(vi) Mouse hepatitis virus.
Mouse hepatitis virus (MHV) is probably the most important pathogen of laboratory mice. Rats may also become infected but only as sucklings and only under experimental conditions. MHV is an ssRNA virus of the family Coronaviridae. It is extremely contagious and is transmitted primarily via aerosol, direct contact, fomites, and, experimentally, via transplantable tumors and transplacental passage.
Susceptibility, tissue tropism, clinical signs, and pathologic lesions are dependent on several host, environmental, and pathogen factors. Approximately 25 strains or isolates of MHV have been described and have been classified as either respiratory or enterotropic. Recently, an outbreak of a highly hepatotropic strain of MHV was reported from a breeding colony of nude mice in Taiwan. The presence or absence of the MHV receptor, a glycoprotein in the carcinoembryonic antigen family of the Ig superfamily, may determine tissue tropism. Respiratory (polytropic) strains establish in the nasal mucosa, descend to the lungs, and disseminate hematogenously throughout the body or ascend along neurons to the CNS. Intestinal involvement is usually absent. Polytropic strains include MHV-1, MHV-2, MHV-3, A59, S, and JHM. Enterotropic strains may also become established in the nasal mucosa or in the intestinal tract and disseminate only locally to the liver, abdominal lymph nodes, and, in some cases, the CNS. Pulmonary involvement is uncommon. Enterotropic strains include LIVIM, MHV-D, and MHV-Y. While polytropic strains have historically been considered more common, this situation is thought to have reversed. Lesions are present for only 7 to 10 days following infection, are dependent upon strain of virus, and are characterized by multifocal necrosis. Additionally, multinucleate syncytial giant cell formation occurs and may be associated with fragmentation and rearrangement of the Golgi apparatus. Lesions due to polytropic strains may be observed in the olfactory mucosa, brain, lungs, and liver, while lesions due to enterotropic strains are generally, though not always, confined to the intestinal tract. Lesions caused by either strain tend to be more severe and widespread in immunocompromised mice.
Most infections follow one of three clinical patterns. Enzootic (subclinical) infection, commonly seen in breeding colonies, occurs when infection is endemic in the colony and is maintained only by the continual arrival of susceptible animals (newborns). No carrier state exists, although in a recent study viral RNA was detected in the liver up to 60 days after infection. Adults are asymptomatic, and their young become asymptomatically infected by the time passively transferred maternal immunity wanes at weaning. Epizootic (clinical) infection occurs less commonly when the pathogen is introduced to a naive colony. Adult infections are again usually asymptomatic. Clinical signs depend upon the virus and mouse strains and are most evident in infant mice; typically, they include diarrhea, poor growth, and death. As the infection becomes established in the colony, the epizootic pattern is replaced with the enzootic pattern. Immunodeficient mice, such as athymic (nu/nu ) mice, develop a wasting syndrome characterized by severe generalized disease and eventual death. Immunity to MHV is primarily but not entirely cell mediated; is partially protective between closely related virus strains; and is known to involve T lymphocytes, macrophages, IFN, and NK cells.
Numerous reports document effects of natural or experimental infection with MHV on host physiology and research. In immunocompromised mice, these effects include necrotic changes in several organs, including the liver, lungs, spleen, intestine, brain, lymph nodes, and bone marrow; differentiation of cells bearing T-lymphocyte markers; altered enzyme activities, bilirubin concentration, and antibody responses to sheep erythrocytes in serum; enhanced phagocytic activity of macrophages; rejection of xenograft tumors; impaired liver regeneration; and hepatosplenic myelopoiesis. In immunocompetent mice, reported effects include transient immunostimulation followed by immunodepression; thymic involution; depletion of LDEV-permissive macrophages; microcytic anemia and changes in ferrokinetics; decreases in lymphocyte proliferative responses, antibody secretion, phagocytic activity, liver regeneration, blood cell production, number of hepatic sinusoidal endothelial cell fenestrae, incidence of diabetes mellitus in nonobese diabetic mice, and IFN production during SV infection; apoptotic changes in the thymus; increased tumoricidal activity of peritoneal macrophages, hepatic uptake of injected iron, susceptibility or resistance to copathogens, and IFN and IL-12 production; altered hepatic enzyme activity, behavior of ascites myelomas, and expression of cell surface markers on splenic T lymphocytes; molecular mimicry of the host Fc gamma receptor; nerve demyelination; impaired bone marrow pre-B and B cells; induced production of alpha-fetoprotein and antiretinal autoantibodies in serum; and induced macrophage procoagulant activity. Clearly, natural MHV infection of laboratory mice with MHV may affect a plethora of scientific studies and seriously compromise the value of these animals as research subjects.
(vii) Sialodacryoadenitis virus.
Sialodacryoadenitis virus (SDAV) is a common, important, and highly contagious pathogen of laboratory rats. SDAV is an ssRNA virus of the family Coronaviridae. Transmission is via direct contact and fomites. Infant mice, but not adult immunocompetent or scid mice, are susceptible to experimental infection. Natural infection of mice has not been reported. SDAV infections follow patterns similar to those of MHV, another coronavirus. Enzootic infection occurs in breeding colonies and is sustained only by the continual introduction of susceptible hosts (newborns). Suckling rats develop transient conjunctivitis. Weanlings and adults are asymptomatic. Epizootic infection occurs when the agent is introduced to a fully susceptible population. Clinical signs are again transient, may vary in severity, and include cervical edema, sneezing, photophobia, conjunctivitis, nasal and ocular discharge, porphyrin staining, and corneal ulceration and keratoconus.
Multiple strains of SDAV exist, and tissue tropisms differ somewhat among strains. SDAV has a tissue tropism for tubuloalveolar glands of the serous or mixed serous-mucous types. Therefore, inflammatory changes consisting primarily of diffuse necrosis are seen in the lacrimal (including the Harderian) glands and submandibular and orbital salivary glands. Secondary damage may occur to structures of the eye. Cervical lymph nodes and the thymus may also be mildly necrotic. Some strains of SDAV affect the respiratory tract, where pathologic changes may include patchy necrotizing rhinitis, tracheitis, bronchitis, and bronchiolitis, with multifocal pneumonitis. SDAV causes more severe respiratory tract lesions in LEW rats than in F344 rats. Virus is present in tissues for only about 1 week. There is no carrier state, so clinical signs and pathologic changes are transient. In athymic rats, infection is more severe, is persistent, and may be fatal. SDAV has been shown to alter estrous cycles, increase embryonic and postnatal mortality, cause depletion of epidermal growth factor in submaxillary salivary glands, cause anorexia and weight loss, and reduce IL-1 production by alveolar macrophages. In addition, SDAV potentiates lesions caused by M. pulmonis, though not by altering pulmonary clearance or intrapulmonary killing. Natural infections of laboratory rats with SDAV would be expected to interfere with studies involving the lacrimal, salivary, respiratory, ocular, olfactory, reproductive, and immune systems and to interfere with growth of infected newborns.
