West Nile virus triggers intestinal dysmotility via T cell-mediated enteric nervous system injury

Hana Janova; Fang R. Zhao; Pritesh Desai; Matthias Mack; Larissa B. Thackray; Thaddeus S. Stappenbeck; Michael S. Diamond

doi:10.1172/JCI181421

West Nile virus triggers intestinal dysmotility via T cell-mediated enteric nervous system injury

Hana Janova,¹ Fang R. Zhao,¹ Pritesh Desai,¹ Matthias Mack,² Larissa B. Thackray,¹ Thaddeus S. Stappenbeck,³ and Michael S. Diamond¹

Published August 29, 2024 - More info

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Abstract

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 find that within one week of WNV infection, enteric neurons and glia become 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 damage the enteric nervous system (ENS) and glia, which leads to intestinal dysmotility; these T cells use multiple and redundant effector functions including perforin and Fas ligand. In comparison, WNV-triggered ENS injury and intestinal dysmotility appears to not require infiltrating monocytes and damage may be limited by resident muscularis macrophages. Overall, our experiments support a model whereby 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.

West Nile virus triggers intestinal dysmotility via T cell-mediated enteric nervous system injury

Hana Janova,¹ Fang R. Zhao,¹ Pritesh Desai,¹ Matthias Mack,² Larissa B. Thackray,¹ Thaddeus S. Stappenbeck,³ and Michael S. Diamond¹

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West Nile virus triggers intestinal dysmotility via T cell-mediated enteric nervous system injury

Hana Janova,1 Fang R. Zhao,1 Pritesh Desai,1 Matthias Mack,2 Larissa B. Thackray,1 Thaddeus S. Stappenbeck,3 and Michael S. Diamond1

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Hana Janova,¹ Fang R. Zhao,¹ Pritesh Desai,¹ Matthias Mack,² Larissa B. Thackray,¹ Thaddeus S. Stappenbeck,³ and Michael S. Diamond¹