The silent invasion of the killer fungus

Emerging fungi threaten crop security, biodiversity and human health. So why are we looking the other way?

Sheba Agarwal-Jans, PhDThe threat of fungal infections has become severe enough to be addressed at two major conferences this spring, the first of which starts today at the Royal Society of London. Here, Elsevier Publisher Dr. Sheba Agarwal-Jans, who has a PhD in molecular biology and genetics, writes about the issue and presents related research.

Think of fungal infections and one immediately envisions athlete’s foot, ringworm and thrush – irksome but easy enough to cure. Or perhaps zombie ants or a certain X-files episode.

Looking at the big picture, however, it becomes apparent that the threat of the fungal contagion in plants and animals, including human beings, looms larger than ever and is potentially more devastating than we imagined. In the past two decades alone, there has been an unprecedented number of new and emerging pathogenic fungi as well as variants of existing fungi that cause serious diseases and mortality in many organisms across the globe.

Meetings for public awareness

Most people do not know the havoc that infectious fungi can cause. To educate policymakers, healthcare professionals, funding agencies and the general public, two meetings on the subject will take place this spring. The first meeting, Tackling emerging fungal threats to animal health, food security and ecosystem resilience (#RSfungalthreats), will be March 7 and 8 at the Royal Society of London. This meeting will be followed by a related satellite meeting, Tackling emerging fungal threats to animal health, food security and ecosystem resilience: the state of the art, on March 9 and 10.

The second event is part of the yearly spring meeting organized by the CBS-KNAW Fungal Biodiversity Centre in Utrecht: Fungi and Global Challenges. It will be held in Amsterdam April 14 and 15.

Just how serious is the problem of the killer fungus?

Fungal infections of plants, crops and forests

Fungi have long been known to cause widespread disease in plant species, and some have altered the course of human history. An example is ergot of rye, a plant disease caused by the fungus Claviceps purpurea, which contains compounds useful in pharmaceutics and is also incidentally the original source of LSD. Instances of both convulsive and gangrenous ergotism has been documented since the Middle Ages, and ergot has a part to play in the plague of Holy Fire, the bubonic plague, Jewish mystical movements and possibly even the witch trials during the 15th and 18th centuries.

Today, fungi continue to threaten both cash crops like citrus fruits, coffee, cacao and tobacco, as well as the world’s top four staple crops: wheat, rice, maize and potatoes. Out of all biotic threats to crops, fungi (and oomycetes, see box) pose the greatest to global food security. The fungal genome is also incredibly plastic, resulting in the emergence of even more aggressive versions of existing pathogens, which can potentially overcome the defenses of the plant, and gain resistance to existing fungicides.

Oomycetes vs fungi

Oomycetes are another group of important plant pathogens. For a long time, oomycetes were classified as fungi because they have common characteristics. However, we now know they are genetically, morphologically and physiologically distinctive and belong to different taxonomic groups altogether. However, many phytopathologists study oomycetes alongside fungi as the two most important groups of plant pathogens. The most famous example of an oomycete disease is the Irish potato blight, caused by Phytophthora infestans, which changed the course of Irish/British history in the 19th century. In fact, P. infestans still affects world potato growers today due to its rapid speed of adaptation to its host plant. Oomycetes can also infect other species; for example, the Saprolegnia genus infects fish.

The scenario is further complicated by an increased rate of invasion of new territories by pathogens, due to various factors including changes in agricultural practices, habitat disturbances, introduction from other areas into new ones, and global climate change. In fact, a recent model predicted that some plant pathogens are marching pole-wards at a rate of 8 km per year due to climate change, bringing diseases that have never been dealt with into these latitudes. Ironically, the climate change that drives this unprecedented spread of fungal pathogens is also exacerbated by fungal infections. For example, the loss of forests (like pine, elm and chestnut) in the Northern Hemisphere will result in a serious loss of fixed carbon, resulting in an increased amount of carbon dioxide gas in the atmosphere, leading to global warming.

Fungal infections pose serious challenges to world food security, with many nations underestimating the burden of pathogens in their farmers’ fields. To demonstrate the magnitude of the problem, recent models have shown that if we can save the crops lost to even low level diseases, we could feed 8.5 percent of the 7 billion humans alive – nearly 600 million people. And if the stars were to align to create severe epidemics in all food crops simultaneously, we would only be able to feed 39 percent of the world’s population. While the mathematical probability of this happening is very low, it is a very sobering scenario.Rice blast, caused by <em>Magnaporthe oryzae</em>, occurs in 85 countries and causes a 10 percent to 35 percent loss of harvest. (Photo by Nick Talbot, University of Exeter)

