A major cause of morbidity and mortality among patients with AIDS is cryptococcal meningoencephalitis, caused by infection with the ubiquitous, encapsulated yeast, Cryptococcus neoformans. The natural reservoir of C. neoformans is exogenous, and cryptococcosis is acquired by inhalation of the yeast cells or basidiospores. Although the determinants of virulence have not been elucidated, a growing list of phenotypic properties, including the production of a capsule and a laccase, are known to be essential but not necessarily sufficient for pathogenicity. Indeed, isolates of C. neoformans vary extensively in the expression of many phenotypes, including properties known to affect the clinical outcome. In the previous grant period, DNA-based methods were developed to compare global isolates of C. neoformans from patients with AIDS and other sources, to analyze the distribution and relatedness of strains, and to identify genotypes of clinical importance. In all areas, substantial progress has been made, and this proposal will take advantage of powerful new analytical techniques to continue these studies. Defined genetic markers, such as PCR- RFLP, AFLP, and multigene sequencing, will be used to investigate the population structure of C. neoformans. Specific genotypes will be identified that represent clones that have significantly diverged with respect to clinically relevant phenotypes, including susceptibility to antifungal drugs and the expression of virulence factors. The project will also investigate the relationships between clinical and environmental populations. Population genetic and phylogenetic analyses will be used to estimate patterns of genetic variation, recombination and migration among populations. These approaches will lead to predictive information about the epidemiology, diagnosis and prognosis of cryptococcosis in patients with AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI025783-16
Application #
6723722
Study Section
Special Emphasis Panel (ZRG1-AARR-4 (01))
Program Officer
Lambros, Chris
Project Start
1987-09-30
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2006-03-31
Support Year
16
Fiscal Year
2004
Total Cost
$192,500
Indirect Cost
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Van Wyk, Marelize; Govender, Nelesh P; Mitchell, Thomas G et al. (2014) Multilocus sequence typing of serially collected isolates of Cryptococcus from HIV-infected patients in South Africa. J Clin Microbiol 52:1921-31
Litvintseva, Anastasia P; Mitchell, Thomas G (2012) Population genetic analyses reveal the African origin and strain variation of Cryptococcus neoformans var. grubii. PLoS Pathog 8:e1002495
Litvintseva, Anastasia P; Carbone, Ignazio; Rossouw, Jenny et al. (2011) Evidence that the human pathogenic fungus Cryptococcus neoformans var. grubii may have evolved in Africa. PLoS One 6:e19688
Miglia, Kathleen J; Govender, Nelesh P; Rossouw, Jenny et al. (2011) Analyses of pediatric isolates of Cryptococcus neoformans from South Africa. J Clin Microbiol 49:307-14
Hu, Guanggan; Wang, Joyce; Choi, Jaehyuk et al. (2011) Variation in chromosome copy number influences the virulence of Cryptococcus neoformans and occurs in isolates from AIDS patients. BMC Genomics 12:526
Byrnes 3rd, Edmond J; Bildfell, Robert J; Frank, Sheryl A et al. (2009) Molecular evidence that the range of the Vancouver Island outbreak of Cryptococcus gattii infection has expanded into the Pacific Northwest in the United States. J Infect Dis 199:1081-6
Lin, Xiaorong; Patel, Sweta; Litvintseva, Anastasia P et al. (2009) Diploids in the Cryptococcus neoformans serotype A population homozygous for the alpha mating type originate via unisexual mating. PLoS Pathog 5:e1000283
Litvintseva, Anastasia P; Mitchell, Thomas G (2009) Most environmental isolates of Cryptococcus neoformans var. grubii (serotype A) are not lethal for mice. Infect Immun 77:3188-95

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