Noroviruses are nonenveloped RNA viruses with high environmental resistance and belong to the family Caliciviridae, genus Norovirus. They were first identified after an outbreak of acute gastroenteritis at a school in Norwalk/Ohio (USA) in 1968 and cause about 90% of nonbacterial epidemic gastroenteritis in humans. Noroviruses found in animals include bo-vine, porcine and murine noroviruses. Noroviruses are not known to cross species.

The first norovirus to infect mice was described in 2003 (1). Experimental inoculation studies with this murine norovirus (MNV-1) show that duration of infection and disease manifestation vary depending on the mouse strain (1-3). In immunocompetent strains, MNV-1 infection is variable in length (e.g. ≥ 7-14 days in 129S6 mice, ≥ 5 weeks in Hsd:ICR mice) and does not induce clinical signs. Infection is associated with mild histopathological alterations in the small intestine (increase in inflammatory cells) and spleen (red pulp hypertrophy and white pulp activation) of 129S6 mice. In certain immunodeficient strains, however, infection can cause lethal systemic disease (encephalitis, vasculitis, meningitis, hepatitis and pneumonia in interferon-abg receptor-/- and Stat1-/- mice) or persist without symptoms (≥ 90 days in Rag1-/- und Rag2-/- mice). These findings indicate that components of the innate immune system are critical for resistance to MNV-1 induced disease. Consistent with this hypothesis, Wobus et al. (4) demonstrated that MNV-1 replicates in macrophages and dendritic cells. Meanwhile, many additional strains of MNV with diverse biological properties were isolated (5, 6). An analysis of 26 MNV isolates revealed 15 distinct MNV strains that comprise a single genogroup and serotype (6). Experimental inoculation studies show that several MNV strains are able to persist in various tissues (small intestine, mesenteric lymph node, spleen) of immunocompetent mice (C57BL/6J, Hsd:ICR) with viral shedding in faeces for the duration of at least 5-8 weeks (5, 6). MNV is transmitted via the faecal-oral route and is efficiently transferred to sentinel mice by soiled bedding (7, 8).

Embryo transfer (8, 9) and hysterectomy are most likely effective means of eliminating MNV from mouse colonies. Since 1- to 3-day-old pups are resistent to infection, elimination of MNV may also be achieved by transferring neonates from infected dams to uninfected foster dams ("cross fostering") (10, 11). This transfer should ideally be performed within 24 hours after birth.

MNV infection can be detected directly by RT-PCR on faecal pellets or tissue specimens (see above) and indirectly by serology (1-3, 5-13). Detection is facilitated by high stability of MNV RNA in faeces (at least 2 weeks at room temperature) (7) and by broad serological cross-reactivity among different strains of MNV (5, 6). Data from the Research Animal Diagnostic Laboratory (RADIL) at the University of Missouri (Columbia, Missouri) suggest a high prevalence of MNV infection in laboratory mice: evaluation of 12,639 mouse serum samples submitted by research institutions in the USA and Canada showed that 22.1% of samples had anti-MNV antibodies (2). It can be assumed that a high prevalence also exists in European laboratory mouse colonies. First studies in Germany revealed the presence of MNV at a rate of 50-70% within some mouse colonies (9, 12, 13).

The impact of MNV on animal experiments remains to be evaluated. A recent study indicates that MNV may alter the phenotype of disease in a mouse model of inflammatory bowel disease (14).

References:

1. Karst SM, Wobus CE, Lay M, Davidson J, Virgin HW. 2003. STAT1-dependent innate immunity to a Norwalk-like virus. Science 299:1575-8.
2. Hsu CC, Wobus CE, Steffen EK, Riley LK, Livingston RS. 2005. Development of a micro-sphere-based serologic multiplexed fluorescent immunoassay and a reverse transcriptase PCR assay to detect murine norovirus 1 infection in mice. Clin Diagn Lab Immunol 12:1145-51.
3. Mumphrey SM, Changotra H, Moore TN, Heimann-Nichols ER, Wobus CE, Reilly MJ, Moghadamfalahi M, Shukla D, Karst SM. 2007. Murine norovirus 1 infection is associated with histopathological changes in immunocompetent hosts, but clinical disease is prevented by STAT1-dependent interferon responses. J Virol 81:3251-63.
4. Wobus CE, Karst SM, Thackray LB, Chang K-O, Sosnovtsev SV, Belliot G, Krug A, Mackenzie JM, Green KY, Virgin HW. 2004. Replication of Norovirus in cell culture reveals a tropism for dendritic cells and macrophages. PLoS Biol 2:2076-84.
5. Hsu CC, Riley LK, Wills HM, Livingston RS. 2006. Persistent infection with and serologic cross-reactivity of three novel murine noroviruses. Comp Med 56:247-51.
6. Thackray LB, Wobus CE, Chachu KA, Liu B, Alegre ER, Henderson KS, Kelley ST, Virgin HW. 2007. Murine noroviruses comprising a single genogroup exhibit biological diversity despite limited sequence divergence. J Virol 81:10460-73.
7. Manuel CA, Hsu CC, Riley LK, Livingston RS. 2006. Soiled bedding sentinel detection of murine norovirus 4 (MNV-4) (Abstract). J Am Assoc Lab Anim Sci 45:87.
8. Perdue KA, Green KY, Copeland M, Barron E, Mandel M, Faucette LJ, Williams EM, Sosnovtsev SV, Elkins WR, Ward JM. 2007. Naturally occurring murine norovirus infection in a large research institution. J Am Assoc Lab Anim Sci 46:39-46.
9. Nicklas W, Mauter P, Schneider E, Wobus C. Seroprevalence of murine norovirus (MNV) in European mouse colonies (Abstract). FELASA-ICLAS Joint Meeting 2007, Cernobbio, Italy, Abstract book: p. 317.
10. Artwohl JE, Purcell JE, Chrusciel K, Lang M, Fortman J. 2007. Assessment of cross-foster rederivation in the elimination of mouse norovirus and Helicobacter (Abstract). J Am Assoc Lab Anim Sci 46:84.
11. Compton SR. 2007. Susceptibility of neonatal mice to murine norovirus infection (Abstract). J Am Assoc Lab Anim Sci 46:84.
12. Mahabir E, Brielmeier M, Schmidt J. 2007. Prevalence of mouse norovirus (MNV) in a large breeding and experimental mouse facility (Abstract). FELASA-ICLAS Joint Meeting 2007, Cernobbio, Italy, Abstract book: p. 99.
13. Müller B, Klemm U, Mas Marques A, Schreier E. 2007. Genetic diversity and recombination of murine noroviruses in immunocompromised mice. Arch Virol 152:1709-19.
14. Chase K, Seamons A, Treuting P, Lai L, Maggio-Price L, Brabb TL. 2007. Murine norovirus, an intercurrent variable in a mouse model of bacterial-induced inflammatory bowel disease (Abstract). J Am Assoc Lab Anim Sci 46:83.

Author: Michael Mähler

Date: 08/12/2007