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Fungal Virulence - From the Genomic Point of View

In a recent commentary, Arturo Casadevall [101] pointed out the link between thermotolerance and fungal virulence: only fungal species that can tolerate the body temperatures of endothermic animals are potential pathogens, and these still have to be able to cope with the slight alkalinity of mammalian body fluids and the immune defense of their prospective host. Most fungi prefer temperatures between 25 °C and 35 °C and acidic pH [5]. In contrast, ectothermic organisms like plants, insects, amphibians, and some reptiles appear more susceptible to fungal disease. Consequently, Casadevall even argues that fungi could have been involved in the demise of the dinosaurs and the rise of mammals about 65 million years ago [101].

Commensal fungi like C. albicans have evolved towards an intimate relationship with their host and only cause endogenous mycoses when the host becomes immunocompromised. Soil fungi such as the dimorphic fungi become pathogens when their infectious propagules are inhaled in sufficient quantities. Here Casa-devall and his group suggest that selective processes instigated by amoebae and/ or other soil microorganisms might prime certain fungal species for virulence in the mammalian host [102, 103]. For example, the predatory relationship of Acanthamoeba castellanii with C. neoformans and the intracellular survival strategy of the fungi could be a "battle training" for the encounter with mammalian macrophages [104]. Furthermore, once an infection has been "successful," animal passage could select for strains that are more adapted to the host environment and thus more virulent. Since fungal pathogenicity is polyphyletic and virulence is certainly multifactorial, only detailed study of each fungal pathogen and its close apathogenic relatives will reveal the traits that in combination render one species or strain more virulent than another. Tolerance of higher temperatures and alkaline conditions may be common denominators, but pathogenic species might have reached these qualities through different evolutionary paths. Additional factors important for virulence, such as adhesins, pigments, capsules, extracellular enzymes, or other secreted products, are very specific to the pathogen.

Comparative genomics of close relatives, pathogenic versus nonpathogenic, will help to identify candidates for virulence determinants, while functional genomics and molecular genetics will be needed to validate these factors. Comparisons between phylogenetically distant species like S. cerevisiae and C. albicans are probably too imprecise due to the long period of divergent evolution, but overall trends may be revealed. The remarkable reductive evolution of some microsporidian species (see above) can hardly be missed. It will be interesting to see whether com-mensalism or close association with the mammalian host as seen with C. albicans or Pneumocystis spp. has led in all cases to reductive evolution in certain functional categories (e.g., nucleotide metabolism as in E. cuniculi) while other functional areas remain unchanged or are expanded, as for instance the SAP gene family in C. albicans.

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