A Link between Virulence and Homeostatic Responses to Hypoxia during Infection by the Human Fungal Pathogen Cryptococcus neoformans
Open accessAbstract
Fungal pathogens of humans require molecular oxygen for several essential biochemical reactions, yet virtually nothing is known about how they adapt to the relatively hypoxic environment of infected tissues. We isolated mutants defective in growth under hypoxic conditions, but normal for growth in normoxic conditions, in Cryptococcus neoformans, the most common cause of fungal meningitis. Two regulatory pathways were identified: one homologous to the mammalian sterol-response element binding protein (SREBP) cholesterol biosynthesis regulatory pathway, and the other a two-component-like pathway involving a fungal-specific hybrid histidine kinase family member, Tco1. We show that cleavage of the SREBP precursor homolog Sre1-which is predicted to release its DNA-binding domain from the membrane-occurs in response to hypoxia, and that Sre1 is required for hypoxic induction of genes encoding for oxygen-dependent enzymes involved in ergosterol synthesis. Importantly, mutants in either the SREBP pathway or the Tco1 pathway display defects in their ability to proliferate in host tissues and to cause disease in infected mice, linking for the first time to our knowledge hypoxic adaptation and pathogenesis by a eukaryotic aerobe. SREBP pathway mutants were found to be a hundred times more sensitive than wild-type to fluconazole, a widely used antifungal agent that inhibits ergosterol synthesis, suggesting that inhibitors of SREBP processing could substantially enhance the potency of current therapies.
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The SREBP pathway mediated by Sre1 and Scp1 in Cryptococcus neoformans is crucial for adaptation to hypoxia and sterol biosynthesis.
“As in fission yeast, the SREBP pathway mediated by Sre1 and Scp1 in C. neoformans was crucial for adaptation to hypoxia and sterol biosynthesis.”
From A Sterol-Regulatory Element Binding Protein Is Required for Cell Polarity, Hypoxia Adaptation, Azole Drug Resistance, and Virulence in Aspergillus fumigatus (2008) · cites this paper as [33]
C. neoformans Sre1/Scp1 mutants failed to proliferate in host tissue, failed to cause fatal meningoencephalitis, and displayed hypersensitivity to the azole class of antifungal drugs.
“these mutants also failed to proliferate in host tissue, failed to cause fatal meningoencephalitis, and displayed hypersensitivity to the azole class of antifungal drugs [32],[33]”
From A Sterol-Regulatory Element Binding Protein Is Required for Cell Polarity, Hypoxia Adaptation, Azole Drug Resistance, and Virulence in Aspergillus fumigatus (2008) · cites this paper as [33]
There is an important link between sterol biosynthesis, hypoxia adaptation, azole drug resistance, and the virulence of pathogenic yeasts.
“Taken together, these observations demonstrate an important link between sterol biosynthesis, hypoxia adaptation, azole drug resistance, and the virulence of pathogenic yeasts.”
From A Sterol-Regulatory Element Binding Protein Is Required for Cell Polarity, Hypoxia Adaptation, Azole Drug Resistance, and Virulence in Aspergillus fumigatus (2008) · cites this paper as [33]
In the yeasts S. pombe and C. neoformans, SREBP homologs are crucial for sterol biosynthesis, survival under hypoxic conditions, resistance to azole antifungal agents, and fungal virulence.
“In the yeasts S. pombe and C. neoformans, SREBP homologs are crucial for sterol biosynthesis, survival under hypoxic conditions, resistance to azole antifungal agents, and fungal virulence [25],[32],[33].”
From A Sterol-Regulatory Element Binding Protein Is Required for Cell Polarity, Hypoxia Adaptation, Azole Drug Resistance, and Virulence in Aspergillus fumigatus (2008) · cites this paper as [33]
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Self-citation
- Authors
- Chun, C. D., Liu, O. W., & Madhani, H. D.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Madhani, Hiten D
- ORCID
- Madhani, Hiten D
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2007-02-23
- Volume
- 3
- Issue
- 2
- Pages
- e22
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC1803011
- OpenAlex
- W1985692664
- Cited by
- 181
- References
- 36
- Citations by year
- 2025: 10 · 2024: 7 · 2023: 9 · 2022: 5 · 2021: 11 · 2020: 9 · 2019: 9 · 2018: 7 · 2017: 7 · 2016: 11 · 2015: 6 · 2014: 14 · 2013: 11 · 2012: 16
- FWCI
- 8.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Funders
- National Science Foundation
- Centers for Disease Control and Prevention
- National Institute of Allergy and Infectious Diseases (R01AI065519)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Keywords
- Cryptococcus neoformans, hypoxia, fungal virulence, SREBP pathway, hybrid histidine kinase, two-component systems, ergosterol biosynthesis, fungal meningitis, host-pathogen interaction, antifungal resistance, oxygen-dependent enzymes
- MeSH terms
- Histidine Kinase, Amino Acid Sequence, Animals, Hypoxia, Antifungal Agents, Cryptococcosis, Cryptococcus neoformans, Disease Models, Animal, Female, Homeostasis, Humans, Mice, Inbred Strains, Molecular Sequence Data, Mutation, Protein Kinases, Virulence, Fluconazole, Gene Expression Regulation, Fungal, Mice, Sterol Regulatory Element Binding Proteins
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