Microevolution of Cryptococcus neoformans in high CO 2 converges on mutations isolated from patients with relapsed cryptococcosis

Benjamin J Chadwick; Laura C Ristow; Emma E Blackburn; Xiaofeng Xie; Damian J Krysan; Xiaorong Lin

doi:10.1016/j.celrep.2025.115349

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Microevolution of Cryptococcus neoformans in high CO 2 converges on mutations isolated from patients with relapsed cryptococcosis

Journal article

Open access

Peer reviewed

Microevolution of Cryptococcus neoformans in high CO 2 converges on mutations isolated from patients with relapsed cryptococcosis

Benjamin J Chadwick, Laura C Ristow, Emma E Blackburn, Xiaofeng Xie, Damian J Krysan and Xiaorong Lin

Cell reports (Cambridge), Vol.44(3), 115349

02/24/2025

DOI: 10.1016/j.celrep.2025.115349

PMCID: PMC12911315

PMID: 39998950

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Abstract

Cryptococcus neoformans is an environmental fungus that causes an estimated 180,000 deaths annually and transitions from the external environment to the host environment to cause disease. CO concentrations in the atmosphere (0.04%) are dramatically lower than in mammalian tissues (5%). Environmental C. neoformans strains that cannot tolerate 5% CO are less virulent than CO -tolerant strains. Microevolution at elevated CO generates loss-of-function mutations in the nucleotide binding protein Avc1 that confer CO tolerance to CO -intolerant strains. Mechanistically, Avc1 positively regulates the expression of plasma membrane transporters, including PDR9, a phospholipid floppase that negatively modulates CO fitness. Deletion of AVC1 in five CO -intolerant environmental strains increases competitive fitness in host CO and in a mouse infection model. Importantly, strains with similar AVC1 mutations emerge in patients with relapsed cryptococcosis. Therefore, this microevolutionary convergence strongly suggests that adaptation to host CO is a significant driver of C. neoformans fitness during infection.

host adaptation

Cryptococcus neoformans

cryptococcal meningitis

fungal virulence traits

CP: Microbiology

microevolution

fungal pathogenesis

Details

Title: Subtitle: Microevolution of Cryptococcus neoformans in high CO 2 converges on mutations isolated from patients with relapsed cryptococcosis
Creators: Benjamin J Chadwick - University of Georgia
Laura C Ristow - University of Iowa
Emma E Blackburn - University of Georgia
Xiaofeng Xie - University of Georgia
Damian J Krysan - University of Iowa
Xiaorong Lin - University of Georgia
Resource Type: Journal article
Publication Details: Cell reports (Cambridge), Vol.44(3), 115349
DOI: 10.1016/j.celrep.2025.115349
PMID: 39998950
PMCID: PMC12911315
NLM abbreviation: Cell Rep
ISSN: 2639-1856
eISSN: 2211-1247
Publisher: CELL PRESS
Grant note: National Institutes of Health: R01AI147541 University of Georgia Gene E. Michaels Fund
This work was supported by National Institutes of Health (R01AI147541 to D.J.K. and X.L.) and the University of Georgia Gene E. Michaels Fund (to X.L.). The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication. We thank all Lin labmembers and the UGA fungal group for helpful suggestions, Nhu Pham and Ran Shi for assistance with the mouse infection model, and Dr. James Fraser for the gifts of plasmid pKLO2 and the AVC1mutant strain along with corresponding complemented strains.
Language: English
Date published: 02/24/2025
Academic Unit: Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984793978402771

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