Journal article
Cryptococcus neoformans adapts to host CO2 concentrations via metabolic and stress-response remodeling
PLoS biology, Vol.24(5), e3003561
05/05/2026
DOI: 10.1371/journal.pbio.3003561
PMID: 42085498
Abstract
Cryptococcus neoformans is an environmental pathogen that remodels its cellular physiology to survive within mammals and, in susceptible hosts, cause life-threatening meningoencephalitis. Of the many distinctions between the external environment and mammalian tissues, CO2 concentration in the host is two orders of magnitude higher than in the environment and represents a critical stress for C. neoformans. C. neoformans strains that do not replicate at host CO2 concentrations are less virulent in mouse models of infection, further supporting CO2 tolerance as a virulence trait. To further understand the genetic determinants of C. neoformans CO2 tolerance, we performed a near genome-wide screen for deletion mutants with altered CO2 fitness using a competitive growth assay. A total of 301 of 4,692 deletion mutants showed altered CO2 tolerance (245 reduced fitness; 56 increased fitness) demonstrating the global effect of host CO2 on C. neoformans physiology. Based on this data set as well as a metabolomic analysis of C. neoformans adaptation to host CO2, we show that remodeling of central carbon metabolism, oxidative stress buffering, and membrane homeostasis represent an integrated response to CO2 stress that is mediated in part by the TOR-Ypk1 signaling axis. We propose that CO2-induced capsule formation leads to reduced cellular glucose which, in turn, triggers remodeling of central carbon metabolism toward utilization of alternative carbon sources and increased mitochondrial respiration/reactive oxygen generation. Thus, these data provide a near genome-wide profile of the genetic determinants of C. neoformans CO2 tolerance as well as a model for how this important environmental human fungal pathogen alters its physiology to proliferate in the host.
Details
- Title: Subtitle
- Cryptococcus neoformans adapts to host CO2 concentrations via metabolic and stress-response remodeling
- Creators
- Laura C. Ristow - University of IowaEmma E. Blackburn - University of GeorgiaAndrew J. Jezewski - University of IowaXiaorong Lin - University of GeorgiaDamian J. Krysan - University of Iowa
- Resource Type
- Journal article
- Publication Details
- PLoS biology, Vol.24(5), e3003561
- DOI
- 10.1371/journal.pbio.3003561
- PMID
- 42085498
- ISSN
- 1544-9173
- eISSN
- 1545-7885
- Publisher
- Public Library Science
- Number of pages
- 26
- Grant note
- R01AI147541 / National Institute of Allergy and Infectious Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) N/A / The University of Georgia Gene Michaels Fund
- Language
- English
- Date published
- 05/05/2026
- Academic Unit
- Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9985161341102771
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