II. Chronic Respiratory Disease
III. Corynebacterium bovis (Hyperkertitis Associated Coryneform)
IV. Helicobacter Infections
V. Pasteurellosis
VI. Pseudomonas Septicemia
VII. Salmonellosis
VIII. Staphylococcal Furunculosis
IX. Tyzzer's Disease
X. Miscellaneous Bacterial Diseases
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 unless mucosal 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.
II. Chronic Respiratory Disease
A. Etiology: Mycoplasma pulmonis is a microorganism lacking a cell wall. Cilia-associated respiratory (CAR) bacillus is a Gram-negative filamentous rod that moves by gliding motility. Both organisms can induce a chronic pulmonary disease syndrome.
B. Transmission: Transmission by direct contact with infected secretions has been reported. Although the incidence of infection with either organism is rare, the significance when present is very high, often leading to fulminating respiratory disease. Rats may act as asymptomatic carriers for Mycoplasma pulmonis.
C. Clinical Signs: Infection with either agent begins without
clinical signs. Adverse environmental factors, such as high cage
ammonia levels, and/or the acquisition of primary viral or bacterial respiratory
pathogens, activate subclinical infections. Early signs of overt
disease include an oculonasal discharge and torticollis (see photo).
As the organisms travel down the respiratory tract, labored breathing,
anorexia, and hunched posture occur. Other clinical signs include
snuffling, chattering, anorexia with weight loss, rough hair coat, hunched
posture, and reduced fertility. 
D. Pathology: In the upper respiratory tract, a purulent
discharge may be found on the nasal mucosa and within the tympanic bullae.
This purulent exudate can be found in the trachea and bronchi causing yellow
parenchymous foci which may progress to form bullae (bronchiectasis) and
red to grey areas of consolidation.
E. Diagnosis: Histological examination of lungs reveals
a purulent bronchopneumonia with moderate hyperplasia of the normally rare
peribronchial lymphoid aggregates (A.). Mycoplasma pulmonis
does not stain with histochemical stains due to the absence of a cell wall.
Examination of silver-stained respiratory sections will help identify the
presence of CAR bacillus, which will stain with silver and are present
among the cilia of the airways (arrow in B.).
. 
The preferred sites to culture for Mycoplasma are the nasopharynx and middle ear. The media needed for primary mycoplasma recovery must contain swine or horse serum and yeast extract supplementation. ELISAs are commercially available for serological screening for Mycoplasma pulmonis and CAR bacillus infections in mouse and rat colonies. PCR assays on nasal or tracheal samples are also used for diagnosis of both agents. CAR bacillus can not be cultured on cell-free media, and is diagnosed through histopathologic and serologic examination. Diagnostic tests usually identify Mycoplasma pulmonis and/or CAR bacillus along with other respiratory pathogens such as Pasteurella pneumotropica and Sendai virus.
F. Treatment: Overt disease is just suppressed by antibiotic therapy. Oxytetracycline (0.1 mg/ml water), ampicillin (500 mg/L drinking water), sulfamerazine (500 mg/L drinking water or 1 mg/4 gm food), and enrofloxacin (165 mg/L drinking water) have all been reported to reduce mortality. CAR bacillus was eliminated from experimentally infected mice that received either sulfamerazine or ampicillin treatments for 4 weeks. The carrier state of Mycoplasma pulmonis, however, is not affected by an antibiotic regimen.
G. Control: Since uterine colonization may occur, Cesarian derivation may not eliminate Mycoplasma infection. However, culture of uterus at the time of Cesarian delivery and subsequent testing of young provides a method of salvaging valuable infected mouse strains. Rigid sanitary measures are essential even in the face of a disease outbreak. Rats are known carriers and should never be housed with mice.
III. Corynebacterium bovis (Hyperkertitis Associated Coryneform)
A. Etiology: Corynebacterium bovis has been identified as the cause of a bacterial skin disease of nude mice referred to as "scaley skin disease". The condition typically affects adult homozygous nude mice of both genders, and is manifested as a hyperkeratosis with yellow-white flakes adherent to thickened skin.
