Comparative murine norovirus studies reveal a lack of correlation between intestinal virus titers and enteric pathology

Abstract

Human noroviruses are significant emerging pathogens, causing the majority of non-bacterial gastroenteritis outbreaks worldwide. The recent discovery of 30 murine norovirus strains is beginning to facilitate a detailed investigation of norovirus pathogenesis. Here, we have performed an in vivo comparative analysis of two murine norovirus strains, MNV-1 and MNV-3. In immunocompetent mice, MNV-1 caused modest intestinal pathology whereas MNV-3 was attenuated compared to MNV-1. Surprisingly though, MNV-3 reached higher titers in intestinal tissue than MNV-1. MNV-3 also displayed attenuation in mice deficient in the critical interferon signaling molecule STAT-1, demonstrating that MNV-3 attenuation is not a result of increased interferon sensitivity. Importantly, MNV-3-infected mice lost weight and developed gastric bloating and diarrhea in STAT1−/− mice, from which all animals recovered. This disease profile recapitulates several key features of acute gastroenteritis experienced by people infected with a human norovirus.

A Single-Amino-Acid Change in Murine Norovirus NS1/2 Is Sufficient for Colonic Tropism and Persistence

“…5B, middle). This difference in the spleen was in accordance with recent publications demonstrating the ability of CW3 and MNV1 to spread systemically (31,42) and indicates that the failure of CW3 to persist in the intestine is not due to a failure to establish infection. Both strains were detected in the MLN with no significant difference before day 14 when CW3 was cleared (Fig.…”

Identification of a novel cellular target and a co-factor for norovirus infection – B cells & commensal bacteria

“…19 Two genetically related but pathogenically distinct MuNoV strains called MNV-1 and MNV-3 were selected for our studies since differences in cell tropism could provide clues regarding the differences in overall infection outcome. Specifically, MNV-1 is more virulent than MNV-3 in wild-type and interferon-deficient mice 20 ; MNV-1 is cleared acutely whereas MNV-3 establishes a persistent infection in the colon 21,22 ; and MNV-3 elicits a more robust protective immune response than MNV-1. 17,23 Both MNV-1 and MNV-3 replicated efficiently and lytically in the RAW264.7 murine macrophage cell line but neither strain infected the CMT-93 intestinal epithelial cell line, as expected.…”

Protruding Domain of Capsid Protein Is Necessary and Sufficient To Determine Murine Norovirus Replication and Pathogenesis In Vivo

“…These strains differ both genetically and phenotypically from MNV1 (7,26,30,58). As some of these strains possess E296 in VP1, which is responsible for the decreased virulence of CW1P3 (4, 63), we sought to determine whether residue 296 is a virulence determinant in other MNV strains.…”