Host-induced climate change: Carbon dioxide tolerance as a Cryptococcus neoformans virulence trait

Author: mycolabadmin
8/8/2025
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Summary

When fungi like Cryptococcus neoformans infect humans, they face dramatically higher levels of carbon dioxide in the body compared to the environment. This research shows that the ability to tolerate this higher CO2 is a key virulence factor that helps the fungus cause disease. Scientists discovered that clinical isolates from infected patients are generally better at tolerating CO2 than environmental strains, and this tolerance correlates with how severe infections become.

Background

Environmental fungi like Cryptococcus neoformans must overcome multiple physiological barriers to cause disease in mammals, including elevated body temperature and dramatically different CO2 concentrations. While temperature tolerance is well-established as a virulence trait, recent studies indicate other factors contribute to pathogenic variation. The mammalian host environment contains approximately 100-fold higher CO2 concentrations (~5%) compared to ambient air (0.04%), representing a significant potential stress.

Objective

To investigate whether CO2 tolerance represents a significant virulence trait in C. neoformans and to elucidate the physiological and genetic mechanisms underlying adaptation to host CO2 concentrations. The study aimed to determine the relationship between CO2 tolerance and virulence across different C. neoformans clades.

Results

Clinical isolates demonstrated greater CO2 tolerance than environmental strains, with CO2-intolerant strains showing reduced virulence. CO2 stress induces remodeling of phospholipid asymmetry and affects membrane homeostasis. Three pathways (TOR, RAM, and calcineurin) positively regulate CO2 tolerance while three others (CWI, Rim101, and PKA) negatively regulate it. CO2-tolerant and -intolerant strains were found distributed across all C. neoformans clades, suggesting multiple independent origins of this trait.

Conclusion

CO2 tolerance is a quantitative virulence trait in C. neoformans with multiple genetic loci contributing to differential phenotypes. Host CO2 exerts strong selective pressure during infection in both mice and humans. The finding that CO2-intolerant strains evolve CO2 tolerance during infection and that loss-of-function mutations in AVC1 appear in relapsed cryptococcosis cases supports CO2 tolerance as a clinically relevant virulence factor.

Published in:PLoS Pathogens,
Study Type:Review,
Source: PMID: 40779504; DOI: 10.1371/journal.ppat.1013351