Discovery of CO2 tolerance genes associated with virulence in the fungal pathogen Cryptococcus neoformans

Cryptococcus neoformans is a ubiquitous soil fungus and airborne pathogen that causes over 180,000 deaths each year. Cryptococcus must adapt to host CO2 levels to cause disease, but the genetic basis for this adaptation is unknown. We utilized quantitative trait loci 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, we applied fine mapping through bulk segregant analysis of near-isogenic progeny with distinct tolerance levels to CO2. We found that virulence among near-isogenic strains in a murine model of cryptococcosis correlated with CO2 tolerance. Moreover, we discovered that sensitive strains may adapt in vivo to become more CO2 tolerant and more virulent. These findings highlight the underappreciated role of CO2 tolerance and its importance in the ability of an opportunistic environmental pathogen to cause disease. Quantitative trait loci mapping reveals that tolerance to host CO2 is critical for virulence of the human fungal pathogen Cryptococcus neoformans.