Norovirus Infection
Mouse norovirus (MNV) belongs to the family Calici- viridae, genus Norovirus. Noroviruses are of particular importance because approximately 90% of viral gastroenteritis in humans worldwide is attributed to norovirus infections.
The first recognized norovirus was the Norwalk virus, from which the name “norovirus” was derived. A newly recognized murine norovirus (MNV- 1) was identified and reported in 2003, and since then over 35 new isolates have been found among laboratory mouse colonies throughout the world. MNVs are highly prevalent in contemporary mouse populations, with the potential of disrupting research outcomes. MNVs belong to a single serogroup, but display different biological phenotypes. MNV is unique among noroviruses in that it is the only norovirus that can be replicated in cell culture.Epizootiology and Pathogenesis
Human noroviruses are famous for the rapid spread of illness among cruise ship passengers and the difficulty in decontaminating ships following outbreaks. These features may be important in understanding the epizootiology and control of MNV in animal facilities. However, unlike human noroviruses, MNV is remarkably non- pathogenic, except under highly specific circumstances. MNV infection is lethal in GEMs with STAT1 deficiency, including STAT1 null mice with intact B and T cells, STAT1 null mice lacking B and T cells (RAG null), and STAT1 null mice lacking RNA-dependent protein kinase (PKR null). Infection of 129, B6, RAG1, RAG2, interferon alpha/beta receptor null, interferon gamma receptor null, iNOS null, or PKR null mice with functional STAT1 resulted in no clinical disease. Following oral or intranasal inoculation of susceptible STAT1 null mice, persistent levels of viral RNA were detected in a variety of tissues, including lung, liver, spleen, intestine, blood, and brain. Virus antigen is present in liver Kupffer cells.
In the spleen, antigen is found in the red pulp and marginal zones, but also in nonlymphoid cells in the white pulp. This pattern is suggestive of tropism for macrophages and dendritic cells, which has been confirmed in vitro. In immunodeficient mice, MNV-1 RNA has been detected in the feces for several days postinoculation, and in the mesenteric lymph nodes, spleen, and small intestine for up to 5 weeks postexposure. Macrophages in tissues such as lung, liver, and lymphoid organs are primary sites for MNV-1 replication. In view of the biology of other noroviruses, it is likely that the orofecal route is an important means of natural transmission of MNV-1. Immune-competent mice recover from MNV-1 infection, with seroconversion by day 21, whereas RAG null mice remain persistently infected. These features may be biased by the tissue culture adaptation of MNV-1, as infection of immunocompetent mice with new field isolates, including MNV-2, MNV- 3, and MNV-4, resulted in persistent fecal shedding of virus.Pathology
Microscopic lesions in STAT1 null mice inoculated per os or intranasally include alveolitis, pulmonary edema, and multifocal areas of coagulation necrosis in the liver, with minimal or no inflammatory cell response. There is a striking necrotizing splenitis with disruption of the normal architecture. In STAT1 null mice inoculated intracerebrally with MNV-1, endothelial hypertrophy with focal mononuclear cell infiltration in the neuropil and leptomeninges are present. In another study, lesions encountered in several strains of immunodeficient mice naturally infected with MNV were variable to absent, depending on the strain under study. Changes described included multifocal hepatitis with mononuclear and scattered polymorphonuclear cell infiltration, multifocal interstitial pneumonia, pleuritis, and peritonitis. In mesenteric lymph nodes, degeneration of scattered lymphocytes with focal fibrosis was occasionally observed. In sections stained by immunohistochemistry, intracytoplasmic viral antigen was demonstrated in mononuclear cells scattered in the liver, spleen, intestinal lymphoid tissue, lamina propria of the intestine, and intravascular mononuclear cells.
Diagnosis
Serology for MNV is based upon recombinant baculovi- rus MNV-1 capsid protein virus-like particles, and the antigen is effective at detecting antibody to all MNV isolates. Immunohistochemistry to demonstrate viral antigen in target tissues and PCR to detect MNV RNA in tissues or feces are useful diagnostic procedures. Negative-staining electron microscopy has also been used to visualize virus in infected tissues. Mesenteric lymph nodes appear to be an optimal site for detection and isolation of MNV.