Th17 Cells Provide Mucosal Protection against Gastric Trypanosoma cruzi Infection

Trypanosoma cruzi is the intracellular parasite of Chagas disease, a chronic condition characterized by cardiac and gastrointestinal morbidity. Protective immunity requires CD4 T cells, and Th1 cells and gamma interferon (IFN-γ) are important players in host defense. More recently, Th17 cells and in...

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Bibliographic Details
Published in:Infection and immunity 2021-06, Vol.89 (7), p.e0073820-e0073820
Main Authors: Cai, Catherine W, Eickhoff, Christopher S, Meza, Krystal A, Blase, Jennifer R, Audette, Rebecca E, Chan, David H, Bockerstett, Kevin A, DiPaolo, Richard J, Hoft, Daniel F
Format: Article
Language:English
Subjects:
Animals
Chagas Disease - immunology
Chagas Disease - metabolism
Chagas Disease - parasitology
Disease Models, Animal
Fungal and Parasitic Infections
Gastric Mucosa - immunology
Gastric Mucosa - parasitology
Host-Parasite Interactions - immunology
Immunity, Mucosal
Interleukin-17 - genetics
Interleukin-17 - metabolism
Lymphocyte Activation - immunology
Macrophages - immunology
Macrophages - metabolism
Macrophages - parasitology
Mice
Mice, Knockout
NADPH Oxidases - metabolism
Spotlight
Th17 Cells - immunology
Th17 Cells - metabolism
Trypanosoma cruzi - immunology
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Summary:Trypanosoma cruzi is the intracellular parasite of Chagas disease, a chronic condition characterized by cardiac and gastrointestinal morbidity. Protective immunity requires CD4 T cells, and Th1 cells and gamma interferon (IFN-γ) are important players in host defense. More recently, Th17 cells and interleukin 17A (IL-17A) have been shown to exert protective functions in systemic T. cruzi infection. However, it remains unclear whether Th17 cells and IL-17A protect in the mucosa, the initial site of parasite invasion in many human cases. We found that IL-17RA knockout (KO) mice are highly susceptible to orogastric infection, indicating an important function for this cytokine in mucosal immunity to T. cruzi. To investigate the specific role of Th17 cells for mucosal immunity, we reconstituted RAG1 KO mice with T. cruzi specific T cell receptor transgenic Th17 cells prior to orogastric T. cruzi challenges. We found that Th17 cells provided protection against gastric mucosal T. cruzi infection, indicated by significantly lower stomach parasite burdens. macrophage infection assays revealed that protection by Th17 cells is reduced with IL-17A neutralization or reversed by loss of macrophage NADPH oxidase activity. Consistently with this, mice lacking functional NADPH oxidase were not protected by Th17 cell transfer. These data are the first report that Th17 cells protect against mucosal T. cruzi infection and identify a novel protective mechanism involving the induction of NADPH oxidase activity by IL-17A. These studies provide important insights for Chagas vaccine development and, more broadly, increase our understanding of the diverse roles of Th17 cells in host defense.
ISSN:0019-9567
1098-5522
DOI:10.1128/IAI.00738-20