Thousand cankers disease and black walnuts

Walnut trees dead or dying from thousand cankers disease. The defoliated trees are dead, and the trees with yellow foliage are dying. (Photo by Stacy Hishinuma, Department of Entomology and Nematology, UC Davis)A real time example of an emerging fungal mycosis is the thousand cankers disease, caused by Geosmithia morbida, which is vectored by the walnut twig beetle. This fungus attacks and has already decimated the eastern black walnut, Juglans nigra, in certain parts of United States. The previously unknown disease was first found in 2008. Prof. Richard Bostock is a plant pathologist at UC Davis and a lead researcher on a 3-year study of the disease, along with Dr. Steve Seybold, a research entomologist with the US Forest Service. Dr. Bostock explains:

Thousand cankers disease is a rapidly emerging invasive threat to walnut orchards in California. Only in a few places in the state have English walnut trees died due solely to this disease, but it’s on its way to becoming endemic in all the walnut-growing areas, and we are still not sure where this is going to go.

Fungal infections of animals

In recent years, various epidemics of mycoses due to previously unknown fungi have been recorded in several species. The result has been a high profile decline in wildlife. For example, mass mortalities of up to 75 percent were recently observed in bats due to ascomycete fungus Geomyces destructans, giving rise to white nose syndrome. The fungus Batrachochytrium dendrobatidis (Bd) has been shown to infect over 500 species of amphibians, resulting in a 40 percent decline in some parts of Central America. Interestingly, frogs that survive Bd infection show altered behavior – specifically a more attractive mating call — which facilitates the spread of the pathogen to even more females than uninfected frogs. Colony collapse disorder in bees and their subsequent declining numbers have been attributed to microsporidian fungal infections, and the sea fan coral has been eradicated at many sites in the Florida Keys by a marine Aspergillus species, a newly emerged mycosis. The near wholesale eradication of these and other wild life species in such a short time has created an imbalance in the ecosystem and has adversely affected biodiversity.

Many epidemiological studies now suggest that fungi pose a greater threat to plant and animal biodiversity than any other pathogen, and this threat is increasing. There is even a hypothesis that states that massive fungal proliferation and infection might have given warm-blooded mammals an advantage over dinosaurs approximately 65 million years ago, possibly contributing to the extinction of dinosaurs. One can only conclude that if the humble fungus might have had a hand in felling even the great dinosaurs, the peril it poses today is no less credible and in fact, very urgent.White nose syndrome in little brown bats, a very aggressive disease that is spreading rapidly. (Photo by Al Hicks, New York Department of Environmental Conservation)

Fungal infection of humans

A macrophage (large cell in the center) that has swallowed a <em>Candida</em> cell (green). (Photo by Judith Bain, University of Aberdeen)Fungal infections in humans are either superficial or invasive. Superficial infections of the skin and nails are caused by dematophytes, while Candida affects the oral and genital tracts, causing the common thrush. The four genera Cryptococcus, Candida, Aspergillus and Pneumocystis are responsible for the far more serious invasive mycoses. More people die every year from invasive mycoses than malaria or tuberculosis – up to 1.5 million annually. Just 50 percent of patients with invasive aspergillosis will recover if the disease is diagnosed and treated on time. If the infection is not treated, which is often the case, the disease is fatal in more than 80 percent of patients.

A big hurdle in the treatment of invasive mycoses is the serious shortcomings of diagnostic methods or their late deployment, very often leading to deaths that could have been avoided. Most diagnostic kits lack sensitivity, speed and specificity, and many are unaffordable or inappropriate for the needs of developing countries, where invasive fungal infections are much more serious and widespread.

The second impediment is the relative small arsenal of anti-fungal drugs. Those that are available have so far only managed to make a small dent in the high mortality rate of patients, because of the lack of early diagnosis, drug toxicity and interactions, as well as limitations in spectrum of action and mode of administration. More worryingly, certain fungal pathogens are becoming resistant to antifungal drugs. A startling example of drug resistance is in the case of Aspergillus fumigatus, which causes invasive aspergillosis, most critically in immune-compromised patients. Aspergillosis is treated using azole antifungal drugs. Azole compounds are also used in fungicides to combat phytopathogens in crops, resulting in the development of azole resistance in environmental A. fumigatus. Consequently, the spores that infect patients may already be azole resistant due to prior exposure of the fungus to agrochemical fungicides, resulting in a mortality rate of 88 percent.

There are currently no clinical vaccines available against fungal infections. A few promising vaccines that have been shown to be effective in animal models are now being taken into clinical trials. An additional issue for vaccine development is that most patients suffering invasive mycoses are immune compromised, in whom the use of vaccines is generally contraindicated. The best method of prevention that we have at the moment is anti-fungal prophylaxis, a preventative measure against mycoses, but this is often not economically or medically possible. The prognosis for high-risk patients is therefore very bleak indeed.

So what is to be done?

