycoviruses: nice guys finish last

In contrast to viruses of plants, animals and bacteria that were first described around the beginning of the 19th century, mycoviruses eluded detection by scientists until the 1960s. This was mainly because most fungi infected with mycoviruses do not exhibit any hallmarks of a &lsquotypical&rsquo virus infection, such as cell lysis or extracellular disease transmission. Mycoviruses of microscopic fungi were first discovered within antibiotic-producing strains of the Penicillium genus. These mycoviruses were only identified because their double-stranded RNA genomes elicited an immune reaction in animals experimentally injected with extracts from infected Penicillium species. Similarly, &lsquokiller fungi&rsquo, that produce antifungal toxins, were described well before the characterisation of the mycoviruses that are responsible for toxin production.

Intracellular biological warfare

Persistent virus infection requires that a virus replicates efficiently and spreads within a host population. Fungi encode a variety of antiviral mechanisms that target mycoviruses to disrupt these processes, while mycoviruses have evolved countermeasures to subvert them.

One example of a potent antiviral mechanism within fungi is RNA interference (RNAi), which recognises and processes mycovirus double-stranded RNAs, leading to the inhibition of mycovirus replication. Disruption of RNAi within fungi can lead to excessive mycovirus replication, resulting in the dilapidation of fungal colonies. Several mycoviruses are known to interfere with fungal RNAi to prevent the inhibition of their replication. In the absence of an active RNAi system, fungi have been shown to leverage alternative pathways to limit mycovirus infection. For example, within Saccharomyces cerevisiae the SKI genes target mycovirus RNAs for degradation. Mycoviruses counter SKI genes by protecting their RNAs with folded RNA structures, RNA modification or by stealing protective &lsquocaps&rsquo from host RNAs. &lsquoVegetative incompatibility&rsquo is another striking example of how fungi protect themselves from mycoviruses by preventing cell-to-cell fusion between unrelated fungal species. This often creates a line of demarcation between two incompatible fungi, usually due to cell death, blocking mycovirus transmission.

From an evolutionary standpoint, competing virus&ndashhost interactions are known to select for the accumulation of mutations that benefit either the host or the virus. For example, if a mycovirus were to steal a fungal protein to aid in its replication, evolution would select for mutations within the fungal protein that would prevent its acquisition by the mycovirus. Faced with an altered fungal protein, compensatory mutations may arise within the mycovirus that again allows the hijack of the fungal protein. This back-and-forth antagonistic evolutionary cycle can be thought of as a biological arms race, which leads to signatures of evolution that can be detected by statistical methods. There is some evidence of arms race dynamics occurring within fungi however, their relevance to mycovirus infection remains to be investigated.

Killer satellites

The budding yeast S. cerevisiae is an important producer of fermented foodstuffs and is chronically infected with several different types of mycoviruses. As a result of infection by mycoviruses, &lsquokiller&rsquo Saccharomyces yeasts secrete protein toxins that kill competing fungi. In the laboratory, killer strains cultured on solid growth media produce dramatic clear zones free of other yeasts. These antifungal toxins are produced by satellite double-stranded RNAs that are dependent on the Totiviridae family of mycoviruses for their stable maintenance. Satellite RNAs &lsquosteal&rsquo proteins that are produced by totiviruses and use them for their own replication. Alone, totiviruses have a minimal impact upon S. cerevisiae, but the additional presence of satellite RNAs provides an important example of a beneficial virus system.

Viral killer toxins have been described within many fungi, but there are also examples of killer toxins produced from double-stranded DNA linear plasmids and the genomes of some fungi. Killer toxins can have a very broad host range and kill important human and plant pathogens, but the commercial use of these toxins is often limited due to low environmental stability, narrow host range and potential toxic side effects. However, there has been some success in the production of novel antifungal antibodies and peptides derived from killer toxins and the use of killer fungi as biocontrol agents in agriculture.

Mycoviruses as an antifungal biocontrol

There are a considerable number of agricultural diseases that are caused by fungal invasion of economically important plants. For example, chestnut blight is a canker-producing disease of Castanea species of chestnut, caused by the fungus Cryphonectria parasitica. The fungus was introduced into the USA from Asia in the 19th century, ultimately leading to the loss of an estimated half a billion chestnut trees, forever changing the woodland landscapes of North America. Microbiological analysis of recovering American chestnut trees identified strains of Cryphonectria parasitica that were hypovirulent (less able to cause disease). Hypovirulence was found to correlate with the presence of a mycovirus of the family Hypoviridae. Efforts to control chestnut blight have used hypovirulent Cryphonectria parasitica to transmit mycovirus to pathogenic Cryphonectria parasitica. There has been mixed success of this approach, as therapeutic outcomes appear to be dependent on factors such as the method of treatment application and the vegetative incompatibility of hypovirulent Cryphonectria parasitica. The development of transgenic hypovirulent Cryphonectria parasitica to improve mycovirus transmission is an area of active research.

The broader application of mycovirus-based management of pathogenic fungi is worthy of further research, as there are many examples of mycovirus-dependent hypovirulence in pathogenic fungi of commercial fruits, tubers and cereals. However, mycovirus infection can result in fungal hypervirulence (more able to cause disease), and so a comprehensive understanding of host&ndashvirus interactions would avoid potential undesirable outcomes of therapeutic mycovirus infection and increase the utility of current therapies.

There are about 100,000 known fungal species (with an estimated 0.8&ndash5.1 million species in total), but only about 250 mycoviruses have been so far discovered. With the current renewed focus on the development of novel antimicrobial compounds, the untapped diversity of mycoviruses could potentially improve our understanding of the evolution, mechanism and utility of mycovirus-based strategies focused against pathogenic fungi.

PAUL A. ROWLEY

Department of Biological Sciences, University of Idaho, Moscow, ID 83844-3051, USA
[email protected]
@DrPaulARowley

FURTHER READING

Ghabrial, S. (2013). Mycoviruses. Advances in Virus Research 86.

Xie, J. & Jiang, D. (2014). New insights into mycoviruses and exploration for the biological control of crop fungal diseases. Annu Rev Phytopathol 52, 45&ndash68.

Image: Mycoviruses growing on medium. Paul Rowley. Circular colonies of killer S. cerevisiae producing a viral killer toxin that prevents the growth of a competing yeast strain. Paul Rowley. The structure of the L-A totivirus capsid from S. cerevisiae, which contains the viral double stranded RNA genome. Paul Rowley..


Deadly Fungi Are the Newest Emerging Microbe Threat All Over the World

Maryn McKenna is a journalist specializing in public health, global health, and food policy and a senior fellow at the Center for the Study of Human Health at Emory University. She is author, most recently, of Big Chicken: The Incredible Story of How Antibiotics Created Modern Agriculture and Changed the Way the World Eats (National Geographic Books, 2017).
Credit: Nick Higgins

AUTHOR

Maryn McKenna is a journalist specializing in public health, global health, and food policy and a senior fellow at the Center for the Study of Human Health at Emory University. She is author, most recently, of Big Chicken: The Incredible Story of How Antibiotics Created Modern Agriculture and Changed the Way the World Eats (National Geographic Books, 2017).

I t was the fourth week of June in 2020, and the middle of the second wave of the COVID pandemic in the U.S. Cases had passed 2.4 million deaths from the novel coronavirus were closing in on 125,000. In his home office in Atlanta, Tom Chiller looked up from his e-mails and scrubbed his hands over his face and shaved head.

Chiller is a physician and an epidemiologist and, in normal times, a branch chief at the U.S. Centers for Disease Control and Prevention, in charge of the section that monitors health threats from fungi such as molds and yeasts. He had put that specialty aside in March when the U.S. began to recognize the size of the threat from the new virus, when New York City went into lockdown and the CDC told almost all of its thousands of employees to work from home. Ever since, Chiller had been part of the public health agency's frustrating, stymied effort against COVID. Its employees had been working with state health departments, keeping tabs on reports of cases and deaths and what jurisdictions needed to do to stay safe.

Shrugging off exhaustion, Chiller focused on his in-box again. Buried in it was a bulletin forwarded by one of his staff that made him sit up and grit his teeth. Hospitals near Los Angeles that were handling an onslaught of COVID were reporting a new problem: Some of their patients had developed additional infections, with a fungus called Candida auris. The state had gone on high alert.

Chiller knew all about C. auris&mdashpossibly more about it than anyone else in the U.S. Almost exactly four years earlier he and the CDC had sent an urgent bulletin to hospitals, telling them to be on the lookout. The fungus had not yet appeared in the U.S., but Chiller had been chatting with peers in other countries and had heard what happened when the microbe invaded their health-care systems. It resisted treatment by most of the few drugs that could be used against it. It thrived on cold hard surfaces and laughed at cleaning chemicals some hospitals where it landed had to rip out equipment and walls to defeat it. It caused fast-spreading outbreaks and killed up to two thirds of the people who contracted it.

Shortly after that warning, C. auris did enter the U.S. Before the end of 2016, 14 people contracted it, and four died. Since then, the CDC had been tracking its movement, classifying it as one of a small number of dangerous diseases that doctors and health departments had to tell the agency about. By the end of 2020 there had been more than 1,500 cases in the U.S., in 23 states. And then COVID arrived, killing people, overwhelming hospitals, and redirecting all public health efforts toward the new virus and away from other rogue organisms.

But from the start of the pandemic, Chiller had felt uneasy about its possible intersection with fungal infections. The first COVID case reports, published by Chinese scientists in international journals, described patients as catastrophically ill and consigned to intensive care: pharmaceutically paralyzed, plugged into ventilators, threaded with I.V. lines, loaded with drugs to suppress infection and inflammation. Those frantic interventions might save them from the virus&mdashbut immune-damping drugs would disable their innate defenses, and broad-spectrum antibiotics would kill off beneficial bacteria that keep invading microbes in check. Patients would be left extraordinarily vulnerable to any other pathogen that might be lurking nearby.

Chiller and his colleagues began quietly reaching out to colleagues in the U.S. and Europe, asking for any warning signs that COVID was allowing deadly fungi a foothold. Accounts of infections trickled back from India, Italy, Colombia, Germany, Austria, Belgium, Ireland, the Netherlands and France. Now the same deadly fungi were surfacing in American patients as well: the first signs of a second epidemic, layered on top of the viral pandemic. And it wasn't just C. auris. Another deadly fungus called Aspergillus was starting to take a toll as well.

