title: Insights into the mechanisms of protective immunity against Cryptococcus neoformans infection using a mouse model of pulmonary cryptococcosis.
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.
authors.affiliation: Department of Biology, The University of Texas at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Wozniak
authors.forename: Sailatha
authors.initials: S
authors.lastname: Ravi
authors.forename: Sandra
authors.initials: S
authors.lastname: Macias
authors.forename: Mattie L
authors.initials: ML
authors.lastname: Young
authors.forename: Michal A
authors.initials: MA
authors.lastname: Olszewski
authors.forename: Chad
authors.initials: C
authors.lastname: Steele
authors.forename: Floyd L
authors.initials: FL
authors.lastname: Wormley
mesh_terms: D000818:Animals; D000908:Antibodies, Fungal / Q000276:immunology; D003453:Cryptococcosis / Q000276:immunology* / Q000382:microbiology*; D003455:Cryptococcus neoformans / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007111:Immunity, Cellular / Q000276:immunology; D007962:Leukocytes / Q000276:immunology; D008168:Lung / Q000276:immunology; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology
chemical_list: D000908:Antibodies, Fungal; D016207:Cytokines