CommentaryFungal virulence, vertebrate endothermy, and dinosaur extinction: is there a connection?
Introduction
Of the more than 1.5 million estimated fungal species (Hawksworth, 2001), only about 150 cause disease in mammals and of these species only a few are common pathogens (Kwon-Chung and Bennett, 1992). With the exception of the dermatophytes, which are common causes of skin infection and disease in many mammalian species, systemic fungal diseases are relatively rare in intact mammals compared to those caused by bacteria and viruses. In humans, systemic fungal diseases were considered a rarity until the mid-20th century, when advancements in medicine produced antimicrobial drugs, indwelling venous catheters, and immunosuppressive therapies. In fact, fungal diseases such as cryptococcosis, blastomycosis, and histoplasmosis were not described until the late 19th century when advances in laboratory science led to more detailed pathological descriptions in unusual cases of disease. For example, Cryptococcus neoformans was not associated with human disease until 1894 (Knoke and Schwesinger, 1994). In contrast, tuberculosis, smallpox, plague, and many other infectious diseases were known since antiquity. Presumably, this reflects the relative infrequency of systemic fungal diseases in human populations such that the occasional cases that must have occurred before modern times were not recognized as a distinct disease entity worthy of description. Today systemic fungal diseases are common but most occur in individuals with impaired immunity as a consequence of HIV infection, immunosuppressive drugs, integument compromise by catheters and surgery, and disruption of host commensal bacterial flora by antimicrobial drug use. Hence, humans as a species appear to be remarkably resistant to fungal diseases except in conditions where host defenses are impaired.
Comparisons of the relative frequency of fungal disease across species are difficult because we lack incidence and prevalence data for the overwhelming majority of animal species. However, there is sufficient information emerging in the literature to begin to assemble generalizations and consider hypothesis that are potentially testable. In common with the rarity of human mycoses, systemic fungal diseases appear to be relatively infrequent in other mammals such as rabbits, rodents, cats, and dogs, although some dog breeds are susceptible to blastomycosis and cryptococcosis occurs frequently in Koala bears (Canny and Gamble, 2003, Connole et al., 2000, Kerl, 2003, Krockenberger et al., 2003, Pollock, 2003). Some birds appear to be susceptible to systemic fungal diseases and Aspergillus fumigatus is a relatively common pathogen. Approximately 20% of immature loons succumb to respiratory fungal disease (Sidor et al., 2003) and aspergillosis is common in turkeys and stitchbirds (Cork et al., 1999, Lair-Fulleringer et al., 2003). In contrast to mammals, fungi are frequently associated with disease in ectothermic organisms such as plants, insects, fish, and amphibians. For example, chytridiomycosis has been implicated in the worldwide decline in amphibian populations (Berger et al., 1998, Daszak et al., 1999) and fungi are common pathogens of mites (van der Geest et al., 2000). Fungal diseases may also be critical contributors to the worldwide decline in coral reefs (Rosenberg and Ben Haim, 2002). Two questions emerge from these observations: (1) Why are some fungi virulent for mammals? and (2) Why are most mammals relatively resistant? In pondering these questions some insights emerge that could be relevant to the unsolved problems of the origins of vertebrate endothermy and the causes of past extinctions.
