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-γ-producing C. neoformans strain, H99γ, 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 H99γ compared to mice immunized with heat-killed C. neoformans (HKC.n.). Mice immunized with C. neoformans strain H99γ 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-γ, T cell and B cell deficient mice with C. neoformans strain H99γ demonstrated a requirement for Th1-type T cell-mediated immunity, but not B cell-mediated immunity, for the induction of H99γ-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-γ or TNF-α in lungs of protected mice. In conclusion, immunization with C. neoformans strain H99γ 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.
Highlights
Cryptococcus neoformans, the etiological agent of cryptococcosis, is an opportunistic fungal pathogen that typically affects individuals with impaired T cell function [1,2,3,4,5]
These studies suggested that protection against pulmonary cryptococcosis is mediated by Th1-type cytokines such as IFN-c, tumor necrosis factor (TNF)-a, and IL-12 [14,16,17,22,23,50]
The studies described utilize a model system in which an experimental pulmonary infection with C. neoformans strain H99c in mice results in complete protection against an otherwise lethal challenge with wild-type C. neoformans [40,41]. Previous studies and those presented show that C. neoformans strain H99c is not an attenuated strain but instead induces protective host immune responses resulting in its eradication and the induction of protective anti-cryptococcal immunity
Summary
Cryptococcus neoformans, the etiological agent of cryptococcosis, is an opportunistic fungal pathogen that typically affects individuals with impaired T cell function (i.e., individuals with AIDS, lymphoid malignancies, and recipients of immunosuppressive therapies) [1,2,3,4,5]. Vaccination of mice with various protein preparations has been shown to induce partial protection and delayed-type hypersensitivity (DTH) responses against subsequent challenge [26,27,28,29,30,31]. Studies with IFN-c have yielded some promising results as both clinical and experimental studies show that adjunctive therapy in combination with antifungal agents enhances clearance of the organism [17,36,38,39]. These studies have been unable to demonstrate complete protection against subsequent C. neoformans challenge
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