&ldquoThis is going to be widespread everywhere,&rdquo Chiller says. &ldquoWe don't think we're going to be able to contain this.&rdquo

We are likely to think of fungi, if we think of them at all, as minor nuisances: mold on cheese, mildew on shoes shoved to the back of the closet, mushrooms springing up in the garden after hard rains. We notice them, and then we scrape them off or dust them away, never perceiving that we are engaging with the fragile fringes of a web that knits the planet together. Fungi constitute their own biological kingdom of about six million diverse species, ranging from common companions such as baking yeast to wild exotics. They differ from the other kingdoms in complex ways. Unlike animals, they have cell walls unlike plants, they cannot make their own food unlike bacteria, they hold their DNA within a nucleus and pack cells with organelles&mdashfeatures that make them, at the cellular level, weirdly similar to us.* Fungi break rocks, nourish plants, seed clouds, cloak our skin and pack our guts, a mostly hidden and unrecorded world living alongside us and within us.

In September 2018 Torrence Irvin of Patterson, Calif., felt like he had picked up a cold. Seven months later he had lost 75 percent of his lung capacity. Irvin had Valley fever, a fungal infection, and his life was saved by an experimental drug. Credit: Timothy Archibald

That mutual coexistence is now tipping out of balance. Fungi are surging beyond the climate zones they long lived in, adapting to environments that would once have been inimical, learning new behaviors that let them leap between species in novel ways. While executing those maneuvers, they are becoming more successful pathogens, threatening human health in ways&mdashand numbers&mdashthey could not achieve before.

Surveillance that identifies serious fungal infections is patchy, and so any number is probably an undercount. But one widely shared estimate proposes that there are possibly 300 million people infected with fungal diseases worldwide and 1.6 million deaths every year&mdashmore than malaria, as many as tuberculosis. Just in the U.S., the CDC estimates that more than 75,000 people are hospitalized annually for a fungal infection, and another 8.9 million people seek an outpatient visit, costing about $7.2 billion a year.

For physicians and epidemiologists, this is surprising and unnerving. Long-standing medical doctrine holds that we are protected from fungi not just by layered immune defenses but because we are mammals, with core temperatures higher than fungi prefer. The cooler outer surfaces of our bodies are at risk of minor assaults&mdashthink of athlete's foot, yeast infections, ringworm&mdashbut in people with healthy immune systems, invasive infections have been rare.

That may have left us overconfident. &ldquoWe have an enormous blind spot,&rdquo says Arturo Casadevall, a physician and molecular microbiologist at the Johns Hopkins Bloomberg School of Public Health. &ldquoWalk into the street and ask people what are they afraid of, and they'll tell you they're afraid of bacteria, they're afraid of viruses, but they don't fear dying of fungi.&rdquo

Ironically, it is our successes that made us vulnerable. Fungi exploit damaged immune systems, but before the mid-20th century people with impaired immunity didn't live very long. Since then, medicine has gotten very good at keeping such people alive, even though their immune systems are compromised by illness or cancer treatment or age. It has also developed an array of therapies that deliberately suppress immunity, to keep transplant recipients healthy and treat autoimmune disorders such as lupus and rheumatoid arthritis. So vast numbers of people are living now who are especially vulnerable to fungi. (It was a fungal infection, Pneumocystis carinii pneumonia, that alerted doctors to the first known cases of HIV 40 years ago this June.)

Not all of our vulnerability is the fault of medicine preserving life so successfully. Other human actions have opened more doors between the fungal world and our own. We clear land for crops and settlement and perturb what were stable balances between fungi and their hosts. We carry goods and animals across the world, and fungi hitchhike on them. We drench crops in fungicides and enhance the resistance of organisms residing nearby. We take actions that warm the climate, and fungi adapt, narrowing the gap between their preferred temperature and ours that protected us for so long.

But fungi did not rampage onto our turf from some foreign place. They were always with us, woven through our lives and our environments and even our bodies: every day, every person on the planet inhales at least 1,000 fungal spores. It is not possible to close ourselves off from the fungal kingdom. But scientists are urgently trying to understand the myriad ways in which we dismantled our defenses against the microbes, to figure out better approaches to rebuild them.

I t is perplexing that we humans have felt so safe from fungi when we have known for centuries that our crops can be devastated from their attacks. In the 1840s a funguslike organism, Phytophthora infestans, destroyed the Irish potato crop more than one million people, one eighth of the population, starved to death. (The microbe, formerly considered a fungus, is now classified as a highly similar organism, a water mold.) In the 1870s coffee leaf rust, Hemileia vastatrix, wiped out coffee plants in all of South Asia, completely reordering the colonial agriculture of India and Sri Lanka and transferring coffee production to Central and South America. Fungi are the reason that billions of American chestnut trees vanished from Appalachian forests in the U.S. in the 1920s and that millions of dying Dutch elms were cut out of American cities in the 1940s. They destroy one fifth of the world's food crops in the field every year.

Yet for years medicine looked at the devastation fungi wreak on the plant kingdom and never considered that humans or other animals might be equally at risk. &ldquoPlant pathologists and farmers take fungi very seriously and always have, and agribusiness has,&rdquo says Matthew C. Fisher, a professor of epidemiology at Imperial College London, whose work focuses on identifying emerging fungal threats. &ldquoBut they're very neglected from the point of view of wildlife disease and also human disease.&rdquo

So when the feral cats of Rio de Janeiro began to fall ill, no one at first thought to ask why. Street cats have hard lives anyway, scrounging, fighting and birthing endless litters of kittens. But in the summer of 1998, dozens and then hundreds of neighborhood cats began showing horrific injuries: weeping sores on their paws and ears, clouded swollen eyes, what looked like tumors blooming out of their faces. The cats of Rio live intermingled with humans: Children play with them, and especially in poor neighborhoods women encourage them to stay near houses and deal with rats and mice. Before long some of the kids and mothers started to get sick as well. Round, crusty-edge wounds opened on their hands, and hard red lumps trailed up their arms as though following a track.

In 2001 researchers at the Oswaldo Cruz Foundation, a hospital and research institute located in Rio, realized they had treated 178 people in three years, mostly mothers and grandmothers, for similar lumps and oozing lesions. Almost all of them had everyday contact with cats. Analyzing the infections and ones in cats treated at a nearby vet clinic, they found a fungus called Sporothrix.

The various species of the genus Sporothrix live in soil and on plants. Introduced into the body by a cut or scratch, this fungus transforms into a budding form resembling a yeast. In the past, the yeast form had not been communicable, but in this epidemic, it was. That was how the cats were infecting one another and their caretakers: Yeasts in their wounds and saliva flew from cat to cat when they fought or jostled or sneezed. Cats passed it to humans via claws and teeth and caresses. The infections spread from skin up into lymph nodes and the bloodstream and to eyes and internal organs. In case reports amassed by doctors in Brazil, there were accounts of fungal cysts growing in people's brains.

The fungus with this skill was decreed a new species, Sporothrix brasiliensis. By 2004, 759 people had been treated for the disease at the Cruz Foundation by 2011, the count was up to 4,100 people. By last year, more than 12,000 people in Brazil had been diagnosed with the disease across a swath of more than 2,500 miles. It has spread to Paraguay, Argentina, Bolivia, Colombia and Panama.

&ldquoThis epidemic will not take a break,&rdquo says Flávio Queiroz-Telles, a physician and associate professor at the Federal University of Paraná in Curitiba, who saw his first case in 2011. &ldquoIt is expanding.&rdquo

It was a mystery how: Feral cats wander, but they do not migrate thousands of miles. At the CDC, Chiller and his colleagues suspected a possible answer. In Brazil and Argentina, sporotrichosis has been found in rats as well as cats. Infected rodents could hop rides on goods that move into shipping containers. Millions of those containers land on ships docking at American ports every day. The fungus could be coming to the U.S. A sick rat that escaped a container could seed the infection in the city surrounding a port.

&ldquoIn dense population centers, where a lot of feral cats are, you could see an increase in extremely ill cats that are roaming the streets,&rdquo says John Rossow, a veterinarian at the CDC, who may have been the first to notice the possible threat of Sporothrix to the U.S. &ldquoAnd being that we Americans can't avoid helping stray animals, I imagine we're going to see a lot of transmission to people.&rdquo

To a mycologist such as Chiller, this kind of spread is a warning: The fungal kingdom is on the move, pressing against the boundaries, seeking any possible advantage in its search for new hosts. And that we, perhaps, are helping them. &ldquoFungi are alive they adapt,&rdquo he says. Among their several million species, &ldquoonly around 300 that we know of cause human disease&mdashso far. That's a lot of potential for newness and differentness, in things that have been around for a billion years.&rdquo

Torrence Irvin was 44 years old when his fungal troubles started. A big healthy man who had been an athlete in high school and college, he lives in Patterson, Calif., a quiet town in the Central Valley tucked up against U.S. Route 5. A little more than two years earlier Irvin had bought a house in a new subdivision and moved in with his wife, Rhonda, and their two daughters. He was a warehouse manager for the retailer Crate & Barrel and the announcer for local youth football games.

In September 2018 Irvin started to feel like he had picked up a cold he couldn't shake. He dosed himself with Nyquil, but as the weeks went on, he felt weak and short of breath. On a day in October, he collapsed, falling to his knees in his bedroom. His daughter found him. His wife insisted they go to the emergency room.

Doctors thought he had pneumonia. They sent him home with antibiotics and instructions to use over-the-counter drugs. He got weaker and couldn't keep food down. He went to other doctors, while steadily getting worse, enduring shortness of breath, night sweats, and weight loss similar to a cancer victim's. From 280 pounds, he shrank to 150. Eventually one test turned up an answer: a fungal infection called coccidioidomycosis, usually known as Valley fever. &ldquoUntil I got it, I had never heard of it,&rdquo he says.

But others had. Irvin was referred to the University of California, Davis, 100 miles from his house, which had established a Center for Valley Fever. The ailment occurs mostly in California and Arizona, the southern tip of Nevada, New Mexico and far west Texas. The microbes behind it, Coccidioides immitis and Coccidioides posadasii, infect about 150,000 people in that area every year&mdashand outside of the region the infection is barely known. &ldquoIt's not a national pathogen&mdashyou don't get it in densely populated New York or Boston or D.C.,&rdquo says George R. Thompson, co-director of the Davis center and the physician who began to supervise Irvin's care. &ldquoSo even physicians view it as some exotic disease. But in areas where it's endemic, it's very common.&rdquo

Similar to Sporothrix, Coccidioides has two forms, starting with a thready, fragile one that exists in soil and breaks apart when soil is disturbed. Its lightweight components can blow on the wind for hundreds of miles. Somewhere in his life in the Central Valley, Irvin had inhaled a dose. The fungus had transformed in his body into spheres packed with spores that migrated via his blood, infiltrating his skull and spine. To protect him, his body produced scar tissue that stiffened and blocked off his lungs. By the time he came under Thompson's care, seven months after he first collapsed, he was breathing with just 25 percent of his lung capacity. As life-threatening as that was, Irvin was nonetheless lucky: in about one case out of 100, the fungus grows life-threatening masses in organs and the membranes around the brain.

