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Humans, the environment, and fungi weave a complex relationship marked by "give" and "take." Undoubtedly, fungi have both positive and negative impacts on our daily lives. Fungi can consume decaying organic matter, but can also cause widespread disease and death in bats, frogs, and edible crops. In nature, fungi are engaged in constant chemical warfare with organisms they encounter in their ecological niches. To stay ahead in this arms-race, fungi innovate compounds that we can use as vital medicines, but some fungi can direct their chemical arsenal at us to cause life-threatening, hard-to-treat illnesses.

While we have previously covered the effects of increasing global temperatures and the , the American Academy of Microbiology expands upon these key topics in an upcoming 2019 Colloquium Report titled "One Health: Fungal Pathogens of Humans, Animals, and Plants." The One Health approach that provides the framework for this Report urges us to prioritize and integrate the health of animals, humans, fungi, and the environment, in order to better sustain the condition and well-being of our planet as a whole.

American Academy for Microbiology Colloquia Report: One Health: Fungal Pathogens of Humans, Animals, and Plants

The concept recognizes that humans, animals, and the environment are all inextricably interconnected and influential to one another. play a big role in One Health as well. Rising temperatures and globalization may be affecting the ecosystems in which fungi can thrive, contributing to increased prevalence of severe fungal pathogenesis in humans, plants, and animals. In the face of climate change and ecological shifts, scientists and healthcare professionals must prioritize prevention and treatment of fungal disease—first by recognizing fungal pathogenic potential.

From Benign Yeast to Deadly Pathogen

Because fungi are traditionally regarded as affecting immunocompromised populations, they receive less recognition (and less funding) than life-threatening primary pathogens that threaten all people. This may be because fungi are largely introduced to the lay public through the minor, non-fatal diseases they cause, such as athlete’s foot, ringworm, and oral thrush. It could also be because fungi were originally grouped with plants until the mid-to-late 20th century, since certain species of macroscopic fungi that appear as mushrooms physically resemble plants, thereby undermining their relevance as important infectious pathogens.

Whatever the reason, there is an extensive gap in our knowledge of the incidence and epidemiology of fungal infection in people, because these data are not routinely reported to monitoring agencies such as the Centers for Disease Control and Prevention (CDC), in contrast to other major infectious diseases of bacterial, protozoan, or viral origin. This perspective on fungal disease is beginning to change as physicians see increasing outbreaks of pathogens like , which is often multi-drug resistant, difficult to remove from the hospital environment, and has a . Appropriately, Candida auris made its debut on the list of this year.

Enhancing our knowledge of fungi—from pathogenesis and beyond—is crucial at this point in time because scientists are growing progressively concerned about shifts in fungal behavior and spread. Candida auris was not a global public health threat 15 years ago, and some have linked its . While more evidence is needed to support this developing hypothesis, fungi may be changing to become a bigger threat to public health and the ecosystem as they adapt to hotter temperatures.

Emerging Human Fungal Diseases

Humans have 2 substantial protections against fungi: our 37°C internal temperature, which is too hot for all but ~330 fungal species to tolerate and our innate immune cells, which can kill most fungal invaders. This means that most fungi are not serious pathogenic threats to humans. However, people with weakened immune systems remain susceptible and the incidence of fungal disease has been increasing as various medical breakthroughs have increased this susceptible population. The emergence of new therapeutic agents such as antibiotics, immunomodulatory drugs, and implantable devices may treat a given condition but are also associated with fungal infection risk.

Even in healthy people, fungal infections can be difficult to treat because antifungal drugs are , and like bacteria, some fungi are adept at developing resistance to current antifungal agents.  Fungi are more challenging than bacteria to treat without damaging the host because eukaryotic animal cells and fungal cells share many of the same basic cell structures and machinery. This can lead to off-target drug effects that may manifest as in patients. Because it is exceedingly difficult to find a compatible molecular drug target, there are only 4 classes of antifungal drugs available:

• Polyenes (ex. Amphotericin B)—binds to ergosterol (fungal membrane component); target resembles cholesterol in mammalian cells and can lead to .
• Azoles (ex. Ketoconazole)—inhibits ergosterol synthesis through , which is also present in mammalian cells; generally associated with mild to moderate gastrointestinal side effects, though can occur in rare cases.
• Allylamines (ex. Terbinafine)—inhibits ergosterol synthesis via a fungi-specific enzyme, squalene epoxidase; generally associated with mild-to-moderate gastrointestinal side effects.
• Echinocandins (ex. Micafungin)—target beta-glucans, unique to fungal cell walls, fewer side effects.

