Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA.
Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.
J Clin Invest. 2024 Aug 29;134(21):e181421. doi: 10.1172/JCI181421.
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.
肠动力障碍综合征在流行病学上与多种先前的细菌和病毒感染有关。为了模拟这种表型，我们之前用神经亲和性黄病毒西尼罗河病毒（WNV）感染了小鼠，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。通过使用细胞耗竭抗体、过继转移实验以及缺乏特定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 细胞损伤肠神经系统（ENS）和神经胶质细胞，导致肠道动力障碍；这些 T 细胞使用了多种冗余的效应分子，包括穿孔素和 Fas 配体。相比之下，WNV 触发的 ENS 损伤和肠道动力障碍似乎不需要浸润的单核细胞，损伤可能受到固有肌层巨噬细胞的限制。总的来说，我们的实验支持了一种模型，即针对 WNV 感染的抗原特异性 T 细胞亚群及其效应分子直接针对肠神经元和支持神经胶质细胞的免疫病理学，导致肠道动力障碍。
