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 IFN-γ are important players in host defense. More recently, Th17 cells and IL-17 have been shown to exert protective functions in systemic T. cruzi infection. However, it remains unclear whether Th17 cells and IL-17A protect against mucosal infection, which is an important cause of human outbreaks. We found that IL-17RA knock-out (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. In vitro macrophage infection assays revealed that protection by Th17 cells is reversed with IL-17A neutralization or loss of macrophage NADPH oxidase activity. Consistent with this, in vivo, 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 in macrophages 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.

中文翻译：

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Th17细胞可提供直接的保护作用，从而限制口胃粘膜克氏锥虫感染后胃寄生虫的负担

克氏锥虫是南美锥虫病的细胞内寄生虫，它是一种以心脏和胃肠道疾病为特征的慢性疾病。保护性免疫需要CD4 + T细胞，而Th1细胞和IFN-γ是宿主防御中的重要角色。最近，Th17细胞和IL-17已显示出在全身性克鲁维丝菌感染中发挥保护功能。但是，尚不清楚Th17细胞和IL-17A是否能抵抗粘膜感染，这是人类暴发的重要原因。我们发现IL-17RA基因敲除（KO）小鼠高度易受口胃部感染，表明该细胞因子在克鲁维氏菌黏膜免疫中具有重要作用。为了研究Th17细胞在黏膜免疫中的特定作用，我们重建了RAG1 KO老鼠与克氏锥虫之前口胃特异性T细胞受体转基因Th17细胞锥虫挑战。我们发现Th17细胞提供了针对胃粘膜T. cruzi感染的保护作用，这表明胃寄生物负担明显降低。体外巨噬细胞感染测定表明，IL-17A中和或巨噬细胞NADPH氧化酶活性丧失可逆转Th17细胞的保护作用。与此相一致，在体内，缺乏功能性NADPH氧化酶的小鼠不受Th17细胞转移的保护。这些数据是Th17细胞针对粘膜T. cruzi的保护的第一个报道。感染，并确定一种新的保护机制，该机制涉及IL-17A诱导巨噬细胞中NADPH氧化酶活性。这些研究为Chagas疫苗的开发提供了重要的见识，并且更广泛地增加了我们对Th17细胞在宿主防御中的不同作用的理解。