Over a million patients with HIV/AIDS are currently afflicted with fungal meningoencephalitis, and the resultant morbidity and mortality are profoundly significant. The vast majority of these infections are caused by strains of Cryptococcus neoformans var. grubii, which have been recognized by possessing capsular serotype A. This yeast is ubiquitous in the environment, where it is associated with avian habitats and vegetative debris. Infection is not contagious but acquired exogenously by the inhalation of desiccated yeast cells or basidiospores. Although the ability to infect mammals offers no obvious evolutionary advantage to the fungus, most natural isolates are capable of colonizing mammalian hosts, which suggests that pathogenicity evolved in the environment. In preliminary studies, we developed robust multilocus genotyping methods and discovered two unique, genetically isolated subpopulations of serotype A: (i) a global subpopulation comprised of ubiquitous, highly clonal monomorphic strains associated with the excreta of feral pigeons and (ii) a unique, highly-variable, recombining subpopulation in southern Africa that is associated with indigenous African trees. The genetic diversity of this southern African population is unprecedented and suggests that this population may represent ancestral origin of the extant, global strains of serotype A. We also analyzed the frequencies of multilocus genotypes among clinical and environmental samples and discovered that not all strains (or genotypes) are equally likely to cause cryptococcal disease in humans. Despite the enormous diversity of genotypes in the African population, almost half of all patients in Botswana (46%) and a major proportion of patients in South Africa (17%) were infected by strains with three closely related genotypes. In contrast, the distribution of genotypes among environmental isolates in Africa is comparable, and none are dominant. Among global isolates, most genotypes were equally prevalent in both patients and the predominant non-African ecological niche, pigeon feces, although one genotype (A2) was highly prevalent in the environment but never isolated from patients. This proposal will investigate the evolution of pathogenicity in C. neoformans at the population genetic and genomic levels. This project involves two independent but complementary aims.
Aim 1 will use methods of population genetic and phylogenetic analysis to test the hypothesis of the African origin of serotype A.
Aim 2 will use methods of comparative genomics, genome-wide association mapping and phenotypic assays to identify genomic regions that differentiate strains that frequently cause infection from strains that are rarely, if ever, isolated from humans. This application of whole-genome methods to natural strains of C. neoformans will identify genes or genomic regions that are significantly associated with pathogenicity for humans.

Public Health Relevance

This project will utilize methods of population genetics, comparative genomics and the whole-genome association mapping to study evolution of pathogenesis of Cryptococcus neoformans, a leading cause of fungal meningoencephalitis. The project provides a paradigm for studying the population genetics and evolution of other opportunistic and emerging pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI093257-01A1
Application #
8140694
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Duncan, Rory A
Project Start
2011-08-05
Project End
2016-07-31
Budget Start
2011-08-05
Budget End
2012-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$491,599
Indirect Cost
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Perfect, John R; Tenor, Jennifer L; Miao, Yi et al. (2017) Trehalose pathway as an antifungal target. Virulence 8:143-149
Lestner, Jodi; McEntee, Laura; Johnson, Adam et al. (2017) Experimental Models of Short Courses of Liposomal Amphotericin B for Induction Therapy for Cryptococcal Meningitis. Antimicrob Agents Chemother 61:
Desjardins, Christopher A; Giamberardino, Charles; Sykes, Sean M et al. (2017) Population genomics and the evolution of virulence in the fungal pathogen Cryptococcus neoformans. Genome Res 27:1207-1219
Miao, Yi; Tenor, Jennifer L; Toffaletti, Dena L et al. (2017) Structural and In Vivo Studies on Trehalose-6-Phosphate Synthase from Pathogenic Fungi Provide Insights into Its Catalytic Mechanism, Biological Necessity, and Potential for Novel Antifungal Drug Design. MBio 8:
Rhodes, Johanna; Desjardins, Christopher A; Sykes, Sean M et al. (2017) Tracing Genetic Exchange and Biogeography of Cryptococcus neoformans var. grubii at the Global Population Level. Genetics 207:327-346
Chen, Yuan; Farrer, Rhys A; Giamberardino, Charles et al. (2017) Microevolution of Serial Clinical Isolates of Cryptococcus neoformans var. grubii and C. gattii. MBio 8:
Thammahong, Arsa; Puttikamonkul, Srisombat; Perfect, John R et al. (2017) Central Role of the Trehalose Biosynthesis Pathway in the Pathogenesis of Human Fungal Infections: Opportunities and Challenges for Therapeutic Development. Microbiol Mol Biol Rev 81:
Perfect, John R (2017) The antifungal pipeline: a reality check. Nat Rev Drug Discov 16:603-616
Maziarz, Eileen K; Perfect, John R (2016) Cryptococcosis. Infect Dis Clin North Am 30:179-206
Maskarinec, Stacey A; Johnson, Melissa D; Perfect, John R (2016) Genetic Susceptibility to Fungal Infections: What is in the Genes? Curr Clin Microbiol Rep 3:81-91

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