CNLAC1 Is Required for Extrapulmonary Dissemination of Cryptococcus neoformans but Not Pulmonary Persistence

Noverr, Mairi C.; Williamson, Peter R.; Fajardo, Ryan S.; Huffnagle, Gary B.

doi:10.1128/iai.72.3.1693-1699.2004

Cited by 112Fungal Infections and StudiesAntifungal resistance and susceptibilityNail Diseases and Treatments

CNLAC1 Is Required for Extrapulmonary Dissemination of Cryptococcus neoformans but Not Pulmonary Persistence

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Noverr, Mairi C., Williamson, Peter R., Fajardo, Ryan S., Huffnagle, Gary B.·2004·Infection and Immunity

DOI 10.1128/iai.72.3.1693-1699.2004PMC PMC356011

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Abstract

The pathogenic yeast Cryptococcus neoformans produces a laccase enzyme ( CNLAC1 ), which catalyzes the synthesis of melanin in the presence of phenolic compounds. A number of genes have been implicated in the regulation of laccase and melanization, including IPC1 , GPA1 , MET3 , and STE12 . Albino mutants derived from random mutagenesis techniques may contain mutations in genes that regulate multiple virulence factors, including CNLAC1 . The goal of our study is to investigate the role of CNLAC1 in virulence and evasion of pulmonary host defenses after infection via the respiratory tract. Using a set of congenic laccase-positive (2E-TUC-4) and laccase-deficient (2E-TU-4) strains, we found that both strains are avirulent at a lower dose (10 4 CFU/mouse) in mice. After the infectious dose was increased to 10 6 CFU/mouse, 70% mortality was observed in mice infected with 2E-TUC-4 compared to no mortality in mice infected with 2E-TU-4 at day 30 postinfection. This observation confirms the requirement for CNLAC1 in virulence. Interestingly, we observed no differences between the two strains in pulmonary growth or in elicitation of cellular immune responses in the lung. The only measurable defect of 2E-TU-4 was in dissemination to extrapulmonary sites. To examine the role of CNLAC1 in dissemination, mice were infected intravenously. By week 3 postinfection, equal numbers of strains 2E-TUC-4 and 2E-TU-4 were recovered from the brain and spleen. This observation indicates that CNLAC1 facilitates escape from the lung, but not growth in the lungs or brain, and suggests a novel role for CNLAC1 in virulence during an infection aquired via the respiratory tract.

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Laccase-deficient mutants display attenuated pulmonary dissemination in vivo.
“and laccase-deficient mutants display attenuated pulmonary dissemination in vivo67.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [67]

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Authors: Noverr, M. C., Williamson, P. R., Fajardo, R. S., & Huffnagle, G. B.
Affiliations: University of Michigan (US)
University of Illinois Chicago (US)
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine
ORCID: Noverr, Mairi C.
Williamson, Peter R.
Fajardo, Ryan S.
Huffnagle, Gary B.
Venue: Infection and Immunity
Publisher: American Society for Microbiology
Published: 2004-03
Volume: 72
Issue: 3
Pages: 1693-1699
ISSN: 0019-9567 (ISSN-L)
1098-5522
DOI: 10.1128/iai.72.3.1693-1699.2004
PMC: PMC356011
OpenAlex: W2152040152
Cited by: 112
References: 43
Citations by year: 2026: 4 · 2025: 4 · 2024: 4 · 2022: 4 · 2021: 5 · 2020: 3 · 2019: 7 · 2018: 5 · 2017: 4 · 2015: 7 · 2014: 9 · 2013: 4 · 2012: 6
FWCI: 5.27
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Infection and Immunity (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Heart, Lung, and Blood Institute (R01-HL65912, R01HL065912, R01HL063670, R01-HL63670, T32HL007749)
National Institute of Allergy and Infectious Diseases (T32AI07528, R01AI045995, T32AI007528)
Topics: Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Health Sciences › Medicine › Epidemiology › Nail Diseases and Treatments
Keywords: Cryptococcus neoformans, laccase, melanogenesis, virulence, extrapulmonary dissemination, host immune evasion, albino mutants, respiratory infections, cell-mediated immunity
MeSH terms: Animals, Cryptococcosis, Cryptococcus neoformans, Female, Genes, Fungal, Immunity, Cellular, Lung, Lung Diseases, Fungal, Mice, Inbred CBA, Mutation, Virulence, Laccase, Mice

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CNLAC1 Is Required for Extrapulmonary Dissemination of Cryptococcus neoformans but Not Pulmonary Persistence

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