Pathology of Immunodeficient Mice With Naturally Occurring Murine Norovirus Infection

Abstract

Murine norovirus (MNV) was recently discovered in Rag2 −/− /Stat1 −/− mice in a U.S. medical research facility. Presently, little is known concerning the epidemiology and natural history of this virus. We studied the pathology of naturally occurring MNV infection in 28 immunodeficient mice of several different genotypes (, and Rag2 −/− ) that were maintained in two U.S. research facilities. The mice were selected for study because sentinel mice housed in their holding rooms had been identified as positive for MNV-specific antibodies during routine screening for infectious agents. Our data indicate that in certain lines of immunodeficient mice, MNV can establish a disseminated infection that is characteristically associated with inflammation in multiple tissues, including liver (hepatitis), lung (focal interstitial pneumonia) and the peritoneal and pleural cavities. In addition, MNV can establish an asymptomatic infection in the mesenteric lymph nodes of Rag2 −/− mice. Further studies are needed to determine whether MNV presents a confounding variable in immunological, toxicological and pathological studies in mice naturally infected with MNV.[The supplemental data referenced in this paper is not printed in this issue of Toxicologic Pathology. It is available as a downloadable file in the online edition of Toxicologic Pathology, 34(6). In order to access the full article online, you must have either an individual subscription or a member subscription accessed through www.toxpath.org.]

Of Mice and Microflora

“…Thus, Stat1 and Ifra1 (IFNabR) mutant mice will develop clinical disease and death after infection with MNV-1, characterized by severe pneumonia, vasculitis, meningoencephalitis, hepatitis/necrosis, peritonitis, and pleuritis. 57,121 Although the innate immune system is essential to protect against lethal infection by MNV, the acquired immune system is important in clearing MNV. MNV does not cause clinical disease in mice with deficits in the acquired immune system, such as Rag1-and Rag2-deficient mice; however, they fail to clear the virus, which results in prolonged infection 121 (thus serving as virus reservoirs) that may affect immunology studies.…”

“…57,121 Although the innate immune system is essential to protect against lethal infection by MNV, the acquired immune system is important in clearing MNV. MNV does not cause clinical disease in mice with deficits in the acquired immune system, such as Rag1-and Rag2-deficient mice; however, they fail to clear the virus, which results in prolonged infection 121 (thus serving as virus reservoirs) that may affect immunology studies. In addition, coinfection of MNV with Helicobacter spp may accelerate the progression of Helicobacter-associated IBD in the Mdr1a-null mouse, despite the lack of clinical disease with MNV alone.…”

“…However, oral inoculation with a cultureadapted strain of MNV-1 (10 7 plaque-forming units) into 129S6/SvEv inbred mice results in very slight and transient granulocytic infiltration of the lamina propria of the duodenum at 24 hours post infection (without apoptosis of enterocytes) as well as mild increases in extramedullary hematopoiesis and lymphoid hyperplasia in the spleen. 90,121 MNV1 has tropism for macrophage and dendritic cells, which are essential mediators of the innate immune system. 123 In dendritic cells, the cytoplasmic helicase protein MDA5 (melanomadifferentiation-associated gene 5) has been demonstrated to be important in cell sensing of the virus.…”

“…In typical mouse strains without genetic modification, MNV-associated lesions have not been identified. 121 The method of transmission is thought to be fecal-oral. As a nonenveloped virus, MNV has the potential to remain active in the environment.…”

Rodent Immunohistochemistry

“…There have been many review publications and books on IHC that can aid the veterinary pathologist and investigator. 2,[5][6][7][8][9][10][11][12][15][16][17][18][19] We review some of our own methods for IHC interpretation and troubleshooting investigative procedures. Various procedures are used to confirm and optimize specific antigen localization in FFPE mouse tissues.…”