Irvin had been through all the approved treatments. There are only five classes of antifungal drugs, a small number compared with the more than 20 classes of antibiotics to fight bacteria. Antifungal medications are so few in part because they are difficult to design: because fungi and humans are similar at the cellular level, it is challenging to create a drug that can kill them without killing us, too.

It is so challenging that a new class of antifungals reaches the market only every 20 years or so: the polyene class, including amphotericin B, in the 1950s the azoles in the 1980s and the echinocandin drugs, the newest remedy, beginning in 2001. (There is also terbinafine, used mostly for external infections, and flucytosine, used mostly in combination with other drugs.)

For Irvin, nothing worked well enough. &ldquoI was a skeleton,&rdquo he recalls. &ldquoMy dad would come visit and sit there with tears in his eyes. My kids didn't want to see me.&rdquo

In a last-ditch effort, the Davis team got Irvin a new drug called olorofim. It is made in the U.K. and is not yet on the market, but a clinical trial was open to patients for whom every other drug had failed. Irvin qualified. Almost as soon as he received it, he began to turn the corner. His cheeks filled out. He levered himself to his feet with a walker. In several weeks, he went home.

Valley fever is eight times more common now than it was 20 years ago. That period coincides with more migration to the Southwest and West Coast&mdashmore house construction, more stirring up of soil&mdashand also with increases in hot, dry weather linked to climate change. &ldquoCoccidioides is really happy in wet soil it doesn't form spores, and thus it isn't particularly infectious,&rdquo Thompson says. &ldquoDuring periods of drought, that's when the spores form. And we've had an awful lot of drought in the past decade.&rdquo

Because Valley fever has always been a desert malady, scientists assumed the fungal threat would stay in those areas. But that is changing. In 2010 three people came down with Valley fever in eastern Washington State, 900 miles to the north: a 12-year-old who had been playing in a canyon and breathed the spores in, a 15-year-old who fell off an ATV and contracted Valley fever through his wounds, and a 58-year-old construction worker whose infection went to his brain. Research published two years ago shows such cases might become routine. Morgan Gorris, an earth systems scientist at Los Alamos National Laboratory, used climate-warming scenarios to project how much of the U.S. might become friendly territory for Coccidioides by the end of this century. In the scenario with the highest temperature rise, the area with conditions conducive to Valley fever&mdasha mean annual temperature of 10.7 degrees Celsius (51 degrees Fahrenheit) and mean annual rainfall of less than 600 millimeters (23.6 inches)&mdashreaches to the Canadian border and covers most of the western U.S.

Irvin has spent almost two years recovering he still takes six pills of olorifim a day and expects to do that indefinitely. He gained back weight and strength, but his lungs remain damaged, and he has had to go on disability. &ldquoI am learning to live with this,&rdquo he says. &ldquoI will be dealing with it for the rest of my life.&rdquo

Deadly duo of fungi is infecting more people. Coccidioides immitis causes Valley fever, and its range is spreading beyond the Southwest, where it was first identified (top). Aspergillus fumigatus appears in many environments and can be lethal to people suffering from the flu or COVID (bottom). Credit: Science Source

S porothrix found a new way to transmit itself. Valley fever expanded into a new range. C. auris, the fungus that took advantage of COVID, performed a similar trick, exploiting niches opened by the chaos of the pandemic.

That fungus was already a bad actor. It did not behave the way that other pathogenic yeasts do, living quiescently in someone's gut and surging out into their blood or onto mucous membranes when their immune system shifted out of balance. At some point in the first decade of the century, C. auris gained the ability to directly pass from person to person. It learned to live on metal, plastic, and the rough surfaces of fabric and paper. When the first onslaught of COVID created a shortage of disposable masks and gowns, it forced health-care workers to reuse gear they usually discard between patients, to keep from carrying infections. And C. auris was ready.

In New Delhi, physician and microbiologist Anuradha Chowdhary read the early case reports and was unnerved that COVID seemed to be an inflammatory disease as much as a respiratory one. The routine medical response to inflammation would be to damp down the patient's immune response, using steroids. That would set patients up to be invaded by fungi, she realized. C. auris, lethal and persistent, had already been identified in hospitals in 40 countries on every continent except Antarctica. If health-care workers unknowingly carried the organism through their hospitals on reused clothing, there would be a conflagration.

&ldquoI thought, &lsquoOh, God, I.C.U.s are going to be overloaded with patients, and infection-control policies are going to be compromised,'&rdquo she said recently. &ldquoIn any I.C.U. where C. auris is already present, it is going to play havoc.&rdquo

Chowdhary published a warning to other physicians in a medical journal early in the pandemic. Within a few months she wrote an update: a 65-bed I.C.U. in New Delhi had been invaded by C. auris, and two thirds of the patients who contracted the yeast after they were admitted with COVID died. In the U.S., the bulletin that Chiller received flagged several hundred cases in hospitals and long-term care facilities in Los Angeles and nearby Orange County, and a single hospital in Florida disclosed that it harbored 35. Where there were a few, the CDC assumed that there were more&mdashbut that routine testing, their keyhole view into the organism's stealthy spread, had been abandoned under the overwork of caring for pandemic patients.

As bad as that was, physicians familiar with fungi were watching for a bigger threat: the amplification of another fungus that COVID might give an advantage to.

In nature, Aspergillus fumigatus serves as a clean-up crew. It encourages the decay of vegetation, keeping the world from being submerged in dead plants and autumn leaves. Yet in medicine, Aspergillus is known as the cause of an opportunistic infection spawned when a compromised human immune system cannot sweep away its spores. In people who are already ill, the mortality rate of invasive aspergillosis hovers near 100 percent.

During the 2009 pandemic of H1N1 avian flu, Aspergillus began finding new victims, healthy people whose only underlying illness was influenza. In hospitals in the Netherlands, a string of flu patients arrived unable to breathe and going into shock. In days, they died. By 2018 what physicians were calling invasive pulmonary aspergillosis was occurring in one out of three patients critically ill with flu and killing up to two thirds of them.

Then the coronavirus arrived. It scoured the interior lung surface the way flu does. Warning networks that link infectious disease doctors and mycologists around the globe lit up with accounts of aspergillosis taking down patients afflicted with COVID: in China, France, Belgium, Germany, the Netherlands, Austria, Ireland, Italy and Iran. As challenging a complication as C. auris was, Aspergillus was worse. C. auris lurks in hospitals. The place where patients were exposed to Aspergillus was, well, everywhere. There was no way to eliminate the spores from the environment or keep people from breathing them in.

In Baltimore, physician Kieren Marr was acutely aware of the danger. Marr is a professor of medicine and oncology at Johns Hopkins Medical Center and directs its unit on transplant and oncology infectious diseases. The infections that take hold in people who have received a new organ or gotten a bone marrow transplant are familiar territory for her. When COVID arrived, she was concerned that Aspergillus would surge&mdashand that U.S. hospitals, not alert to the threat, would miss it. Johns Hopkins began testing COVID patients in its I.C.U. with the kind of molecular diagnostic tests used in Europe, trying to catch up to the infection in time to try to treat it. Across the five hospitals the Johns Hopkins system operates, it found that one out of 10 people with severe COVID was developing aspergillosis.

Several patients died, including one whose aspergillosis went to the brain. Marr feared there were many others like that patient, across the country, whose illness was not being detected in time. &ldquoThis is bad,&rdquo Marr said this spring. &ldquoAspergillus is more important in COVID right now than C. auris. Without a doubt.&rdquo

The challenge of countering pathogenic fungi is not only that they are virulent and sneaky, as bad as those traits may be. It is that fungi have gotten very good at protecting themselves against drugs we use to try to kill them.

The story is similar to that of antibiotic resistance. Drugmakers play a game of leapfrog, trying to get in front of the evolutionary maneuvers that bacteria use to protect themselves from drugs. For fungi, the tale is the same but worse. Fungal pathogens gain resistance against antifungal agents&mdashbut there are fewer drugs to start with, because the threat was recognized relatively recently.

&ldquoIn the early 2000s, when I moved from academia to industry, the antifungal pipeline was zero,&rdquo says John H. Rex, a physician and longtime advocate for antibiotic development. Rex is chief medical officer of F2G, which makes the not yet approved drug that Torrence Irvin took. &ldquoThere were no antifungals anywhere in the world in clinical or even preclinical development.&rdquo

That is no longer the case, but research is slow as with antibiotics, the financial rewards of bringing a new drug to market are uncertain. But developing new drugs is critical because patients may need to take them for months, sometimes for years, and many of the existing antifungals are toxic to us. (Amphotericin B gets called &ldquoshake and bake&rdquo for its grueling side effects.) &ldquoAs a physician, you're making a choice to deal with a fungal infection at the cost of the kidney,&rdquo says Ciara Kennedy, president and CEO of Amplyx Pharmaceuticals, which has a novel antifungal under development. &ldquoOr if I don't deal with the fungal infection, knowing the patient's going to die.&rdquo

Developing new drugs also is critical because the existing ones are losing their effectiveness. Irvin ended up in the olorofim trial because his Valley fever did not respond to any available drugs. C. auris already shows resistance to drugs in all three major antifungal classes. Aspergillus has been amassing resistance to the antifungal group most useful for treating it, known as the azoles, because it is exposed to them so persistently. Azoles are used all across the world&mdashnot only in agriculture to control crop diseases but in paints and plastics and building materials. In the game of leapfrog, fungi are already in front.

The best counter to the ravages of fungi is not treatment but prevention: not drugs but vaccines. Right now no vaccine exists for any fungal disease. But the difficulty of treating patients long term with toxic drugs, combined with staggering case numbers, makes finding one urgent. And for the first time, one might be in sight if not in reach.

The reason that rates of Valley fever are not worse than they are, when 10 percent of the U.S. population lives in the endemic area, is that infection confers lifelong immunity. That suggests a vaccine might be possible&mdashand since the 1940s researchers have been trying. A prototype that used a killed version of the form Coccidioides takes inside the body&mdashfungal spheres packed with spores&mdashworked brilliantly in mice. But it failed dismally in humans in a clinical trial in the 1980s.

&ldquoWe did it on a shoestring, and everyone wanted it to work,&rdquo says John Galgiani, now a professor and director of the Valley Fever Center for Excellence at the University of Arizona College of Medicine, who was part of that research 40 years ago. &ldquoEven with [bad] reactions and the study lasting three years, we kept 95 percent of the people who enrolled.&rdquo

Enter dogs. They have their noses in the dirt all the time, and that puts them at more at risk of Valley fever than humans are. In several Arizona counties, close to 10 percent of dogs come down with the disease every year, and they are more likely to develop severe lung-blocking forms than human are. They suffer terribly, and it is lengthy and expensive to treat them. But dogs' vulnerability&mdashplus the lower standards that federal agencies require to approve animal drugs compared with human ones&mdashmakes them a model system for testing a possible vaccine. And the passion of owners for their animals and their willingness to empty their wallets when they can may turn possibility into reality for the first time.

