Vaccine-induced protection against 3 systemic mycoses endemic to North America requires Th17 cells in mice
Marcel Wüthrich, Benjamin Gern, Chiung Yu Hung, Karen Ersland, Nicole Rocco, John Pick-Jacobs, Kevin Galles, Hanna Filutowicz, Thomas Warner, Michael Evans, Garry Cole, Bruce Klein
Marcel Wüthrich, Benjamin Gern, Chiung Yu Hung, Karen Ersland, Nicole Rocco, John Pick-Jacobs, Kevin Galles, Hanna Filutowicz, Thomas Warner, Michael Evans, Garry Cole, Bruce Klein
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Research Article

Vaccine-induced protection against 3 systemic mycoses endemic to North America requires Th17 cells in mice

Abstract

Worldwide rates of systemic fungal infections, including three of the major pathogens responsible for such infections in North America (Coccidioides posadasii, Histoplasma capsulatum, and Blastomyces dermatitidis), have soared recently, spurring interest in developing vaccines. The development of Th1 cells is believed to be crucial for protective immunity against pathogenic fungi, whereas the role of Th17 cells is vigorously debated. In models of primary fungal infection, some studies have shown that Th17 cells mediate resistance, while others have shown that they promote disease pathology. Here, we have shown that Th1 immunity is dispensable and that fungus-specific Th17 cells are sufficient for vaccine-induced protection against lethal pulmonary infection with B. dermatitidis in mice. Further, vaccine-induced Th17 cells were necessary and sufficient to protect against the three major systemic mycoses in North America. Mechanistically, Th17 cells engendered protection by recruiting and activating neutrophils and macrophages to the alveolar space, while the induction of Th17 cells and acquisition of vaccine immunity unexpectedly required the adapter molecule Myd88 but not the fungal pathogen recognition receptor Dectin-1. These data suggest that human vaccines against systemic fungal infections should be designed to induce Th17 cells if they are to be effective.

Authors

Marcel Wüthrich, Benjamin Gern, Chiung Yu Hung, Karen Ersland, Nicole Rocco, John Pick-Jacobs, Kevin Galles, Hanna Filutowicz, Thomas Warner, Michael Evans, Garry Cole, Bruce Klein

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Figure 2

IL-17 mediates vaccine immunity against B. dermatitidis infection.

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IL-17 mediates vaccine immunity against B. dermatitidis infection. (...
(A) Antibody neutralization of IL-17 in vaccinated mice after infection. Lung CFU are the mean ± SEM (n = 10–12). Numbers shown are the relative increase in lung CFU of mAb-treated versus rat IgG controls. *P < 0.001 versus vaccinated mice treated with rat IgG. (B) Neutralization of IL-17 by soluble IL-17 receptor (IL-17R:Fc). Values are the mean ± SEM (n = 10–18); representative of 2 experiments. Numbers shown are the fold increase in lung CFU versus AdLuc-treated controls. *P < 0.001 versus vaccinated mice not treated with adenovirus; **P < 0.001 versus vaccinated mice treated with AdLuc. (C) Lung transcripts and number of primed Th1 and Th17 cells recruited to the lung upon fungal challenge in Il17a–/– and Il17ra–/– mice. RNA from lung (middle panel) and the absolute number of IL-17–, IFN-γ–, or IL-13–producing CD4+CD44+ T cells were quantified by real-time PCR and FACS. Data are mean ± SEM (n = 4–6); representative of 2 experiments. *P < 0.05 versus unvaccinated controls; **P < 0.05 versus vaccinated wild-type and Il17ra–/– mice (D) IL-17RA is required for vaccine immunity. Mean ± SEM (n = 8–12); representative of 2 experiments. *P < 0.001 versus vaccinated wild-type. (E) IL-17A is required for vaccine immunity. Lung CFU are the mean ± SEM (n = 10–12); representative of 2 experiments. Numbers shown in D and E are the fold increase in CFU versus corresponding wild-type controls. *P < 0.001 versus wild-type mice.