Mouse Hepatitis Virus                                                                      

Agent

Family Coronaviridae, genus Coronavirus; pleomorphic, ssRNA, enveloped with surface projections (peplomers). MHV is serologically related to

SDAV & several other coronaviruses of pigs, cattle, humans. It is one of the best studied animal viruses, because it has been used extensively in

studies of coronavirus biology and because it was was recognized early on as adversely affecting research results.

"MHV" is not a single virus, but a group of serologically and genetically related but distinct strains. About 25 strains have been reported. Strains

traditionally are characterized by cross-neutralization tests with known strains; however, serologic relationships do not correlate with pathogenicity.

The best studied strains are the "prototype strains" MHV-1, MHV-2, MHV-3, JHM, A59, and S, of which MHV-3 is regarded as the most

virulent. Field isolates often differ more or less from these. MHV, like other coronaviruses, mutates rapidly, and strains readily form recombinants, so

possible number of "strains" is very large. Strains differ in tropisms, tendency to disseminate, and virulence.

Enterotropic strains replicate initially in the intestinal epithelium tend not to disseminate, and usually are only weakly virulent. "Polytropic" strains

replicate initially in the respiratory tract, tend to disseminate to liver, brain, lymph nodes, etc., and usually are more virulent than enterotropic strains.

Some strains of MHV are readily cultivated, whereas others are very difficult. Enterotropic strains tend to be the most difficult to culture. The

preferred cell line varies among strains; the most often used are NCTC-1469, 17Cl-1, DBT, BALB/c-3T3, and CMT-93. Infectivity depends on the

envelope, so these viruses are very susceptible to disinfectants, especially those with detergent activity.

Epizootiology Return to top

Mus musculus is the natural host. Suckling rats inoculated experimentally had transient replication in nasal mucosa and seroconversion but no clinical

disease. Deer mice seroconverted but had no clinical disease.

MHV is extremely contagious and of all mouse infectious agents is probably the single most difficult agent to control. It is nearly ubiquitous among

conventional mice, and not uncommon in "barrier maintained" mice, especially in multipurpose user facilities. In infected colonies, most if not all

weanling and older mice will be ELISA positive.

Mice with active infection shed virus in feces and oral and nasal secretions. Transmission is by several routes, including contact, aerosol, fomites, and

airborne particles of feces, bedding, etc. Vertical transmission has been demonstrated in experimental infections, but it is not known whether this is

important in natural transmission.

MHV is a common contaminant of transplantable tumors and cell lines.

Clinical Signs Return to top

Most MHV infections are subclinical.

Adult immunocompetent mice with MHV infection rarely show clinical signs. Enzootic subclinical infection is typical of conventional breeding

colonies, in which adults are immune, sucklings are passively protected, and infection perpetuated in weanlings that are partially protected by residual

maternal antibody.

Pathology

In most natural infections, gross lesions are not present or are transient and not observed. Susceptible mice infected with virulent virus can have

severe acute hepatitis, in which the liver is diffusely tan or yellow with an accentuated lobular pattern and sometimes petechiae or multiple irregular tan

or yellow slightly depressed foci.

Pathogenesis Return to top

Infection with most strains follows the respiratory pattern. Viral antigen appears first in the nasal mucosa, then in the lungs, followed by lymphoid

organs, bone marrow, brain, liver, and intestine

Intermediate patterns occur with some strains, and variations can be induced by other factors, such as age, genotype, concurrent

infections, and immune status. For example, in suckling BALB/c and ICR mice, enteric strains such as MHV-Y can cause encephalitis.

Immune status. Athymic or neonatally thymectomized mice are very susceptible. In such mice, infection with virulent MHV strains often is rapidly

fatal, and less virulent strains can cause chronic hepatic or intestinal disease. SCID mice also are very susceptible. MHV infections induce strong

immune responses in immunocompetent mice, which confers immunity to the infecting strain, but not necessarily to others. Recovered mice are

protective against re-infection with the same strain of virus, but not necessarily against other strains.

Diagnosis (Serology only) Return to top

ELISA with confirmation of positive results by IFA is the method offered commercially by CRPS (Charles River Professional Services) and MBA

(Microbiological Associates). These tests are much superior in sensitivity to the older CF (complement fixation) and SN (serum neutralization) tests.

Note that they are specific only for serologic groups of coronaviruses; CRPS uses MHV antigen for both MHV and SDAV tests. One problem in

acute outbreaks is that affected mice may not develop ELISA detectable antibodies for up to 10 days, or perhaps more, after initial exposure. In

such cases, a direct detection method may be useful; both antigen and RNA (reverse transcription PCR) methods have been described.

Control Return to top

Difficult in multipurpose multi-user (i.e., typical university) facilities, probably because the virus is so easily transmitted and so prevalent in

conventional mice. For barrier maintenance to work, technique must be very rigorous. If infection occurs, it is best to eliminate affected stock.

Alternatively, immunocompetent mice only shed virus for 2 or 3 weeks, and the virus is not environmentally resistant, so infection can be eliminated

by not introducing new susceptible mice for several weeks (i.e., stop breeding or purchasing).

One successful solution for investigators is to establish a separate room, or at least cubicle or laminar flow rack, and maintain their own animals with

such aids as microisolator cages and a laminar flow work station. A good health monitoring program is critical to detect the inevitable breaks.

Significance Return to top

MHV is the single most important infectious agent of mice, at least in regard to their use as research subjects. More complications of research are

known for MHV than any other agent.