Galgiani and his Arizona group are now working on a new vaccine formula, thanks to financial donations from hundreds of dog owners, plus a boost from a National Institutes of Health grant and commercial assistance from a California company, Anivive Lifesciences. Testing is not complete, but it could reach the market for use in dogs as early as next year. &ldquoI think this is proof of concept for a fungal vaccine&mdashhaving it in use in dogs, seeing it is safe,&rdquo says Lisa Shubitz, a veterinarian and research scientist at the Arizona center. &ldquoI really believe this is the path to a human vaccine.&rdquo

This injection does not depend on a killed Valley fever fungus. Instead it uses a live version of the fungus from which a gene that is key to its reproductive cycle, CPS1, has been deleted. The loss means the fungi are unable to spread. The gene was discovered by a team of plant pathologists and later was identified in Coccidioides by Marc Orbach of the University of Arizona, who studies host-pathogen interactions. After creating a mutant Coccidioides with the gene removed, he and Galgiani experimentally infected lab mice bred to be exquisitely sensitive to the fungus. The microbe provoked a strong immune reaction, activating type 1 T helper cells, which establish durable immunity. The mice survived for six months and did not develop any Valley fever symptoms, even though the team tried to infect them with unaltered Coccidioides. When the researchers autopsied the mice at the end of that half-year period, scientists found almost no fungus growing in their lungs. That long-lasting protection against infection makes the gene-deleted fungus the most promising basis for a vaccine since Galgiani's work in the 1980s. But turning a vaccine developed for dogs into one that could be used in humans will not be quick.

The canine formula comes under the purview of the U.S. Department of Agriculture, but approval of a human version would be overseen by the U.S. Food and Drug Administration. It would require clinical trials that would probably stretch over years and involve thousands of people rather than the small number of animals used to validate the formula in dogs. Unlike the 1980s prototype, the new vaccine involves a live organism. Because there has never been a fungal vaccine approved, there is no preestablished evaluation pathway for the developers or regulatory agencies to follow. &ldquoWe would be flying the plane and building it at the same time,&rdquo Galgiani says.

He estimates achieving a Valley fever vaccine for people could take five to seven years and about $150 million, an investment made against an uncertain promise of earnings. But a successful compound could have broad usefulness, protecting permanent residents of the Southwest as well as the military personnel at 120 bases and other installations in the endemic area, plus hundreds of thousands of &ldquosnowbird&rdquo migrants who visit every winter. (Three years ago the CDC identified cases of Valley fever in 14 states outside the endemic zone. Most were in wintertime inhabitants of the Southwest who were diagnosed after they went back home.) By one estimate, a vaccine could save potentially $1.5 billion in health-care costs every year.

&ldquoI couldn't see the possibility that we'd have a vaccine 10 years ago,&rdquo Galgiani says. &ldquoBut I think it is possible now.&rdquo

I f one fungal vaccine is achieved, it would carve the path for another. If immunizations were successful&mdashscientifically, as targets of regulation and as vaccines people would be willing to accept&mdashwe would no longer need to be on constant guard against the fungal kingdom. We could live alongside and within it, safely and confidently, without fear of the ravages it can wreak.

But that is years away, and fungi are moving right now: changing their habits, altering their patterns, taking advantage of emergencies such as COVID to find fresh victims. At the CDC, Chiller is apprehensive.

&ldquoThe past five years really felt like we were waking up to a whole new phenomenon, a fungal world that we just weren't used to,&rdquo Chiller says. &ldquoHow do we stay on top of that? How do we question ourselves to look for what might come next? We study these emergences not as an academic exercise but because they show us what might be coming. We need to be prepared for more surprises.&rdquo

*Editor&rsquos Note (6/9/21): This sentence was revised after posting to correct the description of how the cells of fungi differ from those of animals.

This article was originally published with the title "Deadly Kingdom" in Scientific American 324, 6, 26-35 (June 2021)


By Andrew R. Moldenke, Oregon State University

THE LIVING SOIL: ARTHROPODS

Many bugs, known as arthropods, make their home in the soil. They get their name from their jointed (arthros) legs (podos). Arthropods are invertebrates, that is, they have no backbone, and rely instead on an external covering called an exoskeleton.

The 200 species of mites in this microscope view were extracted from one square foot of the top two inches of forest litter and soil. Mites are poorly studied, but enormously significant for nutrient release in the soil.

Credit: Val Behan-Pelletier, Agriculture and Agri-Food Canada. Please contact the Soil and Water Conservation Society at [email protected] for assistance with copyrighted (credited) images.

Arthropods range in size from microscopic to several inches in length. They include insects, such as springtails, beetles, and ants crustaceans such as sowbugs arachnids such as spiders and mites myriapods, such as centipedes and millipedes and scorpions.

Nearly every soil is home to many different arthropod species. Certain row-crop soils contain several dozen species of arthropods in a square mile. Several thousand different species may live in a square mile of forest soil.

Arthropods can be grouped as shredders, predators, herbivores, and fungal-feeders, based on their functions in soil. Most soil-dwelling arthropods eat fungi, worms, or other arthropods. Root-feeders and dead-plant shredders are less abundant. As they feed, arthropods aerate and mix the soil, regulate the population size of other soil organisms, and shred organic material.

Shredders

Many large arthropods frequently seen on the soil surface are shredders. Shredders chew up dead plant matter as they eat bacteria and fungi on the surface of the plant matter. The most abundant shredders are millipedes and sowbugs, as well as termites, certain mites, and roaches. In agricultural soils, shredders can become pests by feeding on live roots if sufficient dead plant material is not present.

Millipedes are also called Diplopods because they possess two pairs of legs on each body segment. They are generally harmless to people, but most millipedes protect themselves from predators by spraying an offensive odor from their skunk glands. This desert-dwelling giant millipede is about 8 inches long.
Orthoporus ornatus.

Credit: David B. Richman, New Mexico State University, Las Cruces. Please contact the Soil and Water Conservation Society at [email protected] for assistance with copyrighted (credited) images.

Sowbugs are relatives of crabs and lobsters. Their powerful mouth-parts are used to fragment plant residue and leaf litter.

Credit: Gerhard Eisenbeis and Wilfried Wichard. 1987. Atlas on the Biology of Soil Arthropods. Springer-Verlag, New York. P. 111. Please contact the Soil and Water Conservation Society at [email protected] for assistance with copyrighted (credited) images.

Predators

Predators and micropredators can be either generalists, feeding on many different prey types, or specialists, hunting only a single prey type. Predators include centipedes, spiders, ground-beetles, scorpions, skunk-spiders, pseudoscorpions, ants, and some mites. Many predators eat crop pests, and some, such as beetles and parasitic wasps, have been developed for use as commercial biocontrols.

This 1/8 of an inch long spider lives near the soil surface where it attacks other soil arthropods. The spider's eyes are on the tip of the projection above its head.
Walckenaera acuminata.

Credit: Gerhard Eisenbeis and Wilfried Wichard. 1987. Atlas on the Biology of Soil Arthropods. Springer-Verlag, New York. P. 23. Please contact the Soil and Water Conservation Society at [email protected] for assistance with copyrighted (credited) images.

The wolf-spider wanders around as a solitary hunter. The mother wolf-spider carries her young to water and feeds them by regurgitation until they are ready to hunt on their own.

Credit: Trygve Steen, Portland State University, Portland, Oregon. Please contact the Soil and Water Conservation Society at [email protected] for assistance with copyrighted (credited) images.

The pseudoscorpion looks like a baby scorpion, except it has no tail. It produces venom from glandsin its claws and silk from its mouth parts. It lives in the soil and leaf litter of grasslands, forests, deserts and croplands. Some hitchhike under the wings of beetles.

Credit: David B. Richman, New Mexico State University, Las Cruces. Please contact the Soil and Water Conservation Society at [email protected] for assistance with copyrighted (credited) images.

Long, slim centipedes crawl through spaces in the soil preying on earthworms and other soft-skinned animals. Centipede species with longer legs are familiar around homes and in leaf litter.

Credit: No. 40 from Soil Microbiology and Biochemistry Slide Set. 1976. J.P. Martin, et al., eds. SSSA, Madison, WI. Please contact the Soil and Water Conservation Society at [email protected] for assistance with copyrighted (credited) images.

Predatory mites prey on nematodes, springtails, other mites, and the larvae of insects. This mite is 1/25 of an inch (1mm) long. Pergamasus sp.

Credit: Gerhard Eisenbeis and Wilfried Wichard. 1987. Atlas on the Biology of Soil Arthropods. Springer-Verlag, New York. P. 83. Please contact the Soil and Water Conservation Society at [email protected] for assistance with copyrighted (credited) images.

The powerful mouthparts on the tiger beetle (a carabid beetle) make it a swift and deadly ground-surface predator. Many species of carabid beetles are common in cropland.

Credit: Cicindela campestris. D.I. McEwan/Aguila Wildlife Images. Please contact the Soil and Water Conservation Society at [email protected] for assistance with copyrighted (credited) images.

Rugose harvester ants are scavengers rather than predators. They eat dead insects and gather seeds in grasslands and deserts where they burrow 10 feet into the ground. Their sting is 100 times more powerful than a fire ant sting. Pogonomyrmex rugosus.

Credit: David B. Richman, New Mexico State University, Las Cruces. Please contact the Soil and Water Conservation Society at [email protected] for assistance with copyrighted (credited) images.

Herbivores

Numerous root-feeding insects, such as cicadas, mole-crickets, and anthomyiid flies (root-maggots), live part of all of their life in the soil. Some herbivores, including rootworms and symphylans, can be crop pests where they occur in large numbers, feeding on roots or other plant parts.

The symphylan, a relative of the centipede, feeds on plant roots and can become a major crop pest if its population is not controlled by other organisms.

Credit: Ken Gray Collection, Department of Entomology, Oregon State University, Corvallis. Please contact the Soil and Water Conservation Society at [email protected] for assistance with copyrighted (credited) images.

Fungal Feeders

Arthropods that graze on fungi (and to some extent bacteria) include most springtails, some mites, and silverfish. They scrape and consume bacteria and fungi off root surfaces. A large fraction of the nutrients available to plants is a result of microbial-grazing and nutrient release by fauna.

This pale-colored and blind springtail is typical of fungal-feeding springtails that live deep in the surface layer of natural and agricultural soils throughout the world.

