Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence

Ci Fu; Sarah R Beattie; Andrew J Jezewski; Nicole Robbins; Luke Whitesell; Damian J Krysan; Leah E Cowen

doi:10.1093/genetics/iyab164

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Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence

Journal article

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Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence

Ci Fu, Sarah R Beattie, Andrew J Jezewski, Nicole Robbins, Luke Whitesell, Damian J Krysan and Leah E Cowen

Genetics (Austin), Vol.220(1), iyab164

01/04/2022

DOI: 10.1093/genetics/iyab164

PMCID: PMC8733452

PMID: 34849848

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Abstract

The opportunistic human fungal pathogen Cryptococcus neoformans has tremendous impact on global health, causing 181,000 deaths annually. Current treatment options are limited, and the frequent development of drug resistance exacerbates the challenge of managing invasive cryptococcal infections. In diverse fungal pathogens, the essential molecular chaperone Hsp90 governs fungal survival, drug resistance, and virulence. Therefore, targeting this chaperone has emerged as a promising approach to combat fungal infections. However, the role of Hsp90 in supporting C. neoformans pathogenesis remains largely elusive due to a lack of genetic characterization. To help dissect the functions of Hsp90 in C. neoformans, we generated a conditional expression strain in which HSP90 is under control of the copper-repressible promoter CTR4-2. Addition of copper to culture medium depleted Hsp90 transcript and protein levels in this strain, resulting in compromised fungal growth at host temperature; increased sensitivity to stressors, including the azole class of antifungals; altered C. neoformans morphology; and impaired melanin production. Finally, leveraging the fact that copper concentrations vary widely in different mouse tissues, we demonstrated attenuated virulence for the CTR4-2p-HSP90 mutant specifically in an inhalation model of Cryptococcus infection. During invasion and establishment of infection in this mouse model, the pathogen is exposed to the relatively high copper concentrations found in the lung as compared to blood. Overall, this work generates a tractable genetic system to study the role of Hsp90 in supporting the pathogenicity of C. neoformans and provides proof-of-principle that targeting Hsp90 holds great promise as a strategy to control cryptococcal infection.

Cryptococcus neoformans

Details

Title: Subtitle: Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence
Creators: Ci Fu - University of Toronto
Sarah R Beattie - University of Iowa
Andrew J Jezewski - University of Iowa
Nicole Robbins - University of Toronto
Luke Whitesell - University of Toronto
Damian J Krysan - Roy J. and Lucille A. Carver College of Medicine
Leah E Cowen - University of Toronto
Resource Type: Journal article
Publication Details: Genetics (Austin), Vol.220(1), iyab164
DOI: 10.1093/genetics/iyab164
PMID: 34849848
PMCID: PMC8733452
NLM abbreviation: Genetics
ISSN: 0016-6731
eISSN: 1943-2631
Grant note: T32 AI007511 / NIAID NIH HHS R01 AI120958 / NIAID NIH HHS FDN-154288 / CIHR T32 AI007260 / NIAID NIH HHS F32 AI145160 / NIAID NIH HHS R01 AI147541 / NIAID NIH HHS
Language: English
Date published: 01/04/2022
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984297424702771

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