Unraveling the genetic determinants of virulence in Cryptococcus neoformans

Abstract

Cryptococcus neoformans is a fungal pathogen that causes meningitis, primarily in patients who are immunocompromised. It is most common in populations with advanced HIV disease in low- and middle-income countries, especially in sub–Saharan Africa, South America, and southeast Asia. Even with improvements in treatments, the mortality rate remains unacceptably high. Mortality is associated with both host and pathogen specific factors, including C. neoformans genetic background. C. neoformans has three major lineages: VNI, VNII, and VNB. VNI and VNII are both clonal and globally distributed, with the vast majority of disease caused by VNI. VNB is highly diverse and regional; disease caused by VNB isolates tends to be associated with worse outcomes. Isolates are further divided into sequence types (STs), based on an accepted multi-locus sequence typing scheme. In the last decade, several studies have linked ST to patient outcome, with some STs found to be more virulent than others. When genetically matched mice were infected with patient isolates, mortality was significantly associated with patient mortality, showing that isolate genetic background is important for strain specific mortality. The reasons for the link between patient outcome and isolate genetic background remain unclear. This thesis aims to identify mutations and genes associated with changes in virulence in both patients and mice, understand the evolutionary patterns of virulence-related mutations, and explain the mouse immune response associated with a hypervirulent disease manifestation.