Human norovirus targets enteroendocrine epithelial cells in the small intestine

Kim Y Green,Sangeetha R Moturi,Bianca M Nagata,Allison Behrle Yardley,Jordan A Johnson,Eric A Levenson,Daniel Y Kim,Natthawan Chaimongkol,Stanislav V Sosnovtsev,Nada A Yazigi,Ian N Moore,Khalid M Khan,Thomas M Fishbein,Stuart S Kaufman,Ana Beatriz F Barletta,Christine M Tin,Sukanya Subramanian

doi:10.1038/s41467-020-16491-3

Abstract

Human noroviruses are a major cause of diarrheal illness, but pathogenesis is poorly understood. Here, we investigate the cellular tropism of norovirus in specimens from four immunocompromised patients. Abundant norovirus antigen and RNA are detected throughout the small intestinal tract in jejunal and ileal tissue from one pediatric intestinal transplant recipient with severe gastroenteritis. Negative-sense viral RNA, a marker of active viral replication, is found predominantly in intestinal epithelial cells, with chromogranin A-positive enteroendocrine cells (EECs) identified as a permissive cell type in this patient. These findings are consistent with the detection of norovirus-positive EECs in the other three immunocompromised patients. Investigation of the signaling pathways induced in EECs that mediate communication between the gut and brain may clarify mechanisms of pathogenesis and lead to the development of in vitro model systems in which to evaluate norovirus vaccines and treatment.

Highlights

Human noroviruses are a major cause of diarrheal illness, but pathogenesis is poorly understood
Intestinal epithelial cell types are diverse in morphology and function[23], and we investigated the identity of norovirus-positive epithelial cells that did not morphologically resemble absorptive enterocytes
Because Murine norovirus (MNV) has been reported to replicate in B and T cells, we examined whether human norovirus VP1 antigen was present in these lymphoid immune cells (Fig. 6)

Summary

Introduction

Human noroviruses are a major cause of diarrheal illness, but pathogenesis is poorly understood. Negative-sense viral RNA, a marker of active viral replication, is found predominantly in intestinal epithelial cells, with chromogranin Apositive enteroendocrine cells (EECs) identified as a permissive cell type in this patient. These findings are consistent with the detection of norovirus-positive EECs in the other three immunocompromised patients. Replication of human norovirus in an in vitro stem cell-derived intestinal enteroid cell culture system supported the identification of enterocytes as a permissive target cell[10]. The purpose of this study is to identify target cells in the human enteric tract that support active norovirus replication

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Conclusion