West Nile virus triggers intestinal dysmotility via T cell–mediated enteric nervous system injury
Hana Janova, … , Thaddeus S. Stappenbeck, Michael S. Diamond
Hana Janova, … , Thaddeus S. Stappenbeck, Michael S. Diamond
Published August 29, 2024
Citation Information: J Clin Invest. 2024;134(21):e181421. https://doi.org/10.1172/JCI181421.
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Research Article Gastroenterology Infectious disease

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

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 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.

Authors

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

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Figure 6

CD4+ and CD8+ T cells injure neurons and glia using multiple effector functions.

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CD4+ and CD8+ T cells injure neurons and glia using multiple effector fu...
(A–D, H, and K) GI tract transit was measured after oral gavage of carmine red dye at 7 dpi. Transit time for sham, WNV-infected WT, or WNV-infected (A) Prf1–/–, (B) Faslgld/gld, (C) Ifngr–/–, and (D) WT mice treated with anti-TNF or isotype control mAb or WNV-infected (H) Prf1–/– or (K) Faslgld/gld mice treated with anti-CD4, anti-CD8β, or isotype control mAb. (E, F, I, J, and L) The muscularis externa was isolated from the middle regions of small intestines from sham-infected, WNV-infected WT, or Prf1–/– mice (E), Faslgld/gld mice (F), WNV-infected Prf1–/– mice (I and J), or Faslgld/gld mice (L) treated with anti-CD4 or anti-CD8β mAb at 7 dpi and then stained. The fraction of the area that stained positive for calretinin, nNOS, or S100β was determined, and values were normalized to those for sham-infected WT mice. (J) Representative images were obtained from the myenteric plexus of the middle region of the small intestine. Scale bars: 100 μm. Original magnification, ×2.5 (enlarged insets). Data were pooled from (A–C, F, I, and J) 3; (D, G, and L) 2; (E and K) 5; and (H) 4 experiments. The numbers of mice per group were as follows: (A) n = 4–11; (B) n = 7–10; (C) n = 4–11; (D) n = 10; (E) n = 4–13; (F) n = 6–11; (G) n = 6; (H) n = 9–12; (I) n = 9–12; (K) n = 7–15; (L) n = 6–7. Lines indicate (A–D and G) median or (H and K) mean values, and column heights indicate the mean values. *P < 0.05 and **P < 0.01, by (A–F, I, and L) Mann-Whitney U test and (H and K) ANOVA with Dunnett’s post test (comparison with the isotype control group).