I. Citrobacter rodentium
II. Endoparasites
III. Epizootic Diarrhea of Infant
Mice (EDIM)
IV. Helicobacter Infections
V. Miscellaneous Viral Diseases
VI. Mouse Hepatitis Virus (MHV)
VII. Parvovriuses (MMV and MPV)
VIII. Pseudomonas Septicemia
IX. Salmonellosis
X. Tyzzer's Disease
A. Etiology: Citrobacter rodentium is a Gram-negative, enteric bacterium implicated as a cause of proliferative bowel disease in young mice. The pathogenic helicobacters (see I.) are also implicated in a proliferative bowel disease, but usually affect older mice.
B. Transmission: Citrobacter rodentium is transmitted through fecal-oral ingestion. Suckling and recently weaned pups are more susceptible than adults, with higher mortality in some inbred strains (C3H/HeJ, C57BL/6, DBA/2J and NIH Swiss) as compared to others. The incidence of infection is low to moderate; the incidence of disease is low.
C. Clinical Signs: This disease is usually transient in
mice, lasting only about 4 weeks. Affected mice look sick and may
excrete soft feces. Mortality is variable. Survivors may often have rectal prolapses (see photo).
Adults show no clinical illness. 
D. Pathology: The colon, especially the descending portion,
and occasionally the cecum, have a greatly thickened mucosa, increasing
the relative size of the large bowel (A.). Even if treated and eliminated
as soon as 2 days post-infection, mucosal hyperplasia still occurs.
Bacterial colonization of the bowel for 10 days results in maximum mucosal
hyperplasia at around day 16 post-infection. The crypts of the colon
are greatly elongated with active cellular mitoses at the base of the crypts
and little inflammatory reaction (B.). When stained with silver or Gram
stains, the bacteria may be seen attached to the surface epithelium.
The mucosa reverts to normal by day 45.
. 
E. Diagnosis: Culture may be unrewarding since bacterial colonization is transient and proliferative colonic lesions persist beyond the period of colonization. Features of this disease that differ from those of pathogenic Helicobacter infection include the following: 1) hyperplastic lesions occur principally in descending colon (involves cecum and colon with pathogenic Helicobacter) 2) there is minimal inflammatory cell infiltrate of mucosa except when erosions occur (usually mild to moderate mixed inflammatory cell infiltrate with pathogenic Helicobacter), and 3) mortality is common in young mice, and colonic lesions in mice of all ages (nonfatal large bowel disease most often in aged mice infected with pathogenic Helicobacter). Isolation and biotyping of C. rodentium are essential since nonpathogenic but related Citrobacter sp. can be found in mouse intestine.
F. Treatment: The disease is contagious but self-limiting. Treatment with neomycin sulfate, tetracycline hydrochloride in drinking water reduces losses but does not completely eliminate the infection. 12.5 % sulfadimethoxine in the drinking water may also prove beneficial in managing mortality. Good sanitation is probably the most important control method. Rectal prolapses usually occur after Citrobacter rodentium has been eliminated from the gut. The rectal prolapse may be reduced by using a moistened cotton micro swab.
G. Control: Use strict sanitation and microisolator cage barriers to prevent cage to cage transmission by fecal contamination. Depopulation and restocking with uninfected mice, and Cesarian rederivation have been successful methods for eliminating the infection.
Hymenolepid Tapeworms
A.Rodentolepis nana is the dwarf tapeworm and Hymenolepis diminuta is the rat tapeworm. Both tapeworms are capable of infecting mice. The incidence of parasitism is rare.
B. Transmission: Rodentolepis nana and Hymenolepis diminuta can be transmitted by an indirect mode with cockroaches, grain beetles, or fleas as intermediate hosts. Rodentolepis nana can also be transmitted by direct ingestion of hexacanth ova or by autoinfection in which the entire life cycle occurs in the host's small intestine (complete life cycle in 14 to 16 days).
C. Clinical Signs: Usually there are no external signs of infection. However, catarrhal enteritis, diarrhea, emaciation and chronic weight loss may occur with heavy infestations.
D. Pathology: Rodentolepis nana adults range from
25 to 40 mm long and less than l mm wide and have an armed rostellum (see
photo). Hymenolepis diminuta adults range from 20 to 60 mm in length
and 3 to 4 mm wide without hooks on the scolex. These tapeworms may
migrate up the pancreatic and biliary ducts. Since R. nana can complete
its life cycle without an intermediate host, strobelocerci may be observed
within the lamina propria of the small intestine.
