Obstructive Lymphangitis Precedes Colitis in Murine Norovirus–Infected Stat1-Deficient Mice

Abstract

Murine norovirus (MNV) is an RNA virus that can prove lethal in mice with impaired innate immunity. We found that MNV-4 infection of Stat1 mice was not lethal, but produced a 100% penetrant, previously undescribed lymphatic phenotype characterized by chronic-active lymphangitis with hepatitis, splenitis, and chronic cecal and colonic inflammation. Lesion pathogenesis progressed from early ileal enteritis and regional dilated lymphatics to lymphangitis, granulomatous changes in the liver and spleen, and, ultimately, typhlocolitis. Lesion development was neither affected by antibiotics nor reproduced by infection with another enteric RNA virus, rotavirus. MNV-4 infection in Stat1 mice decreased expression of vascular endothelial growth factor (Vegf) receptor 3, Vegf-c, and Vegf-d and increased interferon (Ifn)-γ, tumor necrosis factor-α, and inducible nitric oxide synthase. However, anti-IFN-γ and anti-tumor necrosis factor-α antibody treatment did not attenuate the histologic lesions. Studies in Ifnαβγr mice suggested that canonical signaling via interferon receptors did not cause MNV-4-induced disease. Infected Stat1 mice had increased STAT3 phosphorylation and expressed many STAT3-regulated genes, consistent with our findings of increased myeloid cell subsets and serum granulocyte colony-stimulating factor, which are also associated with increased STAT3 activity. In conclusion, in Stat1 mice, MNV-4 induces lymphatic lesions similar to those seen in Crohn disease as well as hepatitis, splenitis, and typhlocolitis. MNV-4-infected Stat1 mice may be a useful model to study mechanistic associations between viral infections, lymphatic dysfunction, and intestinal inflammation in a genetically susceptible host.

A Novel Small Animal Model of Norovirus Diarrhea

“…3) . We also observed lacteal dilation, a pathology previously noted in MNV-4-infected Stat1 -/- mice 30 that can be indicative of impaired fat absorption. 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.…”

The role of innate lymphoid cells in response to microbes at mucosal surfaces

“…106 Murine norovirus (MNV) is typically asymptomatic, but it induced intestinal inflammation in genetically susceptible mice. [107][108][109] In fact, MNV promoted healthy intestinal function and reversed intestinal abnormalities in germ-free mice. 68 Interestingly, MNV improved the outcome following intestinal injury through induction of IL-22 by ILC3s in an IFNα R1-and CCR2-dependent manner.…”

IFN-I and IL-22 mediate protective effects of intestinal viral infection

“…MNV is a single-stranded RNA virus that frequently establishes a persistent asymptomatic gastrointestinal infection in mice. Like commensal bacteria, MNV induces or exacerbates intestinal inflammation in genetically susceptible backgrounds 3–5 . In mice with mutation in the autophagy gene Atg16L1 , a model of the inflammatory bowel disease (IBD) Crohn’s disease, we showed that MNV infection triggers structural defects in small intestinal Paneth cells similar to patients harboring the disease-associated variant of ATG16L1 3,6 .…”