Credit: Andrew R. Moldenke, Oregon State University, Corvallis. Please contact the Soil and Water Conservation Society at [email protected] for assistance with copyrighted (credited) images.

Oribatid turtle-mites are among the most numerous of the micro-arthropods. This millimeter-long species feeds on fungi. Euzetes globulus.

Credit: Gerhard Eisenbeis and Wilfried Wichard. 1987. Atlas on the Biology of Soil Arthropods. Springer-Verlag, New York. P. 103. Please contact the Soil and Water Conservation Society at [email protected] for assistance with copyrighted (credited) images.

What Is In Your Soil?

If you would like to see what kind of organisms are in your soil, you can easily make a pitfall trap to catch large arthropods, and a Burlese funnel to catch small arthropods.

Make a pitfall trap by sinking a pint- or quart-sized container (such as a yogurt cup) into the ground so the rim is level with the soil surface. If desired, fashion a roof over the cup to keep the rain out, and add 1/2 of an inch of non-hazardous antifreeze to the cup to preserve the creatures and prevent them from eating one another. Leave in place for a week and wait for soil organisms to fall into the trap.

To make a Burlese funnel, set a piece of 1/4 inch rigid wire screen in the bottom of a funnel to support the soil. (A funnel can be made by cutting the bottom off a plastic soda bottle.) Half fill the funnel with soil, and suspend it over a cup with a bit of anti-freeze or ethyl alcohol in the bottom as a preservative.

Suspend a light bulb about 4 inches over the soil to drive the organisms out of the soil and into the cup. Leave the light bulb on for about 3 days to dry out the soil. Then pour the alcohol into a shallow dish and use a magnifying glass to examine the organisms.

What Do Arthropods Do?

Although the plant feeders can become pests, most arthropods perform beneficial functions in the soil-plant system.

Shred organic material. Arthropods increase the surface area accessible to microbial attack by shredding dead plant residue and burrowing into coarse woody debris. Without shredders, a bacterium in leaf litter would be like a person in a pantry without a can-opener &ndash eating would be a very slow process. The shredders act like can-openers and greatly increase the rate of decomposition. Arthropods ingest decaying plant material to eat the bacteria and fungi on the surface of the organic material.

Stimulate microbial activity. As arthropods graze on bacteria and fungi, they stimulate the growth of mycorrhizae and other fungi, and the decomposition of organic matter. If grazer populations get too dense the opposite effect can occur &ndash populations of bacteria and fungi will decline. Predatory arthropods are important to keep grazer populations under control and to prevent them from over-grazing microbes.

Mix microbes with their food. From a bacterium&rsquos point-of-view, just a fraction of a millimeter is infinitely far away. Bacteria have limited mobility in soil and a competitor is likely to be closer to a nutrient treasure. Arthropods help out by distributing nutrients through the soil, and by carrying bacteria on their exoskeleton and through their digestive system. By more thoroughly mixing microbes with their food, arthropods enhance organic matter decomposition.

Mineralize plant nutrients. As they graze, arthropods mineralize some of the nutrients in bacteria and fungi, and excrete nutrients in plant-available forms.

Enhance soil aggregation. In most forested and grassland soils, every particle in the upper several inches of soil has been through the gut of numerous soil fauna. Each time soil passes through another arthropod or earthworm, it is thoroughly mixed with organic matter and mucus and deposited as fecal pellets. Fecal pellets are a highly concentrated nutrient resource, and are a mixture of the organic and inorganic substances required for growth of bacteria and fungi. In many soils, aggregates between 1/10,000 and 1/10 of an inch (0.0025mm and 2.5mm) are actually fecal pellets.

Burrow. Relatively few arthropod species burrow through the soil. Yet, within any soil community, burrowing arthropods and earthworms exert an enormous influence on the composition of the total fauna by shaping habitat. Burrowing changes the physical properties of soil, including porosity, water-infiltration rate, and bulk density.

Stimulate the succession of species. A dizzying array of natural bio-organic chemicals permeates the soil. Complete digestion of these chemicals requires a series of many types of bacteria, fungi, and other organisms with different enzymes. At any time, only a small subset of species is metabolically active &ndash only those capable of using the resources currently available. Soil arthropods consume the dominant organisms and permit other species to move in and take their place, thus facilitating the progressive breakdown of soil organic matter.

Control pests. Some arthropods can be damaging to crop yields, but many others that are present in all soils eat or compete with various root- and foliage-feeders. Some (the specialists) feed on only a single type of prey species. Other arthropods (the generalists), such as many species of centipedes, spiders, ground-beetles, rove-beetles, and gamasid mites, feed on a broad range of prey. Where a healthy population of generalist predators is present, they will be available to deal with a variety of pest outbreaks. A population of predators can only be maintained between pest outbreaks if there is a constant source of non-pest prey to eat. That is, there must be a healthy and diverse food web.

A fundamental dilemma in pest control is that tillage and insecticide application have enormous effects on non- target species in the food web. Intense land use (especially monoculture, tillage, and pesticides) depletes soil diversity. As total soil diversity declines, predator populations drop sharply and the possibility for subsequent pest outbreaks increases.

Where Do Arthropods Live?

The abundance and diversity of soil fauna diminishes significantly with soil depth. The great majority of all soil species are confined to the top three inches. Most of these creatures have limited mobility, and are probably capable of &ldquocryptobiosis,&rdquo a state of &ldquosuspended animation&rdquo that helps them survive extremes of temperature, wetness, or dryness that would otherwise be lethal.

As a general rule, larger species are active on the soil surface, seeking temporary refuge under vegetation, plant residue, wood, or rocks. Many of these arthropods commute daily to forage within herbaceous vegetation above, or even high in the canopy of trees. (For instance, one of these tree-climbers is the caterpillar-searcher used by foresters to control gypsy moth). Some large species capable of true burrowing live within the deeper layers of the soil.

Below about two inches in the soil, fauna are generally small &ndash 1/250 to 1/10 of an inch. (Twenty-five of the smallest of these would fit in a period on this page.) These species are usually blind and lack prominent coloration. They are capable of squeezing through minute pore spaces and along root channels. Sub-surface soil dwellers are associated primarily with the rhizosphere (the soil volume immediately adjacent to roots).

Abundance of Arthropods

A single square yard of soil will contain 500 to 200,000 individual arthropods, depending upon the soil type, plant community, and management system. Despite these large numbers, the biomass of arthropods in soil is far less than that of protozoa and nematodes.

In most environments, the most abundant soil dwellers are springtails and mites, though ants and termites predominate in certain situations, especially in desert and tropical soils. The largest number of arthropods are in natural plant communities with few earthworms (such as conifer forests). Natural communities with numerous earthworms (such as grassland soils) have the fewest arthropods. Apparently, earthworms out-compete arthropods, perhaps by excessively reworking their habitat or eating them incidentally. However, within pastures and farm lands arthropod numbers and diversity are generally thought to increase as earthworm populations rise. Burrowing earthworms probably create habitat space for arthropods in agricultural soils.

Bug Biography: Springtails

Springtails are the most abundant arthropods in many agricultural and rangeland soils. populations of tens of thousands per square yard are frequent. When foraging, springtails walk with 3 pairs of legs like most insects, and hold their tail tightly tucked under the belly. If attacked by a predator, body fluid rushes into the tail base, forcing the tail to slam down and catapult the springtail as much as a yard away. Springtails have been shown to be beneficial to crop plants by releasing nutrients and by feeding upon diseases caused by fungi.


Deadly Fungi Are the Newest Emerging Microbe Threat All Over the World

Maryn McKenna is a journalist specializing in public health, global health, and food policy and a senior fellow at the Center for the Study of Human Health at Emory University. She is author, most recently, of Big Chicken: The Incredible Story of How Antibiotics Created Modern Agriculture and Changed the Way the World Eats (National Geographic Books, 2017).
Credit: Nick Higgins

AUTHOR

Maryn McKenna is a journalist specializing in public health, global health, and food policy and a senior fellow at the Center for the Study of Human Health at Emory University. She is author, most recently, of Big Chicken: The Incredible Story of How Antibiotics Created Modern Agriculture and Changed the Way the World Eats (National Geographic Books, 2017).

I t was the fourth week of June in 2020, and the middle of the second wave of the COVID pandemic in the U.S. Cases had passed 2.4 million deaths from the novel coronavirus were closing in on 125,000. In his home office in Atlanta, Tom Chiller looked up from his e-mails and scrubbed his hands over his face and shaved head.

Chiller is a physician and an epidemiologist and, in normal times, a branch chief at the U.S. Centers for Disease Control and Prevention, in charge of the section that monitors health threats from fungi such as molds and yeasts. He had put that specialty aside in March when the U.S. began to recognize the size of the threat from the new virus, when New York City went into lockdown and the CDC told almost all of its thousands of employees to work from home. Ever since, Chiller had been part of the public health agency's frustrating, stymied effort against COVID. Its employees had been working with state health departments, keeping tabs on reports of cases and deaths and what jurisdictions needed to do to stay safe.

Shrugging off exhaustion, Chiller focused on his in-box again. Buried in it was a bulletin forwarded by one of his staff that made him sit up and grit his teeth. Hospitals near Los Angeles that were handling an onslaught of COVID were reporting a new problem: Some of their patients had developed additional infections, with a fungus called Candida auris. The state had gone on high alert.

Chiller knew all about C. auris&mdashpossibly more about it than anyone else in the U.S. Almost exactly four years earlier he and the CDC had sent an urgent bulletin to hospitals, telling them to be on the lookout. The fungus had not yet appeared in the U.S., but Chiller had been chatting with peers in other countries and had heard what happened when the microbe invaded their health-care systems. It resisted treatment by most of the few drugs that could be used against it. It thrived on cold hard surfaces and laughed at cleaning chemicals some hospitals where it landed had to rip out equipment and walls to defeat it. It caused fast-spreading outbreaks and killed up to two thirds of the people who contracted it.

Shortly after that warning, C. auris did enter the U.S. Before the end of 2016, 14 people contracted it, and four died. Since then, the CDC had been tracking its movement, classifying it as one of a small number of dangerous diseases that doctors and health departments had to tell the agency about. By the end of 2020 there had been more than 1,500 cases in the U.S., in 23 states. And then COVID arrived, killing people, overwhelming hospitals, and redirecting all public health efforts toward the new virus and away from other rogue organisms.

But from the start of the pandemic, Chiller had felt uneasy about its possible intersection with fungal infections. The first COVID case reports, published by Chinese scientists in international journals, described patients as catastrophically ill and consigned to intensive care: pharmaceutically paralyzed, plugged into ventilators, threaded with I.V. lines, loaded with drugs to suppress infection and inflammation. Those frantic interventions might save them from the virus&mdashbut immune-damping drugs would disable their innate defenses, and broad-spectrum antibiotics would kill off beneficial bacteria that keep invading microbes in check. Patients would be left extraordinarily vulnerable to any other pathogen that might be lurking nearby.

