II. Parvoviruses (MMV, MPV)
III. Epizootic Diarrhea of Infant Mice (EDIM)
IV. Sendai Virus
V. Mousepox (Ectromelia Virus)
VI. Lymphocytic Choriomeningitis (LCM) Virus
VII. Mouse Norovirus (MNV)
VIII. Miscellaneous Viral Diseases
I. Mouse Hepatitis Virus (MHV)
A. Etiology: MHV is an RNA coronavirus. Several MHV strains display tropisms for different tissues but all share the ability to replicate in the intestinal tract.
B. Transmission: Fecal-oral, direct contact, aerosols, and fomites have been reported. Vertical transmission has been reported in experimental infections, but doesn't appear to occur in spontaneous infections. The incidence of MHV infection is moderate.
C. Clinical Signs: There are 2 major patterns of disease
based on the tropism of the virus strain. The respiratory pattern
begins with virus replication in the nasal cavity and lungs with viremia
and dissemination to other organs. Intestinal involvement is minimal.
The enteric pattern infects the upper respiratory and intestinal tract,
with variable spread to other viscera. Some strains may spread to
the brain. There is overlap between these 2 disease patterns depending
on which strain of MHV is involved. Disease expression is dependent
on virus species and on host factors, including age, genotype and immune
function. MHV infections in immunocompetent mice are generally subclinical.
In suckling mice, watery diarrhea with mortality may occur with virulent
enterotropic MHV infections. Immune deficient mice progressively lose weight
and die (see photo).
D. Pathology: In immunocompetent mice, gross lesions of
MHV infection occur infrequently. Lesions, when present, may include
gasseous distention of the intestinal tract in suckling mice, and multiple
white liver foci in older mice. Gross lesions are common in MHV-infected
immunodeficient mice. The livers of infected immunodeficient mice may have
multifocal white foci along with a hob-nail, nodular appearance (see photo).
.
Histopathological examinations of intestinal tracts reveal transient
syncytia (arrow) of the mucosal epithelial cells in mice infected with
enterotropic virus strains (A.). Focal coagulative liver necrosis
can be seen in mice infected with polytropic virus strains (B.). Hepatocellular
syncytia (arrow) are rarely present around necrotic foci in immunocompetent
mice (C.). In immunodeficient mice, intestinal epithelial cells,
hepatocytes and vascular endothelial cells undergo syncytial cell formation,
necrosis and replacement with scarring in certain organs, especially liver.
E. Diagnosis: The most useful diagnostic test for screening mouse
colonies is the ELISA or the IFA. Histologic lesions are transient
in immunocompetent mice, so histopathologic examination of target tissues
may be helpful in the face of an outbreak.or in identification of infection
in immunodeficient mice. PCR has been shown to help identify virus in tissue
specimens, feces and environmental swipes.
F. Treatment: None.
G. Control: The three most common control measures for immunocompetent mice are to 1) "burn-out" the viral infection through stop breeding of breeders with removal of suckling mice and purposeful mixing of mice to enhance infection of any susceptible mice for 8 weeks, 2) rederive the colony by Cesarian derivation or embryo transfer, or 3) restock with clean animals. Since MHV infections are not transient in immunodeficient mice, the stop-breeding technique would not be recommended. Once MHV-free mice are obtained, husbandry practices must be modified to prevent reintroduction of the virus. Such practices may include use of approved commercial suppliers that can provide recent health monitoring data, quarantine of new arrivals with MHV screening before admittance into facility, use of microisolator cages, use of barrier facilities.
II. Parvovriuses (MVM and MPV)
A. Etiology: Parvoviruses of mice are single stranded DNA viruses of several species: Minute Virus of Mice (MMV) and Mouse Parvovirus (MPV).
B. Transmission: Mice are infected primarily by direct contact with virus shed in feces or urine. Parvoviruses are capable of surviving in the environment for extended periods of time (weeks), so fomite transmission is likely.
C. Clinical Signs and Pathology: Naturally-occurring parvovirus infections do not produce clinical signs or lesions in infected mice. In immunocompetent mouse hosts, MMV appears to cause a short-lived infection while MPV causes persistent infections of lymphoid tissue (especially mesenteric lymph nodes).