B. Transmission: The bacterium is carried on the skin and in the oral cavity of mice, and is transmitted by direct contact and by fomite transmission (handling, flake contact, etc.). C. bovis has been cultured from affected nude mice, and also from skin of asympomatic hisute immunocompetent mice. The association of bacterium with disease may be related to lack of hair since the hairless immunocompetent SKH-1 mouse is also susceptible to bacterial hyperkeratosis
C. Pathology: Affected mice may lose weight and are often
removed from study because of reports of poor growth of transplanted tumors
or hinderence of immunologic studies. Mortality is low and the hyperkeratosis
is transient but may recur. Histologic examination of the skin reveals
acanthosis, orthokeratotic hyperkeratosis with a mononuclear cell dermal
infiltrate (A.). Short, Gram-positive rods arranged in clusters (arrow)
and pallisades can be recognized in the stratum corneum on Gram-stained
skin sections (B.).
. 
D. Diagnosis: The bacterium can be cultured by inoculating blood agar with skin or buccal swabs and grows in punctiform colonies after 48 hrs of incubation in aerobic conditions. The bacterium can also be detected in skin and environmental samples by a C. bovis-specific PCR test.
E. Treatment and Control: Antibiotics such as ampicillin or penicillin VK delivered in drinking water controls the disease but does not eliminate carriage of the bacterium. Control measures include ordering mice from C. bovis-negative mouse colonies, housing mice in sterile microisolator cages, and use of oxidant-based disinfectants on forceps or gloves used for animal handling, and environmental surfaces (including biosafety hoods, animal restrainers, etc.).
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.
A. Etiology: Pasteurella pneumotropica is a Gram-negative, short pleomorphic rod with bipolar staining properties.
B. Transmission: Transmission by aerosol, fecal-oral, and contact with infected secretions (including venereal transmission) has been reported. The bacteria can be consistently isolated from the nasopharynx of subclinically infected mice and is considered an opportunistic pathogen, proliferating in the presence of other respiratory microbial pathogens.
C. Clinical Signs: The majority of infected immunocompetent mice
exhibit no clinical signs. Epidemics of conjunctivitis and panophthalmitis
have occurred in weanling and young adult mice (see photo). An upper
respiratory infection can be manifest by an oculonasal discharge or torticollis
from otitis media, and in the face of respiratory mycoplasmal and viral
diseases, dyspnea may occur. Subcutaneous abscesses, mastitis, metritis
and accessory sex gland abscesses are additional lesions observed in immune
deficient mice. 
D. Pathology: Infected tissues are characterized by mucopurulent inflammation with mild necrosis.
E. Diagnosis: Cultures of the ocular, skin or glandular tissues usually reveal mixed infections of Pasteurella pneumotropica with other bacterial flora. Pasteurella pneumotropica is likely to be isolated in pure cultures from abscesses in immune deficient mice. An ELISA is commercially available to identify antibody in colonized mice.
F. Treatment: Enrofloxacin at 165 mg/liter of drinking water for 2 weeks has been effective in eliminating colonization.
G. Control: The primary concern for disease is in immune deficient mice. Mice should be obtained from colonies free from infection. Do not house infected with uninfected mice.
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.
VIII. Staphylococcal Furunculosis
Staphylococcal species common to the flora of the skin and mucous
membranes of mice are Staphylococcus aureus and S. epidermidis.
Although S. aureus has not been recognized as a primary pathogen,
several reports point to its role in outbreaks of cutaneous infections
in athymic nude mice. Thymic deficient nude mice develop conjunctivitis
and facial abscesses from which S. aureus can be recovered in pure
culture (A.). Inoculation of the bacteria into the skin apparently
occurs from grooming or bite wounds, and although the skin usually remains
intact, the resultant abscesses progressively enlarge and occasionally
spread subcutaneously to form disfiguring lumps, primarily about the face
and head. Histologically, the abscess contains a core of bacteria
(arrow) surrounded by neutrophils, macrophages and fibrocytes (B.).
The condition does not respond well to antibiotic therapy. S.
aureus is considered a pathogen in nude mice and the presence
of these bacteria denotes a breakdown in the gnotobiotic status of the
environment.
. 
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.
X. Miscellaneous Bacterial Diseases
Several Gram-negative bacteria that are frequently part of the
fecal flora of mice have contributed to septicemia or ascending urinary
tract infections. Klebsiella pneumoniae has been recovered
from mice with suppurative lymphadenopathy. E. coli, Proteus mirabilis
and Klebsiella oxytoca have been associated with vaginitis, cystitis,
pyelonephritis and preputial gland abscesses. Antibiotic therapy
has not been routinely initiated when clinical signs are observed, but
may be effective for the localized infections.
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