Murine Norovirus 1 Infection Is Associated with Histopathological Changes in Immunocompetent Hosts, but Clinical Disease Is Prevented by STAT1-Dependent Interferon Responses

Abstract

Human noroviruses are the major cause of nonbacterial epidemic gastroenteritis worldwide. However, little is known regarding their pathogenesis or the immune responses that control them because until recently there has been no small animal model or cell culture system of norovirus infection. We recently reported the discovery of the first murine norovirus, murine norovirus 1 (MNV-1), and its cultivation in macrophages and dendritic cells in vitro. We further defined interferon receptors and the STAT-1 molecule as critical in both resistance to MNV-1-induced disease in vivo and control of virus growth in vitro. To date, neither histopathological changes upon infection nor viral replication in wild-type mice has been shown. Here we extend our studies to demonstrate that MNV-1 replicates and rapidly disseminates to various tissues in immunocompetent mice and that infection is restricted by STAT1-dependent interferon responses at the levels of viral replication and virus dissemination. Infection of wild-type mice is associated with histopathological alterations in the intestine (mild inflammation) and the spleen (red pulp hypertrophy and white pulp activation); viral dissemination to the spleen, liver, lung, and lymph nodes; and low-level persistent infection in the spleen. STAT-1 inhibits viral replication in the intestine, prevents virus-induced apoptosis of intestinal cells and splenocytes, and limits viral dissemination to peripheral tissues. These findings demonstrate that murine norovirus infection of wild-type mice is associated with initial enteric seeding and subsequent extraintestinal spread, and they provide mechanistic evidence of the role of STAT-1 in controlling clinical norovirus-induced disease.

Norovirus in symptomatic and asymptomatic individuals: cytokines and viral shedding

“…high viral titres) mount greater proinflammatory responses in an attempt to limit viral replication. Murine NoV research suggests that IFN-g and other Th-1 cytokines are important for limiting viral replication [26,27]. However, murine NoV is able to suppress type 1 IFN production [28].…”

“…4). Histological studies of NoV-infected individuals [31] and select animal models [26,32,33] indicate that NoV infection causes damage to the gut mucosa, particularly the epithelium. This damage may lead to immune activation, or the presence of virus alone may stimulate immune activation.…”

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

“…While previous studies suggested that B cells were targeted by NoVs in vivo, [15][16][17][18] we performed experiments to provide unequivocal proof. MNV-1 and MNV-3 titers were reduced in the distal ileums at 0.5 and 1 dpi, and in the mesenteric lymph nodes (MLNs) that drain the small intestine at 1 dpi, but not in the colons of B cell-deficient mMT mice compared to wild-type B6 mice.…”

“…First, nonstructural protein indicative of intracellular viral replication was observed in the B cell zones of STAT1 ¡/¡ mice infected with a MuNoV. 15 Second, viral genome was detected in Peyer's patch lymphocytes of MuNoV-infected IL-10 ¡/ ¡ mice. 16 These results suggest that NoVs can infect B cells at least under certain conditions of immunocompromise.…”

A Pitfall in Mouse Norovirus (MNV) Detection in Fecal Samples Using RT-PCR, and Construction of New MNV-Specific Primers

“…while the MnV genome can be detected in various tissues, including the small intestine, cecum, large intestine, liver, mesenteric lymph nodes, spleen, and lungs [2,6,8,12,15], feces are commonly used for MnV testing because they can be collected noninvasively [10,14,17]. nested rT-PCr thus requires a sensitive primer set and no nonspecific reactions.…”