Intestinal dysmotility syndromes have been epidemiologically associated with several antecedent bacterial and viral infections. To model this phenotype, we previously infected mice with the neurotropic flavivirus West Nile virus (WNV) and demonstrated intestinal transit defects. Here, we found that within 1 week of WNV infection, enteric neurons and glia became damaged, resulting in sustained reductions of neuronal cells and their networks of connecting fibers. Using cell-depleting antibodies, adoptive transfer experiments, and mice lacking specific immune cells or immune functions, we show that infiltrating WNV-specific CD4⁺ and CD8⁺ T cells damaged the enteric nervous system (ENS) and glia, which led to intestinal dysmotility; these T cells used multiple and redundant effector molecules including perforin and Fas ligand. In comparison, WNV-triggered ENS injury and intestinal dysmotility appeared to not require infiltrating monocytes, and damage may have been limited by resident muscularis macrophages. Overall, our experiments support a model in which antigen-specific T cell subsets and their effector molecules responding to WNV infection direct immune pathology against enteric neurons and supporting glia that results in intestinal dysmotility.

中文翻译：

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西尼罗河病毒通过 T 细胞介导的肠道神经系统损伤引发肠道运动障碍


肠动力障碍综合征在流行病学上与几种先前的细菌和病毒感染有关。为了模拟这种表型，我们之前用嗜神经性黄病毒西尼罗河病毒 （WNV） 感染小鼠，并证明了肠道转运缺陷。在这里，我们发现在 WNV 感染后 1 周内，肠道神经元和神经胶质细胞受损，导致神经元细胞及其连接纤维网络持续减少。使用细胞耗竭抗体、过继转移实验和缺乏特异性免疫细胞或免疫功能的小鼠，我们表明浸润的 WNV 特异性 CD4 ⁺ 和 CD8 ⁺ T 细胞会损害肠道神经系统 （ENS） 和神经胶质细胞，从而导致肠道运动障碍;这些 T 细胞使用多个冗余的效应分子，包括穿孔素和 Fas 配体。相比之下，WNV 触发的 ENS 损伤和肠道运动障碍似乎不需要浸润单核细胞，并且损伤可能受到常驻肌层巨噬细胞的限制。总体而言，我们的实验支持一个模型，在该模型中，抗原特异性 T 细胞亚群及其效应分子响应 WNV 感染，直接免疫病理学针对肠道神经元并支持导致肠道运动障碍的神经胶质细胞。