Norovirus infection causes acute self-resolving diarrhea in wild-type neonatal mice

Alexa N Roth,Stephanie M Karst,Laura B Eurell,Emily W Helm,Sourish Ghosh,Carmen Mirabelli,Christiane E Wobus,Nihal Altan-Bonnet,Jonathan C Smith,Erin Kirsche

doi:10.1038/s41467-020-16798-1

Abstract

Human noroviruses are the leading cause of severe childhood diarrhea worldwide, yet we know little about their pathogenic mechanisms. Murine noroviruses cause diarrhea in interferon-deficient adult mice but these hosts also develop systemic pathology and lethality, reducing confidence in the translatability of findings to human norovirus disease. Herein we report that a murine norovirus causes self-resolving diarrhea in the absence of systemic disease in wild-type neonatal mice, thus mirroring the key features of human norovirus disease and representing a norovirus small animal disease model in wild-type mice. Intriguingly, lymphocytes are critical for controlling acute norovirus replication while simultaneously contributing to disease severity, likely reflecting their dual role as targets of viral infection and key components of the host response.

Highlights

Human noroviruses are the leading cause of severe childhood diarrhea worldwide, yet we know little about their pathogenic mechanisms
The incidence of diarrhea was significantly higher in MNV-1-infected 3-day-old BALB/c mice compared with 4-day-old BALB/c mice, with a 91% versus 49% incidence, respectively (Fig. 2c, d), and slightly, not significantly, higher in female BALB/c mice than in male mice (Fig. 2e, f)
Compared with the 91% incidence of diarrhea in MNV-1-infected BALB/c pups, MNV-3 and MNV-CR6 caused diarrhea in 43% and 32% of pups, respectively (Fig. 1d, e and Supplementary Fig. 1d, e). These data reveal that MNV-1 infection causes selfresolving acute diarrhea in neonatal BALB/c mice and that MNV3 and MNV-CR6 cause a reduced incidence of diarrhea relative to MNV-1, mirroring their virulence patterns previously observed in adult IFN-deficient mice[14,17]

Summary

Introduction

Human noroviruses are the leading cause of severe childhood diarrhea worldwide, yet we know little about their pathogenic mechanisms. Murine noroviruses cause diarrhea in interferon-deficient adult mice but these hosts develop systemic pathology and lethality, reducing confidence in the translatability of findings to human norovirus disease. Rotaviruses cause severe acute diarrhea in people yet fail to cause disease in adult wild-type mice. It is well-established that neonatal wild-type mice are susceptible to rotavirus-induced diarrhea[18,19,20]. Histopathological changes in MNV-infected neonatal mice are entirely consistent with these human biopsies: While the epithelium itself remained intact and only modest inflammation was observed, there was villous broadening, epithelial disorganization and vacuolization, and crypt cell hyperplasia (Fig. 3a and Supplementary Fig. 2). Overall pathology was more pronounced in the proximal half of the small intestine than the distal half, and it positively correlated with diarrhea incidence when comparing intestinal sections from pups infected with MNV-1, MNV-3, and MNV-CR6 (Fig. 3b, c and Supplementary Fig. 2)

Methods

Results

Conclusion