In a collaborative review article published in the journal mBio, fellows in CIFAR’s Fungal Kingdom: Threats & Opportunities program explain why we should take the threats from fungi seriously.
Fellows and advisors in CIFAR’s new Fungal Kingdom: Threats & Opportunities program know that there is more to fungi than is commonly appreciated. Fungi may be well-known as sources of nutrition, with varieties like shiitake or portobello common in the grocery store, and in forest ecosystems they often break down organic matter so it can be recycled. However, a recent review article in the journal mBio co-authored by all 19 members of the program warns that fungal diseases pose significant danger to humans, to the plants we rely on, and to the planet’s wildlife.
Drawing on expertise from genetics, medicine, epidemiology, ecology, and including mycologists who specialize in fungi that infect plant, human, and wildlife hosts, the authors unite previously disparate fields to paint a holistic picture of fungal threats.
“We have an incredible interdisciplinary group of international luminaries who are focused on diverse aspects of fungi,” says program co-director Cowen, who is also a Canada Research Chair in Microbial Genomics and Infectious Disease at the University of Toronto. “The Fungal Kingdom presents tremendous opportunities and challenges to humanity through its remarkable diversity, exceptional metabolic capacity, and rapid ability to change.”
According to the authors, the human cost of fungal pathogens is immense.
“Fungi kill approximately 1.5 million people every year,” says Cowen.
“This is on par with conditions like malaria and tuberculosis.” Fungal diseases are particularly difficult to treat in humans because, while they may look more like plants, fungi are closely related to animals. Their cells have similar structures and processes, which makes developing drugs that only target the invading fungi without affecting the human host difficult.
Four types of fungus - Aspergillus, Cryptococcus, Candida, and Pneumocystis - are responsible for the vast majority (90%) of fungi-related deaths. The authors report that species of Cryptococcus cause 15% of all AIDS-associated deaths, and that Candida auris is a new and particularly concerning species.
“People are very worried about Candida auris because many of the isolates are resistant to all of the antifungal drugs that we have available,” says Cowen. “This emerging pathogen also has a remarkable ability to survive on surfaces, which means it can spread through healthcare settings pretty easily.”
Species like Aspergillus fumigatus are some of the most common fungi in the world, occurring naturally in soils across the globe. When inhaled, the spores can cause fatal lung disease, especially for people with compromised immune systems. Usually treated with a compound called an azole, doctors are increasingly finding strains of A. fumigatus that are resistant to these chemicals.
“Because some of the same antifungals are used in agriculture as in medicine, we see that the widespread use of antifungals in agriculture can select for resistance in the field, which can jeopardize the effectiveness of clinical treatments,” says Cowen. “Coordination is really important in part to understand the fundamental mechanisms of drug resistance, but then also to strategize effective antimicrobial stewardship so that we preserve key life-saving medicines.”
Fungi can interfere with human health not just directly, by causing infections, but also by destroying the plants people rely on. The authors describe significant fungal threats to wild species like myrtle and elm, as well as calorie crops like wheat and soybean, and cash crops like bananas.
They examine with particular concern the danger to the Cavendish banana, the well-known yellow cultivar that accounts for nearly half of the world’s banana production. They focus on the banana because it is the most traded global fruit and a central part of many countries’ economies. For example, the authors report that Costa Rica exports 13% of the world’s trade in bananas, and that the revenue generated covers 40% of the cost of Costa Rica’s food imports.
Cavendish bananas are susceptible to a fungal disease called Fusarium wilt, which devastates the plant’s leaves, roots, and water-carrying systems. A strain of the disease called TR4 has been spreading around the world since the 1990s, and has recently made incursions into banana-producing regions in South America, where the authors fear it may wreak considerable damage. There are currently no commercial banana cultivars resistant to TR4, and the authors warn that the low genetic diversity of bananas, combined with the virulence of this disease, make Fusarium wilt a significant threat.
And while chemical controls like fungicide risk building resistance, the authors point to exciting, innovative work by researchers like CIFAR fellow Hailing Jin. She has developed an unconventional strategy that uses small RNA to interfere with pathogens on a genetic level, sidestepping the problem of fungicide resistance.
The threats from fungi are not limited to the human realm, and pose particular danger to wildlife populations. “Fungi are currently the only organisms causing extinctions in real time,” says Cowen. “We're witnessing extinctions of species due to fungal infections.”
The CIFAR researchers discuss two examples of fungal diseases devastating wildlife: White Nose syndrome in hibernating bats (caused by Pseudogymnoascus destructans), and chytridiomycosis in amphibians (caused by Batrachochytrium dendrobatidis and Batrachochytrium salamandrivorans). They report that this amphibian disease, which is now present on every continent except Antarctica (where there are no amphibians to infect), has caused declines in 501 species of amphibian and has totally wiped out 90 species of frog.
Reflecting on the COVID-19 pandemic, Cowen and the Fungal Kingdom team see many parallels.
“We are seeing essentially a pandemic in the frogs,” says Cowen.
“There are massive, global spreads of fungal pathogens, and fundamentally, it's crucial that researchers are always looking very carefully for what emerging threats are out there, where antimicrobial resistance occurs, and how we can develop effective control strategies.”
One example of the power of the CIFAR team’s interdisciplinary approach is the unlikely collaboration of a medical doctor (Bruce Klein) and a wildlife biologist (David Blehert) on a vaccine for bats against White Nose Syndrome. Each bringing their unique expertise, they are now deploying a promising vaccine candidate in wild populations at risk.
The way forward
The forces of fungi arrayed against humans, plants, and wildlife are deadly, dangerous, and growing. But there is hope. By integrating knowledge, methods, and ideas across traditionally separate fields, members of CIFAR’s Fungal Kingdom team are producing new treatments and control strategies.
“We have multiple drug development programs, where we are using new strategies to develop fungal-selective molecules that can kill the fungus and not the human host,” says Cowen.
Among the other avenues being explored are vaccines, RNA interference, genetic engineering, and new drug combinations—cocktails of drugs that can rescue the activity of existing antifungals by crippling a fungus’s resistance mechanisms.
In order to prevent future pandemics like COVID-19, the team is adamant that support for fundamental research must not wane. “I think the key lesson is the importance of focusing on the science, being aware of the threats, and monitoring pathogens,” says Cowen.
“There's a tremendous mobilization of scientific efforts now on this one acute, massive challenge with SARS-CoV-2, and we must make sure we maintain capacity to keep going with research to address future threats, because there will be more.”
CIFAR’s Fungal Kingdom: Threats & Opportunities program includes diverse experts to understand the unique facets of fungal biology and develop new strategies to mitigate the threats posed by fungi and harness their extraordinary potential.
Read the mBio review: Threats Posed by the Fungal Kingdom to Humans, Wildlife, and Agriculture.