To further complicate treatment of fungal infections, resistance against all 4 classes of antifungal drugs has been reported among different fungal pathogens, galvanizing researchers to devise new strategies and drugs for combating infection. Several new antifungal drugs are currently in clinical trials, including drugs such as , which targets pyrimidine synthesis in specific fungi.

If approved, , a group of experimental drugs that target dihydroorotate dehydrogenase (DHODH) to inhibit fungal growth. While Olorofim has no activity against Candida species—commonly used as the fungal species of choice in novel compound screening assays during early development—it has robust potency in eliminating growth of Aspergillus species. Aspergillus species are clinically important fungi that most commonly affect immunocompromised patients with mortality rates ranging from 30-90%. Olorofim is currently in for use against aspergillosis and difficult-to-treat fungal infections and is in pre-clinical development for broader usage against other fungal pathogens. It is expected to move on to larger Phase III studies in mid-to-late 2020, with a potential approval date as early as 2023.

Fungal Diseases Threaten Biodiversity

While threats to human health remain of critical importance, fungi are also a significant threat to environmental health and preservation. A wide variety of species do not have high internal body temperature for a fungal defense mechanism, such as plants and certain animals with lower body temperatures, such as amphibians, snakes, fish, and even bats (when they are hibernating). For these organisms, fungi present a major threat. Outbreaks of fungal diseases such as in bats, and in frogs, toads, and salamanders, have caused millions of deaths within the past few years. These mass extinctions cause potentially harmful perturbations to the ecosystems in which these animals live and contribute to loss of biodiversity.

White nose syndrome is caused by a cool-temperature loving organism, Pseudogymnoascus destructans, which flourishes between . When bats hibernate in winter, their body temperatures cool, allowing the fungi to grow and causing distinctive fuzzy, white patches to develop on their noses, ears, and wings. The disease causes abnormalities in bat behavior and depletes the bats’ fat reserves in the winter, causing them to awaken and expend energy they cannot replace during the winter. In the United States, the disease first appeared in the northeast in 2006, and is . Bats are important pollinators and predators of insect species, and this steep decline in the bat population will create disturbances in ecological balance. Currently, there is no widespread, approved treatment for the disease, but are underway, as well as a potential therapy using a strain of , and potentially, a natural solution—as chubby bats are more likely to survive the disease in endemic areas.

Fungal Impact on Agriculture and the Food Supply

Fungi also threaten human health indirectly by infecting and damaging food crops. Magnaporthe is a well-known "plant-destroyer," but a number of fungal species have contributed to famines, blight, and economic turmoil. In addition to killing crops, fungal growth can lead to mycotoxin contamination of crops, rendering them inedible. The 2019 Colloquium report supports additional research on new methods for controlling fungal infections in plants and crops, including gene-silencing techniques using small RNAs (sRNAs), a type of short, non-coding RNA that can regulate gene expression.

One proposed sRNA method relies on a transgenic plant variant that expresses virulence gene silencing sRNAs that provide the ability to block expression of fungal virulence factors from a variety of fungal species that promote infection. sRNAs are prevalent in plants, as well as invading pathogens, and function as a communication system between host and microbe. Many sRNAs are components of the plant immune system and can thereby be used to confer specific immunity to fungal pathogens. Potential advantages of this system include the fact that the sRNA genes are heritable, can be spread between organisms, and can target multiple fungal targets simultaneously.

An alternative method for silencing fungal virulence genes in plants proposes the use of a spray-on double-stranded naked RNA (dsRNA) or sRNA that can be applied directly to plants. This approach applies a concept known as , wherein organisms can take up exogenous RNA. Botrytis cinerea, the common gray mold you may have seen enveloping old strawberries and grapes, can take up externally applied RNAs. In contrast to the transgenic plant model, spray-on treatments provide protection for 5-8 days and do not have long-term effects on the plant’s genetic composition. RNAi has already been used successfully to modifiy crops and prevent food waste: the FDA approved apples that do not turn brown and potatoes that produce less of the toxin compound, acrylamide, . Several researchers and biotech industry partners are working to make RNAi-based gene silencing technologies a reality, and some estimate that spray-on RNAi pesticides will be available within .

The exact reasons why fungi have been historically understudied and largely left out of the microbial conversation are complex, but it is evident that fungi demand our immediate attention, as numerous fungi-related problems are emerging that require action to preserve our planet. Fungi are an important and challenging cause of infectious disease across species, populations and ecosystems. The 2019 Colloquium Report aims to redirect our focus and inspire greater interest in understanding the changing role of fungi and how they fit into many cutting-edge scientific issues, from exploring the to preventing global warming. Fungi and fungal research will be critical in determining the future of environmental sustainability and public health.

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