D. Diagnosis: Identification of infected mice relies on serologic testing for parvoviral antibodies and amplification of parvoviral genome by PCR. ELISA and IFA are sensitive methods to screen for antibody to either or both parvoviruses depending on the test antigen. The viral protein, VP2, is antigenically distinct between MMV and MPV. ELISAs using MMV VP2 or MPV VP2 are currently used to detect antibodies to these viruses. PCR assays have been developed to screen samples for either parvovirus. Since both MMV and MPV were initially identified as tissue culture contaminates, PCR is widely accepted as a means to screen cultured cells or other biological materials recovered from mice for parvovirus infection. These PCR assays can also be used to diagnose virus infections in mice.
E. Treatment: None
F. Control: Parvoviruses are hardy viruses, and can survive for weeks in the environment. Special attention to decontamination using sterilization and parvoviracidal disinfectants is key to controlling spread of virus. Mouse colonies have been successfully rederived by embryo transfer or cesarian section. Rigorous serologic monitoring of rederived offspring and foster dam will assure success of rederivation process.
III. Epizootic Diarrhea of Infant Mice (EDIM)
A. Etiology: EDIM virus is an RNA virus of the rotavirus group A.
B. Transmission: Transmission occurs by fecal-oral, direct contact, and aerosol routes. Adult mice are inapparent viral carriers and shed the virus to their susceptible young. The incidence of rotavirus infection is low to moderate.
C. Clinical Signs: Usually no clinical signs are noted in
EDIM-infected mouse colonies. In experimentally-infected mice, a
watery yellow diarrhea develops in 14-17 day old mice (see photo).
Rotavirus-infected mice continue to nurse, a clinical feature that can
be used to differentiate rotavirus from MHV-induced diarrheal disease.
MHV-infected mice quit nursing when diarrhea ensues. Feces often
dry on the perineum causing obstipation and death. Surviving mice
exhibit stunted growth. 
D. Pathology: The intestines contain scant, yellow, gaseous
contents. If a dried perianal fecal plug is present, the intestinal
tract may be dilated with the gaseous contents. Histopathologic features
of the disease include vacuolar degeneration of infected enterocytes (arrows),
typically at the villous tip (A.). Degenerative virus-induced vacuoles
vary in size and are associated enterocyte nuclear pyknosis, and are unlike
uninfected enterocytes with globular lipoprotein vacuoles, which are uniform
with a pink proteinaceous droplet (arrow), and unremarkable nuclei that
are common in suckling mice (B.).
E. Diagnosis: The clinical history and positive serological tests by ELISA, IFA or serum neutralization on sera from the mothers of affected mice allow confirmation of rotavirus infection. Additional diagnostic tests include PCR or commercially-available antigen capture ELISA on feces.
F. Treatment: Remove perianal fecal masses with warm water soaks.
G. Control: To prevent spread of the virus in a colony, individual cage filter covers may be used. The disease is most severe in mice born to nonimmune dams. Multiparous dams ingest infant feces and produce antibodies to protect future litters.
A. Etiology: Sendai virus is an RNA paramyxovirus of the parainfluenza type 1 group.
B. Transmission: Direct contact is the primary means of viral spread. The virus is not environmentally stable, but can be transmitted by fomites because of the quantities of virus excreted from infected mice. The incidence of infection is low.
C. Clinical Signs: Infected mice may exhibit labored breathing and decreased fecundity. In DBA/2 and immune deficient mice, the infection is almost always fatal. This virus is immunosuppressive and may predispose to secondary bacterial infections. Generally, no clinical signs are observed in mice in endemically infected colonies. In clinically apparent infections, signs are variable but may include chattering, mild respiratory distress to labored breathing, and decreased fecundity in adults, deaths (possibly whole litters) in neonates and sucklings, and poor growth in weanling and young adult mice.
