Signalment:  

Four-month old, female, athymic nude, mouse (Mus musculus).Second mouse in cage to develop spontaneous emaciation and paresis.

Gross Description:  

Prior to euthanasia the animal is depressed. Mild splenomegaly and lymph node enlargement is present. The mesenteric lymph node is white and firm. Heart, lung, liver, GI and reproductive tract are grossly normal. 

Histopathologic Description:

The liver has moderate, multifocal necrotizing and suppurative hepatitis. Some necrotic foci contain syncytial cells. Findings in other (not submitted) tissues include necrotizing splenitis and necrosis, variable suppuration and syncytial cells in the brain, bone marrow and lymph nodes, and the nasal cavity has necrosuppurative rhinitis. 

Morphologic Diagnosis:  

Hepatitis, necrotizing, moderate, multifocal with syncytial cells.

Lab Results:  

The fecal, kidney and mesenteric lymph node tissue samples are negative for MPV via PCR. The liver and mesenteric lymph node tissue samples are positive for MHV via RT-PCR.

Condition:  

Mouse hepatitis virus

Contributor Comment:  

This mouse is one in a group of other nude mice housed separately but near a room known to be positive for MHV and MPV. Of the known strains of MHV, this mouse likely presented with a polytropic strain, most notably with neurotropic characteristics. This mouse had characteristic necrotizing lesions with syncytial cells in multiple tissues, suggesting a polytropic strain of MHV.

Mouse hepatitis virus is a single-stranded, enveloped RNA virus of the family Coronaviridae. Approximately 25 strains or isolates of MHV have been described. Isolates can be divided into two biotypes with varying degrees of overlap: the respiratory (polytropic) and enterotropic strains.(3) Respiratory strains of MHV are extremely contagious and are transmitted primarily via aerosol, direct contact, and fomites. Once inhaled, the virus replicates in the nasal mucosa and subsequently spreads via the blood and lymphatics through cervical and mesenteric lymph nodes to multiple tissues.(1) Dissemination is more likely with more virulent strains of virus in infant mice without maternal antibody and in immunocompromised (particularly nude) mice. MHV has high morbidity and mortality in these groups. Immunocompetent mice may clear the infection in five to seven days post-infection with no carrier status. BALB/c mice are generally quite susceptible to MHV, whereas SJL mice are remarkably resistant. The spike protein (SP), responsible for viral entry, is a major determinant of tropism and virulence.(2) SP binds carcinoembryonic antigen-related cell adhesion molecule 1, CEACAM- 1 on either the cell surface or in endosomes. SP also mediates cell-to-cell fusion. The allelic form of CEACAM in a particular strain of mouse is a determinate of susceptibility. Strains that express CEACAM-1α such as Balb/C are susceptible. Strains that express CEACAM -1β such as SJL, are resistant. (2) Disease severity is determined by thrombosis and coagulation necrosis due to induction of procoagulant activity by macrophages in susceptible mice.(5) T cell function is important for viral clearance depending on both CD8 activity and antibody and cytokine induction. (2)

Enterotropic strains of MHV selectively infect intestinal mucosal epithelium, with minimal to no dissemination to other organs, even in immunodeficient mice.(4) All stages and strains of mice are susceptible to enterotropic MHV infection, including SJL mice, which are resistant to polytropic MHV.(5) The severity of intestinal disease is associated with age-related intestinal mucosal proliferative kinetics, thus severe disease occurs only in infant mice.(4) Even in nude or SCID mice, disease can be minimal; however hyperplastic colitis has been reported in nude mice5. Recovery from enterotropic MHV is T-cell dependent; persistent infections can occur in immunodeficient mice. (3)

Diagnosis is usually made via serology using an ELISA, but MHV may also be isolated in susceptible tissue culture cells. Differential diagnoses include Salmonellosis, Tyzzers disease and reovirus infection. (5) Respiratory syncytial virus forms syncytial cells similar to MHV, but these cells are restricted to the pulmonary parenchyma. 

JPC Diagnosis:  

Liver: Hepatitis, necrotizing, multifocal and random, moderate, with viral syncytia.

Conference Comment:  

The contributor provides a very good summary of mouse hepatitis virus (MHV). Conference participants discussed the polytropic nature of the respiratory strains of MHV. Despite being called a hepatitis virus, these viruses actually have a secondary tropism for a variety of cells and tissues other than the liver to include vascular endothelium, lymphoid tissue, hemopoietic tissue, and the central nervous system.(6) The majority of natural polytropic MHV infections are subclinical in immunocompetent mice; whereas infections in immunodeficient mice often result in wasting disease, neurologic signs and mortality. Interferon-gamma deficient mice infected with polytropic MHV develop a unique clinical presentation of granulomatous polyserositis and subsequent abdominal distention.(5,6) Participants also discussed the significance of MHV in laboratory mouse colonies, where its effects on research resulting from immunomodulation can be particularly devastating.(5,6)

References:

1. Barthold SW, Smith AL. Viremic dissemination of mouse hepatitis virus-JHM following intranasal inoculation of mice. Arch Virol. 1992; 112: 35-44.
2. Bender SJ, Weiss SR. Pathogenesis of murine coronavirus in the central nervous system. J Neuroimm Pharm. 2010; 5(3): 336-354.
3. Compton SR, Barthold SW, Smith AL. The cellular and molecular pathogenesis of coronaviruses.  J Lab Animals.  1993; 43: 15-28.
4. Homberger FR. Enterotropic mouse hepatitis virus. J Lab Anim. 1997; 31(2): 97-115.
5. Percy DH, Barthold SW. Coronavirus infection: Mouse Hepatitis Virus. In: Pathology of Laboratory Rodents and Rabbits. 3rd ed. Ames, IA: Blackwell Publishing; 2007: 31-36.
6. Saif LJ. Coroniviridae. In: MacLachlan NJ, Dobovi EJ, eds. Fenners Veterinary Virology. 4th ed. London,UK: Elsevier; 2011:404-406.

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3-1. Liver

3-2. Liver

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