Section snippets
Virulence and pathogenicity
Before analyzing the specific attributes of fungi as pathogenic microbes it is worthwhile to consider the definitions of virulence and pathogenicity, since these are central elements in any discussion of fungal pathogenesis. Virulence is a microbial attribute that is expressed only in the context of a susceptible host, and consequently, it is not an independent microbial property (Casadevall and Pirofski, 2001). Although various definitions for virulence have been proposed over the years, I
The rarity of life-threatening fungal diseases in immunologically intact mammals
Fungal pathogens can be divided into two broad groups depending on their source for infection. The first group is endogenous to mammalian hosts, is considered part of the commensal flora, and is presumably acquired by transmission from other hosts. This group includes Candida spp. and a few other fungal species such as Malassezia (Ashbee et al., 2002). Commensal fungi are adapted to their hosts and systemic disease is almost always associated with an alteration in the ecology and/or immune
Origins of fungal virulence
When entertaining the possible origins of fungal virulence for mammals one possible first step is to consider the diversity of the pathogenic subset at the species and genetic level. If the pathogenic fungi were a closely related group it might suggest origins from a phylogenetic branch that evolved to utilize mammalian hosts for its own purposes. However, if the pathogenic fungi belonged to diverse groups then one might gain insight into the origin of virulence by comparing the estimated
Consequences of animal passage for virulence-capable fungal species
The ability of certain soil fungal species to infect and survive in mammals suggests additional considerations that could have important consequences for the ecology and pathogenicity of these organisms. In this regard it is interesting that many of the soil fungi with pathogenic potential in mammals have the capacity for establishing latent infections in which the organism can persist in the host without eradication. For example, H. capsulatum and C. neoformans are each capable of establishing
Fungi and the rise of mammals
The extinction of the dinosaurs and many other species at the end of the cretaceous has been attributed to various processes including the impact of an extraterrestial bolide approximately 65 million years ago (Alvarez, 1987) and/or increased volcanism (Glasby and Kunzendorf, 1996). The bolide hypothesis is supported by the finding of a global soot-layer at the cretaceous–tertiary (K–T) boundary which could be residue of global wildfires ignited by the collision event (Melosh et al., 1990) and
Closing thoughts
The origins of virulence for the soil fungi are probably intimately related to microbial and physical environmental pressures that select for their capacity to survive, proliferate, and cause damage in an animal host. Animal passage may not be necessary for the life cycle of soil fungi, but survival in animals could confer virulent-capable fungi with mobility and expose these microbes to immune selection pressures that may generate additional diversity. Although the origins of fungal virulence
Acknowledgments
I am grateful to Drs. Francoise Dromer and Liise-anne Pirofski for critically reading the manuscript. National Institute of Health awards AI033142-11, AI033774-11, AI052733-02, HL059842-08, and GM071421-01 support Dr. Casadevall research.
References (78)
- et al.
Human pathogeneic fungi and their close nonpathogenic relatives
Mol. Phylogenet. Evol.
(1996) - et al.
Fungal diseases of rabbits
Veterinary. Clin. North Am. Exot. Anim Pract.
(2003) - et al.
Intracellular parasitism of macrophages by Cryptococcus neoformans
Trends Microbiol.
(2001) The magnitude of fungal diversity: the 1.5 million species estimate revisited
Mycol. Res.
(2001)Integrin-like proteins in Candida spp. and other microorganisms
Fung. Genet. Biol.
(1999)Update on canine and feline fungal diseases
Vet. Clin. North Am. Small Anim. Pract.
(2003)Molecular basis of pathogenicity in Blastomyces dermatitidis: the importance of adhesion
Curr. Opin. Microbiol.
(2000)- et al.
Biomechanical interaction between hyphae of two Pythium species (Oomycota) and host tissues
Fungal Genet. Biol.
(2002) Fungal diseases of laboratory rodents
Vet. Clin. North Am. Exot. Anim. Pract.
(2003)- et al.
Mechanics of solid tissue invasion by the mammalian pathogen Pythium insidiosum
Fungal Genet. Biol.
(2001)
The origin and maintenance of virulence for the human pathogenic fungus Cryptococcus neoformans
Microbes Infect.
Acute histoplasmosis: clinical, epidemiologic and serologic findings of an outbreak associated with exposure to a fallen tree
Am. J. Med.
Mass extinctions caused by large bolide impacts
Phys. Today
Proximal impact deposits at the Cretaceous–Tertiary boundary in the Gulf of Mexico: a restudy of DSDP Leg 77 Sites 536 and 540
Geology
Skin colonization by Malassezia in neonates and infants
Infect. Control Hosp. Epidemiol.
Endothermy and activity in vertebrates
Science
Chytridiomycosis causes amphibian mortality associated with population declines in the rain forests of Australia and Central America
Proc. Natl. Acad. Sci. USA
Effect of temperature on intratesticular cryptococcal infection in rabbits
Sabouraudia
Molecular evolution of the fungi: human pathogens
Mol. Biol. Evol.
Aerial dispersal of pathogens on the global and continental scales and its impact on plant disease
Science
Cryptococcus neoformans: gastronomic delight of a soil amoeba
Sabouraudia
‘Ready-made’ virulence and ‘dual-use’ virulence factors in pathogenic enviromental fungi—the Cryptococcus neoformans paradigm
Curr. Opin. Microbiol.