Chiller and his colleagues began quietly reaching out to colleagues in the U.S. and Europe, asking for any warning signs that COVID was allowing deadly fungi a foothold. Accounts of infections trickled back from India, Italy, Colombia, Germany, Austria, Belgium, Ireland, the Netherlands and France. Now the same deadly fungi were surfacing in American patients as well: the first signs of a second epidemic, layered on top of the viral pandemic. And it wasn't just C. auris. Another deadly fungus called Aspergillus was starting to take a toll as well.

&ldquoThis is going to be widespread everywhere,&rdquo Chiller says. &ldquoWe don't think we're going to be able to contain this.&rdquo

We are likely to think of fungi, if we think of them at all, as minor nuisances: mold on cheese, mildew on shoes shoved to the back of the closet, mushrooms springing up in the garden after hard rains. We notice them, and then we scrape them off or dust them away, never perceiving that we are engaging with the fragile fringes of a web that knits the planet together. Fungi constitute their own biological kingdom of about six million diverse species, ranging from common companions such as baking yeast to wild exotics. They differ from the other kingdoms in complex ways. Unlike animals, they have cell walls unlike plants, they cannot make their own food unlike bacteria, they hold their DNA within a nucleus and pack cells with organelles&mdashfeatures that make them, at the cellular level, weirdly similar to us.* Fungi break rocks, nourish plants, seed clouds, cloak our skin and pack our guts, a mostly hidden and unrecorded world living alongside us and within us.

In September 2018 Torrence Irvin of Patterson, Calif., felt like he had picked up a cold. Seven months later he had lost 75 percent of his lung capacity. Irvin had Valley fever, a fungal infection, and his life was saved by an experimental drug. Credit: Timothy Archibald

That mutual coexistence is now tipping out of balance. Fungi are surging beyond the climate zones they long lived in, adapting to environments that would once have been inimical, learning new behaviors that let them leap between species in novel ways. While executing those maneuvers, they are becoming more successful pathogens, threatening human health in ways&mdashand numbers&mdashthey could not achieve before.

Surveillance that identifies serious fungal infections is patchy, and so any number is probably an undercount. But one widely shared estimate proposes that there are possibly 300 million people infected with fungal diseases worldwide and 1.6 million deaths every year&mdashmore than malaria, as many as tuberculosis. Just in the U.S., the CDC estimates that more than 75,000 people are hospitalized annually for a fungal infection, and another 8.9 million people seek an outpatient visit, costing about $7.2 billion a year.

For physicians and epidemiologists, this is surprising and unnerving. Long-standing medical doctrine holds that we are protected from fungi not just by layered immune defenses but because we are mammals, with core temperatures higher than fungi prefer. The cooler outer surfaces of our bodies are at risk of minor assaults&mdashthink of athlete's foot, yeast infections, ringworm&mdashbut in people with healthy immune systems, invasive infections have been rare.

That may have left us overconfident. &ldquoWe have an enormous blind spot,&rdquo says Arturo Casadevall, a physician and molecular microbiologist at the Johns Hopkins Bloomberg School of Public Health. &ldquoWalk into the street and ask people what are they afraid of, and they'll tell you they're afraid of bacteria, they're afraid of viruses, but they don't fear dying of fungi.&rdquo

Ironically, it is our successes that made us vulnerable. Fungi exploit damaged immune systems, but before the mid-20th century people with impaired immunity didn't live very long. Since then, medicine has gotten very good at keeping such people alive, even though their immune systems are compromised by illness or cancer treatment or age. It has also developed an array of therapies that deliberately suppress immunity, to keep transplant recipients healthy and treat autoimmune disorders such as lupus and rheumatoid arthritis. So vast numbers of people are living now who are especially vulnerable to fungi. (It was a fungal infection, Pneumocystis carinii pneumonia, that alerted doctors to the first known cases of HIV 40 years ago this June.)

Not all of our vulnerability is the fault of medicine preserving life so successfully. Other human actions have opened more doors between the fungal world and our own. We clear land for crops and settlement and perturb what were stable balances between fungi and their hosts. We carry goods and animals across the world, and fungi hitchhike on them. We drench crops in fungicides and enhance the resistance of organisms residing nearby. We take actions that warm the climate, and fungi adapt, narrowing the gap between their preferred temperature and ours that protected us for so long.

But fungi did not rampage onto our turf from some foreign place. They were always with us, woven through our lives and our environments and even our bodies: every day, every person on the planet inhales at least 1,000 fungal spores. It is not possible to close ourselves off from the fungal kingdom. But scientists are urgently trying to understand the myriad ways in which we dismantled our defenses against the microbes, to figure out better approaches to rebuild them.

I t is perplexing that we humans have felt so safe from fungi when we have known for centuries that our crops can be devastated from their attacks. In the 1840s a funguslike organism, Phytophthora infestans, destroyed the Irish potato crop more than one million people, one eighth of the population, starved to death. (The microbe, formerly considered a fungus, is now classified as a highly similar organism, a water mold.) In the 1870s coffee leaf rust, Hemileia vastatrix, wiped out coffee plants in all of South Asia, completely reordering the colonial agriculture of India and Sri Lanka and transferring coffee production to Central and South America. Fungi are the reason that billions of American chestnut trees vanished from Appalachian forests in the U.S. in the 1920s and that millions of dying Dutch elms were cut out of American cities in the 1940s. They destroy one fifth of the world's food crops in the field every year.

Yet for years medicine looked at the devastation fungi wreak on the plant kingdom and never considered that humans or other animals might be equally at risk. &ldquoPlant pathologists and farmers take fungi very seriously and always have, and agribusiness has,&rdquo says Matthew C. Fisher, a professor of epidemiology at Imperial College London, whose work focuses on identifying emerging fungal threats. &ldquoBut they're very neglected from the point of view of wildlife disease and also human disease.&rdquo

So when the feral cats of Rio de Janeiro began to fall ill, no one at first thought to ask why. Street cats have hard lives anyway, scrounging, fighting and birthing endless litters of kittens. But in the summer of 1998, dozens and then hundreds of neighborhood cats began showing horrific injuries: weeping sores on their paws and ears, clouded swollen eyes, what looked like tumors blooming out of their faces. The cats of Rio live intermingled with humans: Children play with them, and especially in poor neighborhoods women encourage them to stay near houses and deal with rats and mice. Before long some of the kids and mothers started to get sick as well. Round, crusty-edge wounds opened on their hands, and hard red lumps trailed up their arms as though following a track.

In 2001 researchers at the Oswaldo Cruz Foundation, a hospital and research institute located in Rio, realized they had treated 178 people in three years, mostly mothers and grandmothers, for similar lumps and oozing lesions. Almost all of them had everyday contact with cats. Analyzing the infections and ones in cats treated at a nearby vet clinic, they found a fungus called Sporothrix.

The various species of the genus Sporothrix live in soil and on plants. Introduced into the body by a cut or scratch, this fungus transforms into a budding form resembling a yeast. In the past, the yeast form had not been communicable, but in this epidemic, it was. That was how the cats were infecting one another and their caretakers: Yeasts in their wounds and saliva flew from cat to cat when they fought or jostled or sneezed. Cats passed it to humans via claws and teeth and caresses. The infections spread from skin up into lymph nodes and the bloodstream and to eyes and internal organs. In case reports amassed by doctors in Brazil, there were accounts of fungal cysts growing in people's brains.

The fungus with this skill was decreed a new species, Sporothrix brasiliensis. By 2004, 759 people had been treated for the disease at the Cruz Foundation by 2011, the count was up to 4,100 people. By last year, more than 12,000 people in Brazil had been diagnosed with the disease across a swath of more than 2,500 miles. It has spread to Paraguay, Argentina, Bolivia, Colombia and Panama.

&ldquoThis epidemic will not take a break,&rdquo says Flávio Queiroz-Telles, a physician and associate professor at the Federal University of Paraná in Curitiba, who saw his first case in 2011. &ldquoIt is expanding.&rdquo

It was a mystery how: Feral cats wander, but they do not migrate thousands of miles. At the CDC, Chiller and his colleagues suspected a possible answer. In Brazil and Argentina, sporotrichosis has been found in rats as well as cats. Infected rodents could hop rides on goods that move into shipping containers. Millions of those containers land on ships docking at American ports every day. The fungus could be coming to the U.S. A sick rat that escaped a container could seed the infection in the city surrounding a port.

&ldquoIn dense population centers, where a lot of feral cats are, you could see an increase in extremely ill cats that are roaming the streets,&rdquo says John Rossow, a veterinarian at the CDC, who may have been the first to notice the possible threat of Sporothrix to the U.S. &ldquoAnd being that we Americans can't avoid helping stray animals, I imagine we're going to see a lot of transmission to people.&rdquo

To a mycologist such as Chiller, this kind of spread is a warning: The fungal kingdom is on the move, pressing against the boundaries, seeking any possible advantage in its search for new hosts. And that we, perhaps, are helping them. &ldquoFungi are alive they adapt,&rdquo he says. Among their several million species, &ldquoonly around 300 that we know of cause human disease&mdashso far. That's a lot of potential for newness and differentness, in things that have been around for a billion years.&rdquo

Torrence Irvin was 44 years old when his fungal troubles started. A big healthy man who had been an athlete in high school and college, he lives in Patterson, Calif., a quiet town in the Central Valley tucked up against U.S. Route 5. A little more than two years earlier Irvin had bought a house in a new subdivision and moved in with his wife, Rhonda, and their two daughters. He was a warehouse manager for the retailer Crate & Barrel and the announcer for local youth football games.

In September 2018 Irvin started to feel like he had picked up a cold he couldn't shake. He dosed himself with Nyquil, but as the weeks went on, he felt weak and short of breath. On a day in October, he collapsed, falling to his knees in his bedroom. His daughter found him. His wife insisted they go to the emergency room.

Doctors thought he had pneumonia. They sent him home with antibiotics and instructions to use over-the-counter drugs. He got weaker and couldn't keep food down. He went to other doctors, while steadily getting worse, enduring shortness of breath, night sweats, and weight loss similar to a cancer victim's. From 280 pounds, he shrank to 150. Eventually one test turned up an answer: a fungal infection called coccidioidomycosis, usually known as Valley fever. &ldquoUntil I got it, I had never heard of it,&rdquo he says.