E. Diagnosis: Visualization of the tapeworm in the small
intestine during necropsy, recovery of hexacanth ova by fecal flotation
or microscopic visualization of segmented parasites or encysted larvae
in histological sections of the small intestine villi (for R. nana) are methods of diagnosis.
F. Treatment: Niclosamide at 10 mg/100 gm body weight should be crushed and given in powdered feed for two treatments at 7 day intervals. Praziquantel, at the equivalent of the cat dose, has been used, but the efficacy of treatment has not been documented.
G. Control: Cockroaches should be eliminated and infected animals treated or eliminated.
Public Health Significance: Humans are susceptible to infections with R. nana; since autoinfection can occur, a heavy parasite load may quickly develop.
Encysted Tapeworms
Mice serve as intermediate hosts for the cat tapeworm Taenia
taeniaformis. The cysticercoid cyst (Cysticercus fasciolaris)
embeds in the liver and causes no clinical signs. Infection occurs
when mice ingest ova from food or bedding contaminated with cat feces.
No treatment is necessary, but feline fecal contamination should be prevented.
Nematodes
A. Pinworms: Syphacia obvelata (note round esophageal bulb in A.)and
Aspiculuris
tetraptera (note oval esophageal bulb in B.) are cecal pinworms commonly
found in mice and other rodents.
. 
B. Transmission: Syphacia obvelata deposits eggs in the perianal region while Aspiculuris tetraptera releases eggs in the colon which then are passed in fecal pellets. Infection occurs via ova ingestion. The eggs of Syphacia obvelata are very light and have been shown to aerosolize, resulting in widespread exposure.
C. Clinical Signs: No signs are usually seen. It has been reported that heavy parasite loads may lead to rectal prolapse or perianal irritation.
D. Pathology: The pinworms are easily recognized as translucent to white, hairlike nematodes in the cecum or colon.
E. Diagnosis: Direct exam of cecal or colonic contents
will identify adults. fecal flotation (for both pinworms) and tape test
of the perianal region (for Syphacia only) will identify eggs. Syphacia
obvelata ova are asymmetrical with pointy ends (C.), while
Aspiculuris
ova are symmetrical and unembryonated (D.). Aspiculuris tetraptera
eggs will be missed by tape test alone.
. 
F. Treatment: If treatment is desired, ivermectin solutions (from horse preparations) diluted to deliver 0.01 mg/ml of drinking water (0.4 mg/kg) can be supplied on days 1, 14, and 28 to break the life cycle. Piperazine (4 to 7 mg/ml water) for 3 to 10 days is also effective, but karo syrup may have to be added to the solution if the mice refuse to drink it. Feed fenbendazole sow cubes (Kent Feed) as sole food source for 3 days; repeat in 7 and 14 days. Have to consider the possible impact of treatment on use of mice before treatment begins.
G. Control: Fenbendazole treated feed has been successful in treating mice, but efforts must be made to remove ova from the environment to prevent re-infection. Disinfectants will not destroy pinworm ova, so they must be either physically removed or inactivated through heat sterilization (cages). Screen incoming animals for pinworms to prevent contamination of other animals. Filtered cage tops will help prevent ova aerosolization during quarantine or treatment of infected mice. Regular parasite examinations with treatment of infected animals may control the parasitism. Cesarian derivation will also eliminate the infection.
Protozoa
A. Spironucleus muris is a flagellated protozoan that dwells
on the small intestinal mucosa. 
1. Transmission: Ingestion of infective cysts is
the primary mode of transmission. A carrier stage occurs in adults.
The incidence of infection is low in conventional mouse colonies.
2. Clinical Signs: Weanling mice (3 to 6 weeks) appear to be most susceptible. Heavily infected mice are usually smaller in size, depressed and have abdominal distension. Dehydration and anorexia follow. A "sticky" fecal mass may be seen on the perineal area.
3. Pathology: The small intestines are rarely dilated and filled with gassy catarrhal fluid contents. Autolysis of the intestines appears to occur more rapidly. No gross lesions are observed in most juvenile and adult mice with this protozoal disease. Histologic exam of the pylorus and upper samll intestine reveal small oval protozoa in the crypts and ocasionally in the space between villi.
4. Diagnosis: Direct smears of small intestinal contents reveal fast darting protozoa.
5. Treatment: Administration of dimetridazole (1 gm/l drinking water) has been reported to reduce mortality, but does not effectively eliminate the parasites.
