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: Karen L Wozniak, Sailatha Ravi, Sandra Macias, Mattie L Young, Michal A Olszewski, Chad Steele, Floyd L Wormley
• Journal: PloS one (PLoS One) Vol. 4 Issue 9 Pg. e6854 (Sep 03 2009) ISSN: 1932-6203 [Electronic] United States
• PMID: 19727388 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibodies, Fungal
• Cytokines

Topics

• Animals
• Antibodies, Fungal (immunology)
• Cryptococcosis (immunology, microbiology)
• Cryptococcus neoformans (metabolism)
• Cytokines (metabolism)
• Disease Models, Animal
• Female
• Immunity, Cellular (immunology)
• Leukocytes (immunology)
• Lung (immunology)
• Lung Diseases, Fungal (immunology, microbiology)
• Mice
• Mice, Inbred BALB C
• T-Lymphocytes (immunology)
• Th1 Cells (cytology, immunology)