But others had. Irvin was referred to the University of California, Davis, 100 miles from his house, which had established a Center for Valley Fever. The ailment occurs mostly in California and Arizona, the southern tip of Nevada, New Mexico and far west Texas. The microbes behind it, Coccidioides immitis and Coccidioides posadasii, infect about 150,000 people in that area every year&mdashand outside of the region the infection is barely known. &ldquoIt's not a national pathogen&mdashyou don't get it in densely populated New York or Boston or D.C.,&rdquo says George R. Thompson, co-director of the Davis center and the physician who began to supervise Irvin's care. &ldquoSo even physicians view it as some exotic disease. But in areas where it's endemic, it's very common.&rdquo

Similar to Sporothrix, Coccidioides has two forms, starting with a thready, fragile one that exists in soil and breaks apart when soil is disturbed. Its lightweight components can blow on the wind for hundreds of miles. Somewhere in his life in the Central Valley, Irvin had inhaled a dose. The fungus had transformed in his body into spheres packed with spores that migrated via his blood, infiltrating his skull and spine. To protect him, his body produced scar tissue that stiffened and blocked off his lungs. By the time he came under Thompson's care, seven months after he first collapsed, he was breathing with just 25 percent of his lung capacity. As life-threatening as that was, Irvin was nonetheless lucky: in about one case out of 100, the fungus grows life-threatening masses in organs and the membranes around the brain.

Irvin had been through all the approved treatments. There are only five classes of antifungal drugs, a small number compared with the more than 20 classes of antibiotics to fight bacteria. Antifungal medications are so few in part because they are difficult to design: because fungi and humans are similar at the cellular level, it is challenging to create a drug that can kill them without killing us, too.

It is so challenging that a new class of antifungals reaches the market only every 20 years or so: the polyene class, including amphotericin B, in the 1950s the azoles in the 1980s and the echinocandin drugs, the newest remedy, beginning in 2001. (There is also terbinafine, used mostly for external infections, and flucytosine, used mostly in combination with other drugs.)

For Irvin, nothing worked well enough. &ldquoI was a skeleton,&rdquo he recalls. &ldquoMy dad would come visit and sit there with tears in his eyes. My kids didn't want to see me.&rdquo

In a last-ditch effort, the Davis team got Irvin a new drug called olorofim. It is made in the U.K. and is not yet on the market, but a clinical trial was open to patients for whom every other drug had failed. Irvin qualified. Almost as soon as he received it, he began to turn the corner. His cheeks filled out. He levered himself to his feet with a walker. In several weeks, he went home.

Valley fever is eight times more common now than it was 20 years ago. That period coincides with more migration to the Southwest and West Coast&mdashmore house construction, more stirring up of soil&mdashand also with increases in hot, dry weather linked to climate change. &ldquoCoccidioides is really happy in wet soil it doesn't form spores, and thus it isn't particularly infectious,&rdquo Thompson says. &ldquoDuring periods of drought, that's when the spores form. And we've had an awful lot of drought in the past decade.&rdquo

Because Valley fever has always been a desert malady, scientists assumed the fungal threat would stay in those areas. But that is changing. In 2010 three people came down with Valley fever in eastern Washington State, 900 miles to the north: a 12-year-old who had been playing in a canyon and breathed the spores in, a 15-year-old who fell off an ATV and contracted Valley fever through his wounds, and a 58-year-old construction worker whose infection went to his brain. Research published two years ago shows such cases might become routine. Morgan Gorris, an earth systems scientist at Los Alamos National Laboratory, used climate-warming scenarios to project how much of the U.S. might become friendly territory for Coccidioides by the end of this century. In the scenario with the highest temperature rise, the area with conditions conducive to Valley fever&mdasha mean annual temperature of 10.7 degrees Celsius (51 degrees Fahrenheit) and mean annual rainfall of less than 600 millimeters (23.6 inches)&mdashreaches to the Canadian border and covers most of the western U.S.

Irvin has spent almost two years recovering he still takes six pills of olorifim a day and expects to do that indefinitely. He gained back weight and strength, but his lungs remain damaged, and he has had to go on disability. &ldquoI am learning to live with this,&rdquo he says. &ldquoI will be dealing with it for the rest of my life.&rdquo

Deadly duo of fungi is infecting more people. Coccidioides immitis causes Valley fever, and its range is spreading beyond the Southwest, where it was first identified (top). Aspergillus fumigatus appears in many environments and can be lethal to people suffering from the flu or COVID (bottom). Credit: Science Source

S porothrix found a new way to transmit itself. Valley fever expanded into a new range. C. auris, the fungus that took advantage of COVID, performed a similar trick, exploiting niches opened by the chaos of the pandemic.

That fungus was already a bad actor. It did not behave the way that other pathogenic yeasts do, living quiescently in someone's gut and surging out into their blood or onto mucous membranes when their immune system shifted out of balance. At some point in the first decade of the century, C. auris gained the ability to directly pass from person to person. It learned to live on metal, plastic, and the rough surfaces of fabric and paper. When the first onslaught of COVID created a shortage of disposable masks and gowns, it forced health-care workers to reuse gear they usually discard between patients, to keep from carrying infections. And C. auris was ready.

In New Delhi, physician and microbiologist Anuradha Chowdhary read the early case reports and was unnerved that COVID seemed to be an inflammatory disease as much as a respiratory one. The routine medical response to inflammation would be to damp down the patient's immune response, using steroids. That would set patients up to be invaded by fungi, she realized. C. auris, lethal and persistent, had already been identified in hospitals in 40 countries on every continent except Antarctica. If health-care workers unknowingly carried the organism through their hospitals on reused clothing, there would be a conflagration.

&ldquoI thought, &lsquoOh, God, I.C.U.s are going to be overloaded with patients, and infection-control policies are going to be compromised,'&rdquo she said recently. &ldquoIn any I.C.U. where C. auris is already present, it is going to play havoc.&rdquo

Chowdhary published a warning to other physicians in a medical journal early in the pandemic. Within a few months she wrote an update: a 65-bed I.C.U. in New Delhi had been invaded by C. auris, and two thirds of the patients who contracted the yeast after they were admitted with COVID died. In the U.S., the bulletin that Chiller received flagged several hundred cases in hospitals and long-term care facilities in Los Angeles and nearby Orange County, and a single hospital in Florida disclosed that it harbored 35. Where there were a few, the CDC assumed that there were more&mdashbut that routine testing, their keyhole view into the organism's stealthy spread, had been abandoned under the overwork of caring for pandemic patients.

As bad as that was, physicians familiar with fungi were watching for a bigger threat: the amplification of another fungus that COVID might give an advantage to.

In nature, Aspergillus fumigatus serves as a clean-up crew. It encourages the decay of vegetation, keeping the world from being submerged in dead plants and autumn leaves. Yet in medicine, Aspergillus is known as the cause of an opportunistic infection spawned when a compromised human immune system cannot sweep away its spores. In people who are already ill, the mortality rate of invasive aspergillosis hovers near 100 percent.

During the 2009 pandemic of H1N1 avian flu, Aspergillus began finding new victims, healthy people whose only underlying illness was influenza. In hospitals in the Netherlands, a string of flu patients arrived unable to breathe and going into shock. In days, they died. By 2018 what physicians were calling invasive pulmonary aspergillosis was occurring in one out of three patients critically ill with flu and killing up to two thirds of them.

Then the coronavirus arrived. It scoured the interior lung surface the way flu does. Warning networks that link infectious disease doctors and mycologists around the globe lit up with accounts of aspergillosis taking down patients afflicted with COVID: in China, France, Belgium, Germany, the Netherlands, Austria, Ireland, Italy and Iran. As challenging a complication as C. auris was, Aspergillus was worse. C. auris lurks in hospitals. The place where patients were exposed to Aspergillus was, well, everywhere. There was no way to eliminate the spores from the environment or keep people from breathing them in.

In Baltimore, physician Kieren Marr was acutely aware of the danger. Marr is a professor of medicine and oncology at Johns Hopkins Medical Center and directs its unit on transplant and oncology infectious diseases. The infections that take hold in people who have received a new organ or gotten a bone marrow transplant are familiar territory for her. When COVID arrived, she was concerned that Aspergillus would surge&mdashand that U.S. hospitals, not alert to the threat, would miss it. Johns Hopkins began testing COVID patients in its I.C.U. with the kind of molecular diagnostic tests used in Europe, trying to catch up to the infection in time to try to treat it. Across the five hospitals the Johns Hopkins system operates, it found that one out of 10 people with severe COVID was developing aspergillosis.

Several patients died, including one whose aspergillosis went to the brain. Marr feared there were many others like that patient, across the country, whose illness was not being detected in time. &ldquoThis is bad,&rdquo Marr said this spring. &ldquoAspergillus is more important in COVID right now than C. auris. Without a doubt.&rdquo

The challenge of countering pathogenic fungi is not only that they are virulent and sneaky, as bad as those traits may be. It is that fungi have gotten very good at protecting themselves against drugs we use to try to kill them.

The story is similar to that of antibiotic resistance. Drugmakers play a game of leapfrog, trying to get in front of the evolutionary maneuvers that bacteria use to protect themselves from drugs. For fungi, the tale is the same but worse. Fungal pathogens gain resistance against antifungal agents&mdashbut there are fewer drugs to start with, because the threat was recognized relatively recently.

&ldquoIn the early 2000s, when I moved from academia to industry, the antifungal pipeline was zero,&rdquo says John H. Rex, a physician and longtime advocate for antibiotic development. Rex is chief medical officer of F2G, which makes the not yet approved drug that Torrence Irvin took. &ldquoThere were no antifungals anywhere in the world in clinical or even preclinical development.&rdquo

That is no longer the case, but research is slow as with antibiotics, the financial rewards of bringing a new drug to market are uncertain. But developing new drugs is critical because patients may need to take them for months, sometimes for years, and many of the existing antifungals are toxic to us. (Amphotericin B gets called &ldquoshake and bake&rdquo for its grueling side effects.) &ldquoAs a physician, you're making a choice to deal with a fungal infection at the cost of the kidney,&rdquo says Ciara Kennedy, president and CEO of Amplyx Pharmaceuticals, which has a novel antifungal under development. &ldquoOr if I don't deal with the fungal infection, knowing the patient's going to die.&rdquo

Developing new drugs also is critical because the existing ones are losing their effectiveness. Irvin ended up in the olorofim trial because his Valley fever did not respond to any available drugs. C. auris already shows resistance to drugs in all three major antifungal classes. Aspergillus has been amassing resistance to the antifungal group most useful for treating it, known as the azoles, because it is exposed to them so persistently. Azoles are used all across the world&mdashnot only in agriculture to control crop diseases but in paints and plastics and building materials. In the game of leapfrog, fungi are already in front.

The best counter to the ravages of fungi is not treatment but prevention: not drugs but vaccines. Right now no vaccine exists for any fungal disease. But the difficulty of treating patients long term with toxic drugs, combined with staggering case numbers, makes finding one urgent. And for the first time, one might be in sight if not in reach.