6. Control: Mice derived by cesarian section and maintained in a barrier environment are usually free of Spironucleus muris.
B. Tritrichomonas sp.(large intestinal flagellate) and Giardia sp. (small intestinal flagellate) are also common protozoal inhabitants of the mouse gut.
1. Transmission: The main route of infection is ingestion of the encysted stage of the organism which is passed in feces of an infected animal.
2. Clinical Signs: No clinical signs have been attributed directly to these organisms. Diarrhea is often exacerbated by the presence of these flagellates.
3. Pathology: No specific pathology accompanies these parasitic infections. Tritrichomonas is most commonly found in the lower small intestine and cecum while Giardia is found primarily in the jejunum.
4. Treatment: Antiflagellate therapy described for Spironucleus can be used, although success in eliminating the parasites is poor. In colony situations, no therapy is attempted.
5. Control: Same as for Spironucleus muris.
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: Helicobacter hepaticus, H. bilis, H. rodentium and H. "typhlonius" are species of Helicobacter that cause disease in laboratory mice. Other helicobacters have been identified and determined to be commensal gut flora. Helicobacters are Gram-negative, microaerophilic spiral motile bacteria.
B. Transmission: The likely mode of transmission is by the fecal-oral route. Rodent helicobacters normally colonize the lower intestinal tract, and can be transmitted to naive mice through contact with feces-laden bedding. H. hepaticus and H. bilis are also capable of colonizing bile canaliculi in susceptible mouse strains. Other rodents, including rats and hamsters, can be colonized by these helicobacters, but do not develop disease. However, these infected rodents may act as reservoirs of bacteria in animal faclities.
C. Clinical Signs: Most mice colonized with helicobacters remain asymptomatic for long periods of time. Certain strains of mice will develop a proliferative, inflammatory typhlitis and/or colitis that may result in rectal prolapse.
D. Pathology: Mouse genotype, age, gender, and the bacterial species
all influence development of lesions. Helicobacter hepaticus
and H. bilis induce a chronic active hepatitis often with necrosis,
portal lymphocytic infiltrates and oval cell hyperplasia (A.) in susceptible
mouse strains including A/J, BALB/c, C3H and immunodeficient mice (SCID
mice and mice with genetically engineered immune defects). Disease develops
in susceptible mice over 6 months of age. Of the immunocompetent susceptible
strains, male mice develop liver disease which may progress to hepatic
carcinoma. Helicobacter hepaticus can be visualized as small
helical organisms in bile canaliculi on silver stained sections (arrowheads).
Helicobacter
bilis is less often observed in silver stained liver sections.
. 
Female mice colonized with H. hepaticus,
H. bilis, and
H.
"typhlonius" often develop an inflammatory bowel disease characterized
by mucosal hyperplasia with erosions/ulcers, mixed inflammatory infiltrate
and rectal prolapse (see photo). Immunodeficient mice of either gender
can develop both liver and intestinal disease.
E. Diagnosis: Helicobacters can be detected by culture, PCR testing,
serology (although no test is commercially available) and histopathology.
Culture provides a standard for documenting infection, but the filtration
methods and microaerophilic incubation conditions for isolation make culture
a laborious option. PCR is a more sensitive and rapid diagnostic
method that is most widely used for screening rodents for infection.
Histopathologic examination of the liver with visualization of characteristic
bacteria is diagnostic; however, not all mice infected with pathogenic
helicobacters develop liver disease.
F. Control: Antibiotic regimens that include bismuth, metronidazole and ampicillin have been used. Success of treatment seems variable, with better results achieved through daily gavage or feeding medicated wafers to young mice. Cesarian derivation and embryo transfer techniques have been used to "clean up" infected mouse colonies.
V. 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 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.
VI. 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.
VII. Parvovriuses (MMV 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 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.
Pseudomonas aeruginosa is a water saprophyte that can colonize the intestinal tract of mice following consumption of nonsterile water. A septicemic and endotoxemic syndrome has been reported in colonized mice that have been treated with immunosuppressive drugs or X-irradiation. Although the systemic disease cannot be treated, the syndrome can be prevented by supplying acidified or chlorinated drinking water to the mice scheduled for immunosuppressive therapy. The desired water pH of 2.2 to 2.5 can be achieved by adding 1N HCl. Water chlorination to 10 to 12 ppm is accomplished by adding sodium hypochlorite (bleach is 6% sodium hypochlorite). Frequent monitoring or changing of treated water is critical to maintain the proper pH or chlorination. There have been a few instances in which clinical inner ear disease has been attributed to natural P. aeruginosa infection, in which animals were seen "circling" or "rolling."
