Fungal pathogens have a major impact on human health; the lack of effective antifungal therapies, the diversity of species infecting humans, and the emergence of new lineages or species represent major challenges to treatment. The GCID fungal project will examine two species causing the largest number of opportunistic invasive mycoses, Candida and Cryptococcus, and a third species representing a major cause of endemic dimorphic mycoses. We will compare clinical isolates from each pathogen to determine the genetic basis of highly virulent or antifungal resistant isolates and to discriminate how isolates that cause invasive infections differ from those of low virulence or that are part of a healthy mycoflora.
Candida albicans, the most common fungal pathogen, can cause life threatening systemic infections in immunocompromised individuals; however, in healthy individuals, C. albicans can be found as a commensal resident of the skin, gastrointestinal system, and urogenital tract. While we have learned a great deal about the composition of the human microbiome, the strain level variation is only beginning to be studied. Cryptococcus neoformans is of enormous clinical importance, causing life-threatening meningoencephalitis that at its peak epidemic levels caused approximately 1 million new infections per year worldwide. Combatting these infections requires a greater understanding of how pathogen variation affects interactions with the host during infection. The thermally dimorphic fungus Talaromyces (formerly Penicillium) marneffei causes life threatening invasive infections. In endemic regions of Vietnam and in southern China, talaromycosis is a leading opportunistic infection and cause of death in HIV-infected individuals.
Each of these projects will leverage genomic approaches to study how the genetic diversity of each pathogens contributes to severe infection cases and drug resistance. In addition,interactions with the host will be examined using RNA sequencing to map host-pathogen responses during infection and with other microbes using metagenomic or amplicon sequencing. Through these aims, this project will develop approaches for the genomic analysis for fungal pathogens and characterize how pathogen genetic variation, host response, and microbial interactions contribute to infection outcome.
To examine the genetic basis of virulence for clinical populations of Cryptococcus neoformans
To study Candida heterogeneity and the genetics of invasive infections
To probe the genomic basis of virulence and drug resistance in Talaromyces marneffei
These aims leverage expertise in genomic analyses of Candida, Cryptococcus, and dimorphic fungi to address fundamental clinically-related questions. This work will advance technological approaches for studying fungi at scale, through synergies with other areas of this GCID.
These projects will result in a new understanding of how pathogen variation contributes to virulence and high-quality genomic data sets, methods, and technologies with broad applicability to the study of fungal pathogens. These findings can also be used to guide the development of new treatments or interventions that target aggressive infections.