The reason that rates of Valley fever are not worse than they are, when 10 percent of the U.S. population lives in the endemic area, is that infection confers lifelong immunity. That suggests a vaccine might be possible&mdashand since the 1940s researchers have been trying. A prototype that used a killed version of the form Coccidioides takes inside the body&mdashfungal spheres packed with spores&mdashworked brilliantly in mice. But it failed dismally in humans in a clinical trial in the 1980s.

&ldquoWe did it on a shoestring, and everyone wanted it to work,&rdquo says John Galgiani, now a professor and director of the Valley Fever Center for Excellence at the University of Arizona College of Medicine, who was part of that research 40 years ago. &ldquoEven with [bad] reactions and the study lasting three years, we kept 95 percent of the people who enrolled.&rdquo

Enter dogs. They have their noses in the dirt all the time, and that puts them at more at risk of Valley fever than humans are. In several Arizona counties, close to 10 percent of dogs come down with the disease every year, and they are more likely to develop severe lung-blocking forms than human are. They suffer terribly, and it is lengthy and expensive to treat them. But dogs' vulnerability&mdashplus the lower standards that federal agencies require to approve animal drugs compared with human ones&mdashmakes them a model system for testing a possible vaccine. And the passion of owners for their animals and their willingness to empty their wallets when they can may turn possibility into reality for the first time.

Galgiani and his Arizona group are now working on a new vaccine formula, thanks to financial donations from hundreds of dog owners, plus a boost from a National Institutes of Health grant and commercial assistance from a California company, Anivive Lifesciences. Testing is not complete, but it could reach the market for use in dogs as early as next year. &ldquoI think this is proof of concept for a fungal vaccine&mdashhaving it in use in dogs, seeing it is safe,&rdquo says Lisa Shubitz, a veterinarian and research scientist at the Arizona center. &ldquoI really believe this is the path to a human vaccine.&rdquo

This injection does not depend on a killed Valley fever fungus. Instead it uses a live version of the fungus from which a gene that is key to its reproductive cycle, CPS1, has been deleted. The loss means the fungi are unable to spread. The gene was discovered by a team of plant pathologists and later was identified in Coccidioides by Marc Orbach of the University of Arizona, who studies host-pathogen interactions. After creating a mutant Coccidioides with the gene removed, he and Galgiani experimentally infected lab mice bred to be exquisitely sensitive to the fungus. The microbe provoked a strong immune reaction, activating type 1 T helper cells, which establish durable immunity. The mice survived for six months and did not develop any Valley fever symptoms, even though the team tried to infect them with unaltered Coccidioides. When the researchers autopsied the mice at the end of that half-year period, scientists found almost no fungus growing in their lungs. That long-lasting protection against infection makes the gene-deleted fungus the most promising basis for a vaccine since Galgiani's work in the 1980s. But turning a vaccine developed for dogs into one that could be used in humans will not be quick.

The canine formula comes under the purview of the U.S. Department of Agriculture, but approval of a human version would be overseen by the U.S. Food and Drug Administration. It would require clinical trials that would probably stretch over years and involve thousands of people rather than the small number of animals used to validate the formula in dogs. Unlike the 1980s prototype, the new vaccine involves a live organism. Because there has never been a fungal vaccine approved, there is no preestablished evaluation pathway for the developers or regulatory agencies to follow. &ldquoWe would be flying the plane and building it at the same time,&rdquo Galgiani says.

He estimates achieving a Valley fever vaccine for people could take five to seven years and about $150 million, an investment made against an uncertain promise of earnings. But a successful compound could have broad usefulness, protecting permanent residents of the Southwest as well as the military personnel at 120 bases and other installations in the endemic area, plus hundreds of thousands of &ldquosnowbird&rdquo migrants who visit every winter. (Three years ago the CDC identified cases of Valley fever in 14 states outside the endemic zone. Most were in wintertime inhabitants of the Southwest who were diagnosed after they went back home.) By one estimate, a vaccine could save potentially $1.5 billion in health-care costs every year.

&ldquoI couldn't see the possibility that we'd have a vaccine 10 years ago,&rdquo Galgiani says. &ldquoBut I think it is possible now.&rdquo

I f one fungal vaccine is achieved, it would carve the path for another. If immunizations were successful&mdashscientifically, as targets of regulation and as vaccines people would be willing to accept&mdashwe would no longer need to be on constant guard against the fungal kingdom. We could live alongside and within it, safely and confidently, without fear of the ravages it can wreak.

But that is years away, and fungi are moving right now: changing their habits, altering their patterns, taking advantage of emergencies such as COVID to find fresh victims. At the CDC, Chiller is apprehensive.

&ldquoThe past five years really felt like we were waking up to a whole new phenomenon, a fungal world that we just weren't used to,&rdquo Chiller says. &ldquoHow do we stay on top of that? How do we question ourselves to look for what might come next? We study these emergences not as an academic exercise but because they show us what might be coming. We need to be prepared for more surprises.&rdquo

*Editor&rsquos Note (6/9/21): This sentence was revised after posting to correct the description of how the cells of fungi differ from those of animals.

This article was originally published with the title "Deadly Kingdom" in Scientific American 324, 6, 26-35 (June 2021)


How a fungus protects itself from the hostile environment faced after infecting maize plants

The fungus Ustilago maydis causes maize smut disease. When infecting maize plants the fungus is recognized through the plant immune system which attacks the intruder through a cocktail of defense molecules. Scientists from the Max Planck Institute for Terrestrial Microbiology in Marburg have uncovered a new mechanism that allows the fungus to protect itself from the anti-fungal activity of two proteins present in this cocktail. They show that these maize proteins do not only attack U. maydis but also other fungal pathogens that parasitize maize. Their finding provides novel insights into the amazing interplay between a pathogen and its host and offers new leads for disease intervention.

Model for the function of Rsp3. In wild type U. maydis hyphae (left) is Rsp3 protein (pink ovals) attached to the fungal surface, providing protection against the mannose-binding antifungal maize proteins AFP1 and AFP2 (double-leaf structures). When Rsp3 is missing (right), AFP1 and AFP2 attack and kill fungal hyphae. This could release mannosylated cell wall fragments, which might bind DUF26 domain containing mannose-binding receptor kinases (double-leaf structure connected to green box) located in the plant plasma membrane, and this could upregulate plant defense responses.

To invade a plant successfully and cause disease, U. maydis secretes several hundred effector proteins, which suppress plant defense responses and reprogram development and metabolism of the host to meet the needs of the pathogen. Most effectors are novel molecules that rarely contain known motifs. To understand how effectors contribute to fungal accommodation in the host tissue and allow disease progression, it is necessary to elucidate their biochemical function. One of these novel effectors is Rsp3, a very unusual protein whose C-terminal half consists of a complex array of several different repetitive units. In field isolates, rsp3 shows strong length polymorphisms resulting from deletions and rearrangements in this repetitive domain. rsp3 is highly expressed during colonization and when the gene is deleted virulence of the fungus is strongly attenuated. By immunostaining of infected plants, Rsp3 was detected exclusively on the surface of hyphae. Biochemically, Rsp3 was shown to interact with two secreted maize DUF26 domain-family proteins designated AFP1 and AFP2. These proteins are related to a mannose-binding antifungal protein from Ginkgo biloba. AFP1 protein could also bind mannose and displayed antifungal activity against the rsp3 mutant but not against an U. maydis strain decorated with Rsp3 protein. In maize plants in which the expression of the AFP1 and AFP2 genes was silenced, the virulence defect of rsp3 mutants was alleviated. This shows that blocking the antifungal activity of AFP1 and AFP2 by the Rsp3 effector is an important virulence function. Rsp3-related proteins are present in all smut fungi suggesting a novel widespread fungal protection mechanism. Interestingly, it could also be demonstrated that maize plants silenced for AFP1 and AFP2 become more susceptible to the fungus Colletotrichum graminicola causing anthracnose stalk rot and leaf blight in maize. This reveals that the antifungal maize proteins discovered in this study play a more general role in restricting growth of plant-infecting fungi.


How Plants React to Fungi

Using special receptors, plants recognize when they are at risk of fungal infection. This new finding could help cultivate resistant crops and reduce pesticide usage.

Plants protect themselves against fungal invaders by closure of their stomatal pores. (Image: Michaela Kopischke)

Plants are under constant pressure from fungi and other microorganisms. The air is full of fungal spores, which attach themselves to plant leaves and germinate, especially in warm and humid weather. Some fungi remain on the surface of the leaves. Others, such as downy mildew, penetrate the plants and proliferate, extracting important nutrients. These fungi can cause great damage in agriculture.

The entry ports for some of these dangerous fungi are small pores, the stomata, which are found in large numbers on the plant leaves. With the help of specialised guard cells, which flank each stomatal pore, plants can change the opening width of the pores and close them completely. In this way they regulate the exchange of water and carbon dioxide with the environment.

Chitin covering reveals the fungi

The guard cells also function in plant defense: they use special receptors to recognise attacking fungi. A recent discovery by researchers led by the plant scientist Professor Rainer Hedrich from Julius-Maximilians-Universität (JMU) Würzburg in Bavaria, Germany, has shed valuable light on the mechanics of this process.

"Fungi that try to penetrate the plant via open stomata betray themselves through their chitin covering," says Hedrich. Chitin is a carbohydrate. It plays a similar role in the cell walls of fungi as cellulose does in plants.

Molecular details revealed

The journal eLife describes in detail how the plant recognizes fungi and the molecular signalling chain via which the chitin triggers the closure of the stomata. In addition to Hedrich, the Munich professor Silke Robatzek from Ludwig-Maximilians-Universität was in charge of the publication. The molecular biologist Robatzek is specialized in plant pathogen defense systems, and the biophysicist Hedrich is an expert in the regulation of guard cells and stomata.

Put simply, chitin causes the following processes: if the chitin receptors are stimulated, they transmit a danger signal and thereby activate the ion channel SLAH3 in the guard cells. Subsequently, further channels open and allow ions to flow out of the guard cells. This causes the internal pressure of the cells to drop and the stomata close – blocking entry to the fungus and keeping it outside.

Practical applications in agricultural systems

The research team has demonstrated this process in the model plant Arabidopsis thaliana (thale cress). The next step is to transfer the findings from this model to crop plants. "The aim is to give plant breeders the tools they need to breed fungal-resistant varieties. If this succeeds, the usage of fungicides in agriculture could be massively reduced," said Rainer Hedrich.

Publication

Anion channel SLAH3 is a regulatory target of chitin receptor-associated kinase PBL27 in microbial stomatal closure. eLife, September 16, 2019, DOI 10.7554/eLife.44474