D. Pathology: The lungs of affected mice may be mottled
with red and tan foci in the parenchyma (A.). Exudate in the major
airways may be seen. Histological examinations reveal characteristic interstitial
pneumonia with perivascular and peribronchiolar lymphoid infiltrates, hyperplasia
of alveolar macrophages, and foci of alveolar and bronchiolar epithelial
necrosis with a neutrophilic infiltrate (B.). Observation of squamous
metaplasia of the bronchial epithelium is associated with the reparative
stage of the infection.
E. Diagnosis: Histologic lesions in susceptible mice and PCR can identify Sendai virus in acute infections. Commercially available ELISA and IFA can be used to identify antibody titers in recovering mice..
F. Treatment: In static colonies, the disease will run its course; no latent infection occurs. In breeding colonies, cessation of breeding for 60 days, elimination of all suckling mice during this time period, and purposeful mixing of weanlings and adults to insure maximum viral exposure of all susceptible mice will prevent infections of future litters.
G. Control: Prevention of exposure or deliberate exposure are the two main approaches to control Sendai virus infection.
V. Mousepox (Ectromelia Virus)
A. Etiology: Ectromelia virus, the agent of mousepox, is a DNA poxvirus of the vaccinia subgroup.
B. Transmission: Natural infections occur via the fecal-oral route, urine contamination or by direct contact. Skin abrasions are thought to provide the main route of entry. Inoculation of mice with poxvirus-infected tumor cells or serum products have also caused disease outbreaks. Severity of disease is dependent on the mouse strain. Incidence of disease is rare, with sporadic epizootics usually resulting from passage of infected cells or other biological material into naive mice.
C. Clinical Signs: Clinical signs are dependent on the genotype of the mouse strain, with strain A, C3H and BALB/c representing suceptible strains, and C57BL/6 considered a resistant strain. In acute disease, there is high morbidity and high mortality with affected animals exhibiting hunched posture, conjunctivitis and facial swelling. Subacute to chronically infected animals develop a cutaneous vesicular body rash which often progresses to swelling, necrosis and sloughing of the extremities. Deaths are sporadic.
D. Pathology: Lesions from animals dying from acute disease include visceral congestion, splenomegaly, white necrotic foci in the liver and spleen, and peritoneal exudate. In addition, focal pancreatic necrosis, erosive enteritis and vesicular pox lesions on the extremities can also be found. Although clinical and gross lesions are suggestive of the disease, histological demonstration of intracytoplasmic inclusion bodies (arrows) in epithelial cells surrounding vesicular skin ulcers, in small intestinal cells and in pancreatic cells is helpful to confirm the diagnosis.
E. Diagnosis: Ruleouts for these signs include Tyzzer's disease, MHV, salmonellosis, skin parasites, ringworm, bite wounds, and arthritis. Electron microscopy and PCR provide excellent forms of documentation of pox virions in infected cells. Serological tests using ELISA, HAI and IFA help screen mouse colonies for the presence of infection.
F. Treatment: None.
G. Control: If the animals are readily available commercially, exterminate the infected colony, sanitize the facility and repopulate with uninfected mice. Valuable mouse strains may be rederived if they can survive the acute infection. Identify the source of virus, and implement measures to prevent re-introduction.
VI. Lymphocytic Choriomeningitis (LCM) Virus
A. Etiology: LCM virus is an arenavirus (RNA virus).
B. Transmission: In utero or perinatal infections (within 1 day post-partum) produce a persistent, subclinical infection. If a mouse is infected after 24 hours of age, antibody production occurs. Virus is continually shed in urine, saliva and milk but antibody is difficult to detect due to low production and to binding with virus to cause circulating antibody-virus complexes. Incidence of disease is rare in commercial breeding colonies. A major source of infection is transplanted mouse (hamster) tumors or cell lines . Vertical (transovarian and/or transuterine) transmission is known to occur and is considered an efficient means of transmission to mice delivered by infected dams.
C. Clinical Signs: Two types of infections are known to occur. The persistent tolerant form results when the infection is acquired in utero or within a few days after birth. There is life-long viremia and shedding of virus. There is modest growth retardation, and at 7-10 months of age, immune complex glomerulonephritis occurs and is associated with emaciation, ruffled fur, hunched posture, ascites and some deaths. The second, nontolerant (acute) infection occurs when the mice are exposed after the first week of life. Viremia develops, but there is no shedding of virus. The outcome is either death within a few days or weeks, or recovery with elimination of the virus.