Host–pathogen interactions: redefining the basic concepts of virulence and pathogenicity
Infect. Immun.
Host–pathogen interactions: the basic concepts of microbial commensalism, colonization, infection, and disease
Infect. Immun.
Host–pathogen interactions: the attributes of virulence
J. Infect. Dis.
The damage–response framework of microbial pathogenesis
Nature Microbiol. Rev.
Natural pathogens of laboratory animals and their effects on research
Med. Mycol.
Aspergillosis and other causes of mortality in the stitchbird in New Zealand
J. Wildl. Dis.
Emerging infectious diseases and amphibian population declines
Emerg. Infect. Dis.
Antibodies to the Cryptococcus neoformans capsular glucuronoxylomannan are ubiquitous in serum from HIV+ and HIV− individuals
Clin. Exp. Immunol.
Individual and environmental factors associated with infection due to Cryptococcus neoformans serotype D
Clin. Infect. Dis.
Invasive candida infections—evolution of a fungal pathogen
N. Engl. J. Med.
Host–pathogen interactions in a varying environment: temperature, behavioural fever and fitness
Proc. R. Soc. Lond. B Biol. Sci.
Cryptococcal meningitis after unusual exposures to birds
N. Engl. J. Med.
Biogeographic range expansion into South America by Coccidioides immitis mirrors New World patterns of human migration
Proc. Natl. Acad. Sci. USA
Pathogenic clones versus environmentally driven population increase: analysis of an epidemic of the human fungal pathogen Coccidioides immitis
J. Clin. Microbiol.
Microevolution of a standard strain of Cryptococcus neoformans resulting in differences in virulence and other phenotypes
Infect. Immun.
Karyotype instability in Cryptococcus neoformans infection
J. Clin. Microbiol.
Phenotypic switching of Cryptococcus neoformans occurs in vivo and influences the outcome of infection
J. Clin. Invest
Cited by (101)
Antifungal activity of thiosemicarbazones, bis(thiosemicarbazones), and their metal complexes
2021, Journal of Inorganic BiochemistryHeterothermy and antifungal responses in bats
2021, Current Opinion in MicrobiologyCitation Excerpt :The antifungal response strikes a careful balance between allowing colonisation and limiting growth in a way that minimises both harm to the host and energy usage [2]. The host’s sophisticated innate and adaptive immune systems, combined with high body temperatures, constitute two important barriers for fungi, preventing life-threatening diseases [3]. However, when individuals are immuno-compromised, fungal infections are not uncommon.
Insoluble organic matter in chondrites: Archetypal melanin-like PAH-based multifunctionality at the origin of life?
2021, Physics of Life ReviewsCitation Excerpt :In this scenario, the dying out of many species of animals and plants was hypothesized to involve an unseen solar companion star, a hypothetical red dwarf or brown dwarf generally referred to as Nemesis, triggering periodic mass extinction, although this hypothesis has been questioned [248]. Melanin-related virulence may have also been implicated in the possible proliferation of fungal species that contributed to the extinctions at the end of the Cretaceous period [249]. In concluding this section, we concur with Dadachova et al., 2007 [209] that: “Melanins are ancient pigments that are likely to have been selected in evolution because they enhanced the survival of microbes in both the environment and in various hosts.
Differential role of gpaB and sidA gene expressions in relation to virulence in Aspergillus species from patients with invasive aspergillosis
2018, Brazilian Journal of MicrobiologyCitation Excerpt :If we want to map the gene network, which is associated with the progression of IA in immunocompromised individuals, we will need detailed information related to the virulence gene profiles of Aspergillus spp. Several putative virulence factors contributing to the pathogenesis of aspergillosis,5 have been identified, including pigment production, adhesion molecules on the cell surface, hydrolytic enzymes and toxin secretion. Additionally, it has been proven that a network of genes is required to support the virulence of the Aspergillus spp.6
Intracellular cytokine expression in invasive fungal sinusitis and its impact on patient outcome
2022, Journal of Laryngology and OtologyFungal heat shock proteins: molecular phylogenetic insights into the host takeover
2024, Science of Nature