QTL Mapping and Bulk Segregant Analysis identifies CO2 tolerance genes associated with virulence in the global pathogen Cryptococcus neoformans

ABSTRACT: Cryptococcus neoformans is a ubiquitous free-living soil yeast and opportunistic pathogen that causes ~223,100 cases of cryptococcal meningitis per year, killing over 180,000 people. The pathogenicity of C. neoformans relies on its adaptation to the host conditions. An important difference between its natural environment and the mammalian host is the concentration of CO2. CO2 levels in the host fluctuate around 5%, which is ~125-fold higher than in ambient air. We recently found that while clinical isolates are tolerant to host levels ofCO2, many environmental isolates are CO2-sensitive and virulence-attenuated in animal models. The genetic basis responsible for cryptococcal adaptation to high levels of CO2 is unknown. Here, we utilized quantitative trait loci (QTL) mapping with 374 progeny from a cross between a CO2-tolerant clinical isolate and a CO2-sensitive environmental isolate to identify genetic regions regulating CO2 tolerance. To identify specific quantitative trait genes (QTGs), we applied fine mapping through backcrossing and bulk segregant analysis coupled with pooled genome sequencing of near-isogenic progeny but with distinct tolerance levels to CO2. The roles of the identified QTGs in CO2 tolerance were verified by targeted gene deletion. We further demonstrated that virulence levels among near-isogenic strains in a murine model of cryptococcosis correlate with their levels of CO2 tolerance. Moreover, we discovered that sensitive strains may adapt in vivo to become more tolerant to increased CO2 levels and more virulent. These findings highlight the underappreciated role of the host CO2 tolerance and its importance in the ability of an opportunistic environmental pathogen to cause disease.

ORGANISM(S): Cryptococcus neoformans

PROVIDER: GSE260932 | GEO | 2024/08/09

REPOSITORIES: GEO