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.