D. Pathology: Gross lesions vary from none to focal visceral
necrosis and splenomegaly. Histological examination of the brain reveals
lymphocytic infiltration of the meninges, choroid plexus, and of submeningeal
and subchoroid perivascular spaces.
In tolerant mice, perivascular lymphoid infiltrates of viscera and
immune-complex glomerulonephritis may be observed. Please note that these
lesions are also common in inbred strains of mice that are prone to development
of autoimmune disease.
E. Diagnosis: ELISA tests may reveal serum antibodies. PCR of kidney or brain from infected mice or of biological samples will identify virus. Virus isolation can be frustrating since LCM does not induce cytopathic effect. Bioassays include suckling mouse inoculation (footpad injection with infected neural tissue with swelling in 5-9 days or cerebral injection with development of neurological signs) or adult mouse inoculation (inject with whole blood and observe clinical signs or antibody titers in 2 weeks confirming the diagnosis).
F. Treatment: None.
G. Control: Eliminate colony since vertical transmission of the virus makes control measures less effective.
Public Health Significance: CDC reports human LCM infections. Most recent LCM virus exposures have been linked to exposure with experimental infection studies in immunocompromised research mice, or to research bench accidents.
Etiology: MNV is an RNA virus in the family Caliciviridae. There are at least 4 strains designated as MNV-1, MNV-2, MNV-3, and MNV-4. The virus causes enteric infections and can also exit the gut to replicate in macrophages and dendritic cells in multiple organs, including mesenteric lymph node and liver.
Transmission: Fecal-oral and fomite transmission have been reported. The incidence of MNV infection is high.
Clinical Signs: Immunocompetent animals exhibit no clinical signs. Mice lacking specific components of the innate immune system (signal transducer and activator of transcription 1 or both the interferon αβ and γ receptors) succumb to lethal infection. Mice with mutations in a number of other innate immune effector molecules survived infection. Stat1 is involved in signaling through both IFN αβ and IFN γ receptors, so collectively these findings implicate Stat1-dependent innate immunity in prevention of lethal MNV-1 infections. Infected immunocompetent and immunodeficient mice persistently shed virus in feces.
Pathology: Immunocompetent animals exhibit no pathology. After experimental inoculation, STAT1 -/- exhibit mortality with the lesions including encephalitis, cerebral vasculitis, pneumonia, meningitis and hepatitis.
Diagnosis: Serologic assays using Multiplex Fluorescent Immunoassay (MFI) detect all four strains of MNV as there is good serologic cross-reactivity. Additionally, RT-PCR is a useful tool for screening due to the occurrence of prolonged fecal shedding. Target tissues for PCR testing include feces and mesenteric lymph node.
Treatment: None.
Control: The virus is nonenveloped and environmentally stable. It can be killed with a 1:10 dilution of bleach or by autoclaving. Anecdotal evidence suggests the virus can be eliminated by rederiving the colony by Caesarian derivation or embryo transfer.
VII. MISCELLANEOUS VIRAL DISEASES
Mouse poliovirus (Theiler's meningoencephalitis virus)
is an cadiovirus that causes asymptomatic enteric infection. Experimental
inoculation of susceptible mouse strains with neurovirulent strains of
TMEV induce encephalitis and demyelinating disease. Experimentally-infected
mice serve as a model for studying immune-mediated demyelinating diseases,
so it is important that such mice are free from the asymptomatic disease
caused by wild-type strains of TMEV. ELISA is the diagnostic test of choice
for identifying infected mice. Reovirus 3 is a reovirus that
causes runting, diarrhea and jaundice of young mice. The spontaneous
disease is rare, as evidenced by the lack of positive titers in ELISA surveys
of mouse colonies. Viruses found in high frequency in transplantable
cells and tumors include mouse cytomegalovirus, mouse thymic virus,
polyoma virus, and LDV (lactate dehydrogenase elevating virus).
The incidence of spontaneous infections with these viruses in research
mice is rare.
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