Laccase of Cryptococcus neoformans Is a Cell Wall-Associated Virulence Factor
Open accessAbstract
Virulence is the outcome of an interaction between the host and a microbe and is characterized by a large array of opposing reactions operating at the host-pathogen interface. Cryptococcus neoformans is an important opportunistic pathogen in immunocompromised patients, including those with human immunodeficiency virus, and expresses a virulence-associated laccase which is believed to oxidize brain catecholamines and iron as a defense against host immune cells. In the present report, we investigated the cellular location of laccase to understand more fully how it contributes to cryptococcal virulence. A monoclonal antibody to the C. neoformans laccase was generated and used to show localization in the cell walls of representative serotype A (H99) and serotype D (B-3501) strains by immunoelectron microscopy. In addition, confocal microscopy was used to show a peripheral location of green fluorescent protein-tagged laccase expressed in live H99 cells. Biochemical studies showed that laccase could be released from intact cells or cell wall fractions with glucanase enzymes but was retained in the cell wall after sequential extraction with 1 M NaCl, 6 M urea, and 1% sodium dodecyl sulfate. The presence of a hydrolyzable bond linking laccase to the cell wall was suggested by removal of laccase from cell wall preparations after they were boiled in 1% sodium dodecyl sulfate, as was the presence of a disulfide or thioester bond by removal with dithiothreitol or β-mercaptoethanol. These data show that laccase is present as a tightly associated cell wall enzyme that is readily accessible for interactions with host immune cells.
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Genes involved in β-1,6-glucan synthesis, melanin production, chitin synthesis and chitosan synthesis are cell wall-related genes whose deletion reduces virulence.
“This includes genes involved in the synthesis of β-1,6-glucan (such as KRE5, KRE6 and SKN1)61, the protective pigment melanin (such as the laccase gene LAC1)62, chitin in the cell wall (including the chitin synthase gene CHS3 and the regulator protein gene CSR2)63 and chitosan (exemplified by the chitin deacetylase genes CDA1, CDA2 and CDA3)64,65.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [62]
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References 39 · Cited by 188
- Authors
- Zhu, X., Gibbons, J., Garcia-Rivera, J., Casadevall, A., & Williamson, P. R.
- Affiliations
- University of Illinois Chicago (US)
- <!--label omitted: 3-->Department of Microbiology and Immunology3 and
- Albert Einstein College of Medicine (US)
- Venue
- Infection and Immunity
- Publisher
- American Society for Microbiology
- Published
- 2001-09
- Volume
- 69
- Issue
- 9
- Pages
- 5589-5596
- ISSN
- 0019-9567 (ISSN-L)
- 1098-5522
- PMC
- PMC98673
- OpenAlex
- W2158040399
- Cited by
- 188
- References
- 39
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 4 · 2023: 2 · 2022: 5 · 2021: 7 · 2020: 10 · 2019: 8 · 2018: 5 · 2017: 4 · 2016: 4 · 2015: 11 · 2014: 11 · 2013: 6 · 2012: 5
- FWCI
- 5.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Infection and Immunity (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Lung Association
- National Institutes of Health (5r29ai038258-05, 5r01hl059842-23, AI3342)
- National Heart, Lung, and Blood Institute (HL 59842, R01-HL059842)
- National Institute of Allergy and Infectious Diseases (T32 AI-07501, AI38258, AI 3342, R01AI045995, AI45995, AI33774, T32AI007501, R01AI033774)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Keywords
- laccase, Cryptococcus neoformans, cell wall-associated enzymes, fungal virulence, cell wall localization, host-pathogen interaction, opportunistic fungal infection, disulfide bonds, thioester bond, monoclonal antibodies, immunocompromised patients
- MeSH terms
- Animals, Antibodies, Monoclonal, Cell Wall, Cryptococcus neoformans, Hybridomas, Immunization, Luminescent Proteins, Male, Mice, Inbred BALB C, Oxidoreductases, Recombinant Fusion Proteins, Virulence, Blotting, Western, Microscopy, Immunoelectron, Microscopy, Confocal, Laccase, Green Fluorescent Proteins, Mice
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