A. Etiology: Salmonella are Gram-negative, toxin-producing, invasive, enteric bacteria. The most common serotype of Salmonella enterica to infect mice is serovar Typhimurium.
B. Transmission: The disease is spread by fecal-oral transmission. Food, water, and bedding may be contaminated by infected feces from wild mice. The incidence of salmonellosis is rare in research mice, and uncommon with sporadic epizootics in mice from colonies raised for pet or zoo industries.
C. Clinical Signs: Disease in susceptible colonies may be manifest only as acute death with no clinical signs of infection. Moderate morbidity characterized by hunched posture, anorexia, lethargy, and high to sporadic mortality may be observed in weanlings and in females in late gestation. Diarrhea may or may not be present. The disease will become endemic, with periodic cycling of overt disease symptoms such as acute deaths, chronic low fertility, fetal reabsorption, or abortion.
D. Pathology: In acute deaths, the spleen may be enlarged
2 to 3 times normal size. Lesions in the small intestine consist of mucosal
congestion and edema with thrombosis of the mesenteric vasculature.
In sub-acute infections, multiple white to yellow foci occur in the liver,
spleen is enlarged, and mesenteric lymph nodes may be enlarged and edematous
(left photo). Histopathological examination may reveal multifocal
necrotizing splenitis and hepatitis, with necrotic foci often accompanied
by colonies of bacteria (arrow in right photo).
. 
E. Diagnosis: The history of the disease outbreak, decreased fecundity in breeding colonies, gross lesions, and identification of wild rodent exposure can be suggestive of salmonellosis. A definitive diagnosis is determined by culture of liver and spleen (in acute cases), feces, mesenteric lymph node, and ileal homogenates (in subacute cases) on selective media such as selenite, brilliant green and MacConkey's agar with serotyping of the isolate.
F. Treatment: Since the carrier state can not be successfully eliminated with antibiotic therapy, elimination of the animal or animals in the colony is suggested. Restock only after extensive sanitation has been performed.
G. Control: Aggressive husbandry improvement procedures should be aimed at prevention of food, bedding, water, or mouse contamination by wild vermin, and proper sanitizing of cages and watering equipment.
Public Health Significance: Humans ingesting Salmonella contaminated food or water may experience a transient diarrhea. Children or immunocompromised adults may experience more severe disease. The disease in humans is reportable.
A. Etiology: Clostridium piliforme is a gram-negative, obligate intracellular, spore-forming rod.
B. Transmission: C. piliforme is transmitted via fecal-oral route by ingestion of spores, which may remain viable in the environment for a year or more. Predisposing factors to overt disease revolve around the immune status of the host and include age (commonly 3 to 7 weeks), strain of mouse and physiological stresses. The incidence of overt disease is rare, but the incidence of infection with recovery may be common in conventionally maintained colonies.
C. Pathology: Resistant mouse strains show little
clinical disease. In weanling or immunodeficient mice, serosal edema
and hemorrhage in the ileocecocolic region of the gut and multiple yellowish-white
foci of necrosis in the liver are prominent lesions. Histological
review of liver sections reveals coagulative to liquifactive necrosis with
variable infifltrates of pyogranulomatous inflammatory cells (A.). Sections
stained with silver help demonstrate large clumps of intracellular bacilli
(arrow in B.) within hepatocytes bordering necrotic liver foci, and in
the cytoplasm of the enterocytes in areas of granulomatous mucosal infiltrates
.
. 
D. Diagnosis: Since the organism cannot be propagated on artificial media, diagnoses are made by demonstration of the bacillus in the tissues, or by detection of antibody with an ELISA.
E. Treatment and Control: Oxytetracycline at 0.1 mg/ml drinking
water for 30 days has been reported to abate deaths in an epizootic, but
is not believed to rid the colony of the infection. Depopulation
and strict sanitation are the current recommendations for eliminating the
disease. The bacterial spores are relatively hardy in the environment,
and may remain viable at room temperature for as long as 1 year. Temperatures
exceeding boiling (from autoclaving) and dilute chlorox solutions (1%)
are capable of killing spores on inert surfaces.
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