Pathology caused by persistent murine norovirus infection

Amita Shortland,James Chettle,Dalan Bailey,Ian Goodfellow,Barbara A Blacklaws,Kathryn Wood,Joy Archer,Jonathan L Heeney

doi:10.1099/vir.0.059188-0

Amita Shortland, James Chettle + Show 6 more

Open Access

https://doi.org/10.1099/vir.0.059188-0

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Abstract

Subclinical infection of murine norovirus (MNV) was detected in a mixed breeding group of WT and Stat1−/− mice with no outward evidence of morbidity or mortality. Investigations revealed the presence of an attenuated MNV variant that did not cause cytopathic effects in RAW264.7 cells or death in Stat1−/− mice. Histopathological analysis of tissues from WT, heterozygous and Stat1−/− mice revealed a surprising spectrum of lesions. An infectious molecular clone was derived directly from faeces (MNV-O7) and the sequence analysis confirmed it was a member of norovirus genogroup V. Experimental infection with MNV-O7 induced a subclinical infection with no weight loss in Stat1−/− or WT mice, and recapitulated the clinical and pathological picture of the naturally infected colony. Unexpectedly, by day 54 post-infection, 50 % of Stat1−/− mice had cleared MNV-O7. In contrast, all WT mice remained infected persistently. Most significantly, this was associated with liver lesions in all the subclinically infected WT mice. These data confirmed that long-term persistence in WT mice is established with specific variants of MNV and that despite a subclinical presentation, active foci of acute inflammation persist within the liver. The data also showed that STAT1-dependent responses are not required to protect mice from lethal infection with all strains of MNV.

Highlights

Understanding the mechanisms of viral persistence of non-integrating RNA viruses will facilitate their control
Persistence of members of the family Caliciviridae has been reported after infection with feline calicivirus (FCV), rabbit haemorrhagic disease virus (RHDV), and human and murine norovirus (HuNoV and MNV) (Capizzi et al, 2011; Coyne et al, 2006; Forrester et al, 2003; Hsu et al, 2006; Siebenga et al, 2008; Thackray et al, 2007)
Natural MNV-O7 infection is subclinical in Stat1−/− mice

Summary

Introduction

Understanding the mechanisms of viral persistence of non-integrating RNA viruses will facilitate their control. The faeces were virus-positive at day 7 p.i. for almost all animals inoculated with MNV-O7mc (three of three WT and two of three Stat1−/− mice, data not shown). These data indicated that MNV-O7 was only secreted actively from persistently infected WT mice, with Stat1−/− mice clearing virus RNA from the gut more rapidly than from the spleen and liver.

Results

Conclusion