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Cited by 99Fungal Infections and StudiesAntifungal resistance and susceptibilityImmune responses and vaccinations

Insights into the Mechanisms of Protective Immunity against Cryptococcus neoformans Infection Using a Mouse Model of Pulmonary Cryptococcosis

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Wozniak, Karen L., Ravi, Sailatha, Macias, Sandra, Young, Mattie L., Olszewski, Michal A., Steele, Chad, Wormley, Floyd L.·2009·PLoS ONE
DOI 10.1371/journal.pone.0006854PMC PMC2731172
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Abstract

Cryptococcus neoformans is an opportunistic fungal pathogen that causes life-threatening pneumonia and meningoencephalitis in immune compromised individuals. Previous studies have shown that immunization of BALB/c mice with an IFN-gamma-producing C. neoformans strain, H99gamma, results in complete protection against a second pulmonary challenge with an otherwise lethal cryptococcal strain. The current study evaluated local anamnestic cell-mediated immune responses against pulmonary cryptococcosis in mice immunized with C. neoformans strain H99gamma compared to mice immunized with heat-killed C. neoformans (HKC.n.). Mice immunized with C. neoformans strain H99gamma had significantly reduced pulmonary fungal burden post-secondary challenge compared to mice immunized with HKC.n. Protection against pulmonary cryptococcosis was associated with increased pulmonary granulomatous formation and leukocyte infiltration followed by a rapid resolution of pulmonary inflammation, which protected the lungs from severe allergic bronchopulmonary mycosis (ABPM)-pathology that developed in the lungs of mice immunized with HKC.n. Pulmonary challenge of interleukin (IL)-4 receptor, IL-12p40, IL-12p35, IFN-gamma, T cell and B cell deficient mice with C. neoformans strain H99gamma demonstrated a requirement for Th1-type T cell-mediated immunity, but not B cell-mediated immunity, for the induction of H99gamma-mediated protective immune responses against pulmonary C. neoformans infection. CD4(+) T cells, CD11c(+) cells, and Gr-1(+) cells were increased in both proportion and absolute number in protected mice. In addition, significantly increased production of Th1-type/pro-inflammatory cytokines and chemokines, and conversely, reduced Th2-type cytokine production was observed in the lungs of protected mice. Interestingly, protection was not associated with increased production of cytokines IFN-gamma or TNF-alpha in lungs of protected mice. In conclusion, immunization with C. neoformans strain H99gamma results in the development of protective anti-cryptococcal immune responses that may be measured and subsequently used in the development of immune-based therapies to combat pulmonary cryptococcosis.

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  • Studies in animal models have emphasized the importance of CD4+ T cell-mediated immunity, particularly T helper 1 cells, in protection against cryptococcosis.

    “Studies in animal models have emphasized the importance of CD4+ T cell-mediated immunity (particularly T helper 1 cells) in protection against cryptococcosis120,121.”

    From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [120]

  • This immune response is mediated by production of cytokines including IL-2, IL-12, TNF and IFNγ, which recruit phagocytes that help to clear the infection.

    “This immune response is mediated by the production of cytokines, including interleukin-2 (IL-2), IL-12, tumour necrosis factor (TNF) and interferon-γ (IFNγ), which in turn recruit phagocytes that help to clear the infection120,122.”

    From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [120]

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Authors
Wozniak, K. L., Ravi, S., Macias, S., Young, M. L., Olszewski, M. A., Steele, C., & Wormley, F. L.
Affiliations
  • The University of Texas at San Antonio (US)
  • VA Ann Arbor Healthcare System (US)
  • University of Alabama at Birmingham (US)
Corresponding author
Wormley, Floyd L.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2009-09-03
Volume
4
Issue
9
Pages
e6854
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0006854
PMC
PMC2731172
OpenAlex
W2076677132
Cited by
99
References
70
Citations by year
2026: 3 · 2025: 2 · 2024: 4 · 2023: 4 · 2022: 7 · 2021: 8 · 2020: 5 · 2019: 6 · 2018: 11 · 2017: 6 · 2016: 8 · 2015: 4 · 2014: 8 · 2013: 6 · 2012: 6
FWCI
3.82
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Veterans Affairs
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL080317, HL080317)
  • National Institute of Allergy and Infectious Diseases (R01AI071752, RO1AI071752)
Topics
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Keywords
Cryptococcus neoformans, pulmonary cryptococcosis, protective immunity, Th1 response, granulomatous inflammation, allergic bronchopulmonary mycosis, cytokine and chemokine production, Th2 cytokines, CD4+ T cells, CD11c+ cells, Gr-1+ cells, meningoencephalitis
MeSH terms
Animals, Antibodies, Fungal, Cryptococcosis, Cryptococcus neoformans, Disease Models, Animal, Female, Immunity, Cellular, Leukocytes, Lung, Lung Diseases, Fungal, Mice, Inbred BALB C, T-Lymphocytes, Cytokines, Th1 Cells, Mice

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