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The emergence of invasive fungal diseases among humans
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In contrast to viral diseases such as AIDS, bacterial diseases such as tuberculosis, and parasitic diseases such as malaria, most humans do not fear fungal diseases. This lack of concern stems from the fact that invasive fungal diseases are very rare in normal individuals. The high resistance of humans and other mammals to invasive fungal diseases stands in contrast to the fact that fungal pathogens are currently ravaging numerous ecosystems, including dramatic amphibian, salamander and coral reef declines. Fungi are major pathogens of plants, insects, reptiles and amphibians but seldom kill mammalian hosts.
While fungal diseases like onychomycosis, dandruff and athlete’s foot are quite common in humans, and these conditions do cause considerable morbidity, they are generally not life-threatening. Although occasional invasive fungal diseases have probably always occurred in human populations, these cases have been rare, and recent findings suggest that their occurrence in otherwise normal hosts is probably a reflection of some genetic error that results in impaired immunity.
In fact, invasive fungal diseases became a major medical problem only in the second half of the 20th century when medical advances such as immunosuppressive therapies, prolonged indwelling IV catheters and chemotherapy generated hosts with impaired host defenses, and the AIDS epidemic resulted in many individuals with severely compromised immunity. Consequently, Candida albicans, Cryptococcus neoformans, Aspergillus spp. and Histoplasma capsulatum are often referred to as “opportunistic pathogens.” These organisms commonly infect humans, but the infection is commonly asymptomatic and seldom causes life-threatening disease in normal hosts.
High metabolic temperatures:The ‘fungal filter’
The relative resistance of immunologically intact humans to invasive fungal diseases appears to be a general mammalian characteristic. Although all vertebrates have adoptive immunity, only mammals and birds are endothermic. The contribution of temperature to host protection against fungal diseases in mammals was made clearly apparent by the white-nose syndrome that has afflicted North American bats in recent years. This disease is caused by a fungus that grows only at lower temperatures and invades bats during their period of hibernation when their basal temperatures drop to conserve energy during the winter. Affected bats can be cured of disease by feeding them, which raises their metabolism and temperature, and results in clearance of the fungal disease.
A similar situation is observed with amphibians, which are currently being decimated by a chytrid fungus. When frogs are removed from their environment and placed in a room with higher temperatures, it is sufficient to cure the infection. Hence, the combination of adoptive immunity and high basal temperatures appears to have a synergistic effect in protecting mammals against fungal diseases. Analysis of the temperature tolerance of fungi has shown that most species are inhibited by mammalian temperatures. Birds are similarly protected against most fungal pathogens, although they can succumb to infection with thermophylic Aspergillus spp.
The so-called “Age of Mammals” began at the end of the Cretaceous when the large animal fauna was replaced from reptilian to mammalian. Although there is considerable agreement that the reptilian megafauna, including the dinosaurs, went extinct as a result of a major cataclysm at the end of the Cretaceous, such as a collision with an extraterrestrial bolide, the causes for the emergence of mammals are less obvious. The mammalian lifestyle is energetically expensive since it requires many calories to maintain endothermy, and this could be a significant disadvantage relative to ectothermic animals, which typically have much lower metabolic rates. For mammals to triumph over the reptiles in the post-Cretaceous epoch implies a strong selective advantage.
Given fossil evidence that the cataclysm that ended the Cretaceous was accompanied by a massive vegetation “die-off” and a fungal bloom, is it conceivable that fungal diseases provided selective pressures that favored mammals. In this scenario, mammals with their higher basal temperatures would have had an advantage relative to ectothermic animals, including reptiles, preventing a second reptilian age. If the age of mammals came about because of a fungal filter, that would also explain the remarkable resistance of this animal group to fungal diseases.
Thermally tolerant fungi and immune-compromised hosts
Despite the relative resistance of normal humans to invasive mycotic diseases, there is no question that fungal pathogens today are tremendously important in clinical settings. They reflect the reality that many patients are living with impaired host defenses as a result of medical advances. Two years ago, an iatrogenic epidemic of invasive fungal diseases with rare fungal pathogen Exserohilum rostratum was traced to contaminated corticosteroid medication, highlighting the potential of certain fungal species to cause disease when introduced systemically with an immunosuppressive compound.
Fungal infections may be contributing to the high prevalence of asthma since there is evidence that fungi such as C. neoformans and Aspergillus spp. elicit immune responses in the lung that predispose to hyperreactive airway disease. Furthermore, there is the concern that with global warming, some fungal species with pathogenic potential will adapt to higher temperatures such that these will be able to tolerate mammalian temperatures raising the specter of the emergence of new fungal pathogens.
Given that medical process is likely to continue to generate individuals with impaired defenses as the price of survival, that the climate is changing, that fungi may already be adapting to higher temperatures, and that the other infections with immunosuppressive potential such as HIV can emerge in the future, humans cannot continue to count on the combination of endothermy and adaptive immunity for protection against fungi. There are currently relatively few antifungal drugs, and invasive fungal diseases are associated with high morbidity and mortality even with therapy. In fact, fungal diseases are remarkable for their chronicity, which often requires prolonged therapy, and for many afflicted individuals cure is not possible without an improvement in immunological function.
If the history of the 20th century is any guide, humanity is likely to face new fungal diseases in the 21st century. To prepare for this continuing threat, we need greater understanding of both the pathogenic potential inherent in the fungal kingdom and of the effective mammalian defense mechanisms. It is notable that there is not a single vaccine approved for the prevention of fungal diseases although there is considerable research in this field.
Despite tremendous progress in recent decades, the field of medical mycology remains small and underdeveloped relative to the current and potential threats from the fungal kingdom. Increased preparedness also would require increased surveillance for fungal threats to all environments, for fungi are nonspecific pathogens that easily cross species barriers. The experience of the bats and frogs shows that some fungal diseases can carry extinction potential for affected species and provide an ominous warning on threats from the fungal kingdom.
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- Arturo Casadevall, MD, PhD, is the Alfred and Jill Sommer Professor and Chair of the W. Harry Feinstone Department of Molecular Microbiology and Immunology at Johns Hopkins Bloomberg School of Public Health.
Disclosures: Casadevall reports consulting relationships and ownership interests with Goodwin & Wells and Pfizer.