Fungal virulence, vertebrate endothermy, and dinosaur extinction: Is there a connection? Fungal Genet Biol

Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA.
Fungal Genetics and Biology (Impact Factor: 2.59). 03/2005; 42(2):98-106. DOI: 10.1016/j.fgb.2004.11.008
Source: PubMed


Fungi are relatively rare causes of life-threatening systemic disease in immunologically intact mammals despite being frequent pathogens in insects, amphibians, and plants. Given that virulence is a complex trait, the capacity of certain soil fungi to infect, persist, and cause disease in animals despite no apparent requirement for animal hosts in replication or survival presents a paradox. In recent years studies with amoeba, slime molds, and worms have led to the proposal that interactions between fungi and other environmental microbes, including predators, select for characteristics that are also suitable for survival in animal hosts. Given that most fungal species grow best at ambient temperatures, the high body temperature of endothermic animals must provide a thermal barrier for protection against infection with a large number of fungi. Fungal disease is relatively common in birds but most are caused by only a few thermotolerant species. The relative resistance of endothermic vertebrates to fungal diseases is likely a result of higher body temperatures combined with immune defenses. Protection against fungal diseases could have been a powerful selective mechanism for endothermy in certain vertebrates. Deforestation and proliferation of fungal spores at cretaceous-tertiary boundary suggests that fungal diseases could have contributed to the demise of dinosaurs and the flourishing of mammalian species.

Full-text preview

Available from:
  • Source
    • "This indicates that additional hostrelated factors or conditions can supersede the need for increased temperature in these models. Furthermore, the ability to grow at 37°C itself can be considered a virulence factor of its own in pathogenic fungi (Casadevall, 2005) and other microbes. For example, the calcineurin pathway is required both for full virulence, and for growth at temperatures of 37°C and above in C. glabrata (Chen et al., 2012) and Cryptococcus neoformans (Odom et al., 1997). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Studying infectious diseases requires suitable hosts for experimental in vivo infections. Recent years have seen the advent of many alternatives to murine infection models. However, the use of non-mammalian models is still controversial, as it is often unclear how well findings from these systems predict virulence potential in humans or other mammals. Here we compare the commonly used models, fruit fly and mouse (representing invertebrate and mammalian hosts) for their similarities and degree of correlation upon infection with a library of mutants of an important fungal pathogen, the yeast Candida glabrata. Using two indices, for fly survival time and for mouse fungal burden in specific organs, we show a good agreement between the models. We provide a suitable predictive model for estimating the virulence potential of mutants in the mouse from fly survival data. As examples, we found cell wall integrity mutants attenuated in flies and mutants of a MAP kinase pathway defective in both fly virulence and relative fitness in mice. In addition, mutants with strongly reduced in vitro growth were generally, but not always, reduced in fly virulence. Overall, we demonstrate that surveying Drosophila survival after infection is a suitable model to predict outcome of murine infections, especially for severely attenuated mutants. Pre-screening of mutants in an invertebrate Drosophila model can thus give a good estimate of the probability for finding a strain with reduced microbial burden in the mouse host. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · Mar 2015 · Disease Models and Mechanisms
  • Source
    • "The fungal cells have a preference for acidic growth conditions, and during infection the mammalian tissues offer a slightly alkaline environment. Therefore, an array of genes must be transcribed to respond to this new environment (Casadevall, 2005). We observed that the ura4 mutant has a dramatic growth defect at elevated pH compared to wild type and reconstituted strains (Fig. 4B). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fungal infections are often difficult to treat due to the inherent similarities between fungal and animal cells and the resulting host toxicity from many antifungal compounds. Cryptococcus neoformans is an opportunistic fungal pathogen of humans that causes life-threatening disease, primarily in immunocompromised patients. Since antifungal therapy for this microorganism is limited, many investigators have explored novel drug targets aim at virulence factors, such as the ability to grow at mammalian physiological temperature (37°C). To address this issue, we used the Agrobacterium tumefaciens gene delivery system to create a random insertion mutagenesis library that was screened for altered growth at elevated temperatures. Among several mutants unable to grow at 37°C, we explored one bearing an interruption in the URA4 gene. This gene encodes dihydroorotase (DHOase) that is involved in the de novo synthesis of pyrimidine ribonucleotides. Loss of the C. neoformans Ura4 protein, by targeted gene interruption, resulted in an expected uracil/uridine auxotrophy and an unexpected high temperature growth defect. In addition, the ura4 mutant displayed phenotypic defects in other prominent virulence factors (melanin, capsule and phospholipase) and reduced stress response compared to wild type and reconstituted strains. Accordingly, this mutant had a decreased survival rate in macrophages and attenuated virulence in a murine model of cryptococcal infection. Quantitative PCR analysis suggests that this biosynthetic pathway is induced during the transition from 30°C to 37°C, and that transcriptional regulation of de novo and salvage pyrimidine pathway are under the control of the Ura4 protein.
    Full-text · Article · Jul 2014 · Fungal Genetics and Biology
  • Source
    • "There is strong reason to suspect that B. dendrobatidis and G. destructans have environmental reservoirs. In general, fungi may be unique pathogens because many can persist in the environment apart from animal hosts, yet environmental pressures can select for fungal traits that contribute to virulence during infection of certain host organisms (31). Fungi in the phylum Chytridiomycota have a nearly global distribution and occupy roles as heterotrophs and saprobes in water and soil (32). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pathogenic fungi have substantial effects on global biodiversity, and 2 emerging pathogenic species-the chytridiomycete Batrachochytrium dendrobatidis, which causes chytridiomycosis in amphibians, and the ascomycete Geomyces destructans, which causes white-nose syndrome in hibernating bats-are implicated in the widespread decline of their vertebrate hosts. We synthesized current knowledge for chytridiomycosis and white-nose syndrome regarding disease emergence, environmental reservoirs, life history characteristics of the host, and host-pathogen interactions. We found striking similarities between these aspects of chytridiomycosis and white-nose syndrome, and the research that we review and propose should help guide management of future emerging fungal diseases.
    Full-text · Article · Mar 2013 · Emerging Infectious Diseases
Show more