Prof. Neil Gow, PhDProf. Sarah Gurr, PhDIt is clear that the possible fallout from fungal infections of plants and animals is very serious and potentially disastrous to the world’s food supply, the world’s ecosystem, and human health. Scientists in agriculture, ecology and (medical) mycology are working steadily to understand the biology and epidemiology of infectious fungi. Critical areas of research include understanding the mechanism of pathogenesis of various fungi, as well as the discovery of more effective anti-fungal drugs, better methods of pathogen detection, identification and monitoring, as well as the development of anti-fungal vaccines.

One question of course is why aren’t we talking about this imminent problem in the media? Why isn’t there more money being channeled into research as well as drug and vaccine development of fungal infections? Ironically, the public is barely aware of the extent of the impact of crop disease on food security, or of fungal disease in both wild life and in hospitals. Perhaps then, the most critical task at the moment is to increase public awareness.

Prof. Matthew Fisher, PhD

To this effect, two meetings have been organized for this spring. The first meeting will be held March 7 and 8 at the Royal Society of London and is organized by Professors Sarah Gurr, Matthew Fisher and Neil Gow. “The emergence of fungi as a worldwide threat stems largely from our inability to provide biosecure trade,” says Prof. Matthew Fisher, professor of fungal disease epidemiology at Imperial College London. “Fungi stealthily cross borders in contaminated goods and hosts, then initiate outbreaks in disease naive-systems. This meeting will bring to the attention of policy-makers the urgent need to increase our ability to trade in a biosecure manner.”

Prof. Gow, a medical mycologist in the University of Aberdeen, states: “We are bringing together a unique group of world authorities in fungal biology to lay out the scale of this challenge alongside the nature of the research and policy-responses that are necessary to address these threats.”

Prof Pedro Crous, PhDThese sentiments are also expressed by Prof. Pedro Crous, the Director of CBS-KNAW Fungal Biodiversity Centre in Utrecht, who is organizing the Fungi and Global Challenges symposium in Amsterdam. Prof. Pedro explains that this special meeting has been organized alongside their annual spring symposium “to create more public awareness and engagement for the challenges that fungi pose to human, plant and animal health.”

The organizers of both meetings hope to engage the public, policy makers and other interested parties to the very real hazard that fungi pose to our wellbeing. Hopefully, this will lead to the tools we need to fight what seems to be, at the moment, a losing battle.

Why invasive mycoses and why now?

Patients who are immune compromised are at the greatest risk for invasive fungal infections. In fact, the incidence of invasive fungal diseases has increased in the past few decades due to a corresponding increase in immunosuppressive infections, the most well-known of which is HIV/AIDS. One of the defining illnesses of AIDS used to be Pneumocystis jirovecii pneumonia, resulting in mortality rates between 20 percent and 80 percent. The vast majority of cryptococcosis patients also have a defect in cellular immune function due to infection with HIV. Antiviral treatments have lessened in the incidence of these AIDS associated fungal infections in developed countries, but in less wealthy countries, the fatal penicilliosis caused by Talaromyces (formerly Penicillium) marneffei has been on the rise in Southeast Asia. There have also been links established between fungal infections and inflammatory/autoimmune diseases like Crohn’s disease, sarcoidosis, colitis, arthritis, and most recently, Alzheimer’s. In addition, the advent of immunosuppressive therapies, invasive medical procedures, extended stays in intensive care units, or the use of advanced medical procedures can predispose patients to hospital acquired blood infections, usually caused by Candida.

Related articles

Elsevier has made the following articles freely available until June 2, 2016:

This is an example of a new article format, the video article, introduced in Elsevier’s journal Fungal Biology and Genetics. These short papers showcase videos that carry the main message of the manuscript, accompanied by a short text. This particular article was one of the first to be published. Prof. Sarah Gurr and Dr. Daniel Bebber highlight the issue of food security and potential crop loss due to fungal infections.

Corresponding author

Prof. Sarah Gurr holds the Chair of Food Security at the University of Exeter. She is interested in crop diseases (notably of rice and wheat), with particular emphasis on fungal infestations and their global movement and control. She is one of the organizers of the Royal Society meeting Tackling emerging fungal threats to animal health, food security and ecosystem resilience,

Corresponding author

Prof. David Denning is Director of the National Aspergillosis Centre at the University Hospital of South Manchester and the University of Manchester. He works principally with the clinical aspects of aspergillosis and the evaluation of new diagnostics and antifungal drugs. He is President of the Global Action For Fungal Infections (GAFFI).

Elsevier Connect Contributor

Dr. Sheba Agarwal-Jans (@ShebaAJ) holds a PhD in Molecular Biology and Genetics from Erasmus Medical Centre in Rotterdam, the Netherlands. She worked as a postdoctoral fellow at the Vrije Universiteit Medical Centre in Amsterdam before joining Elsevier in 2008. She is the Publisher for the Microbiology portfolio of journals and is based in Amsterdam.

Sheba thanks Nancy Keller, Neil Gow and Nik P. Money for their critical review of this story.

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