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Author: Angie Warner, D.V.M.,D.Sc.

1. Learning Objectives:

  • Be ale to explain the importance of maintaining research colony animals that are free of respiratory disease.
  • Be able to list and understand the pathophysiology of the important viral, mycoplasmal and bacterial respiratory diseases of laboratory rodents, rabbits, and guinea pigs.
  • Be able to explain the importance of Pneumocystis carinii in research rodent colonies.
  • Be familiar with the important respiratory diseases of research primates and the agents that cause them.

2. Infectious Disease Control in Rodent Colonies

  1. Infectious disease in research animals is bad for science.
    1. increased variability in data obtained from studies
    2. increased numbers of animals used
    3. possible erroneous conclusions or irreproducible experiments
  2. Infectious disease control measures in rodent animal facilities are extensive. The emphasis is on prevention of infection rather than diagnosis and treatment.
    1. VAF (virus-antibody-free), also called specific pathogen free (SPF) animals used--Vendor rodent colonies are frequently tested, especially for presence of viral disease.
      1. serology, parasitology, necropsy and culture
  3. Careful health screening of animals moved between facilities during collaborative studies and quarantine with serologic testing of all mice entering a facility.
    1. . maintenance in barrier rodent facilities: Contemporary rodent facilities are scrupulously clean and human access is carefully limited.
      1. Disposable lab coats, caps, masks and booties are worn, as in surgical suites; some facilities require showering in
      2. All food, bedding, water and cages are autoclaved before mice are added
      3. User identification is required for entry
      4. Animal care staff are forbidden to own pet rodents
  4. Rodent housing in “micro-isolators” to prevent spread of disease within rodent facilities
    1. These filter top lids limit air flow into cages and require more frequent cage changes to prevent excessive moisture and ammonia build up
    2. Cage changes are performed in laminar flow hoods that prevent air (and pathogens) from flowing back out into the room
    3. The cage interior is considered surgically sterile, and gloves must be worn when animals are handled
    4. There is good evidence that these procedures can limit infectious disease to one cage over an extended period, thus prevent spread throughout the facility.

3. Viral Diseases of Rodents

  1. Sendai virus (Parainfluenza 1 virus/ family Paramyxoviridae) causes acute respiratory infection in mice, rats, and hamsters. The most serious problems are in mouse colonies.
    1. Enzootic subclinical infectious occur in partially immune colonies in which susceptible animals are introduced regularly.
    2. Epizootic infections occur in previously uninfected colonies and last months with animals showing dyspnea, ruffled fur, weight loss and neonatal mortality.
    3. Strains of mice vary markedly in susceptibility to Sendai infection. Outbred mice eliminate virus earlier than inbred ones. Rats appear more resistant than some mouse strains.
    4. Viral replication occurs in the respiratory tract, and low level transient viremia may occur. Sendai infection induces epithelial necrosis, followed by hyperplasia of the bronchiolar epithelium. Sendai predisposes to secondary bacterial infection.
    5. Viral fusion protein leads to giant cell formation.
  2. Pneumonia virus of Mice (PVM): a pneumovirus of the family Paramyxoviridae
    1. Host range includes mice, rats and hamsters (possibly guinea pigs).
    2. Virus replicates in respiratory epithelial cell cytoplasm and virions bud from the cell membrane.
    3. Weaning mice are susceptible, but clinically apparent disease has not been found in immunocompetent mice. Athymic (nude) mice develop diffuse interstitial pneumonia.
    4. Rat develops mild interstitial pneumonia.
  3. Rat Coronavirus: 2 closely related coronaviruses--Sialodacryoadenitis virus (SDA) and rat coronavirus (RCV)
    1. SDA causes sialodacryoadenitis, an acute self-limiting disease with high morbidity and low mortality. There are cervical swellings due to enlarged salivary glands. There is inflammation and necrosis in salivary and lacrimal glands and in the nasal epithelium.
    2. SDA causes (although many other factors cause also cause) periorbital porphyrin staining (these porphyrins are normal secretory products of Hardarian glands, but resemble blood.
    3. After experimental inoculation, SDA can cause lower respiratory tract lesions in rats, such as tracheitis, bronchiolitis and interstitial pneumonia.
    4. RCA usually causes only subclinical infection, with rhinotracheitis and mild interstitial pneumonia. The infection may be fatal in newborns, however.

4. Murine Respiratory Mycoplasmosis

  1. Mycoplasma pulmonis--causes a chronic persistent airway infection.
    1. M. pulmonis has the greatest negative impact on rodent experimental studies, but with current disease-free suppliers and housing conditions, infection is rarely seen anymore.
    2. The organism inhabits the surface of ciliated respiratory epithelium, and clinical signs range from negligible to those of systemic illness (weight loss, hunched posture, roughened hair coat).
    3. Stress exacerbates clinical signs of mycoplasmosis. Factors that contribute to more severe disease include crowding, ammonia exposure from soiled bedding, vitamin deficiencies, Sendai virus and SDA infection, some of which enhance Mycoplasma adherence to the epithelium.
    4. Mice are more likely to develop an acute pneumonia than rats, who generally show rhinitis and otitis.

5. Bacterial Infections in Laboratory Rodents

  1. Corynebacterium kutscheri causes “pseudotuberculosis” in rat and mouse colonies, with multiple organ abscessation (more likely confined to the lungs in rats).
    1. Infections are uncommon in contemporary rodent facilities, but stress factors such as irradiation, corticosteroid treatment, or concurrent infection can lead to outbreaks.
  2. Streptococcus pneumoniae causes asymptomatic infection of the nasopharynx of rats normally, but with stress or concurrent infections a more serious infection with nasal discharge, dyspnea and stridorous breathing may develop.
    1. Infection can progress to the lungs, resulting in a characteristic fibrinous pneumonia and subsequent pericarditis and pleural effusion.
  3. Cilia-associated respiratory (CAR) bacillus: a gram negative filamentous bacterium that is difficult to culture and thus remains unclassified.
    1. CAR bacillus has been isolated from rats with chronic respiratory disease, and can also infect mice, guinea pigs, hamsters and rabbits (possibly cattle).
    2. CAR bacillus colonized ciliated epithelial cells, causing mononuclear infiltration of the underlying tissue.
    3. CAR bacillus is spread by direct contact and is sensitive to antibiotics in placed in drinking water.

6. Protozoal Infections in Laboratory Rodents

  1. Pneumocystis carinii--a ubiquitous organism classified as either protozoa or fungus.
    1. Pc is found as a non-pathogeic natural infection in many colonies of rats and mice. Immunosuppressed or immunodeficient animals will develop progressive pneumonia.
    2. Pc can cause debilitating pneumonia, with alveoli filled with organisms and an amorphous eosinophilic secretion.
    3. A methenamine silver stain will highlight the organism in lung histopath sections.

7. Respiratory Disease in Guinea Pigs (cavae)

  1. Bordatella bronchiseptica is harbored in asymptomatic carriers in the nasal cavity and trachea.
    1. Newly infected animals develop a purulent bronchitis with extension into the parenchymal region. Purulent bronchopneumonia follows.

8. Respiratory Disease in Rabbits (lagomorphs)

  1. Pasteurella multocida commonly colonizes the nasopharynx of rabbits.
    1. The clinical disease is rhinitis, called “snuffles”, with associated conjunctivitis, otitis media, and occasionally pneumonia.
    2. In extreme cases, there is systemic spread of infection, with subsequent , abscesses, pyometra, and septicemia.
    3. Infected dams infect offspring at or shortly after birth. The bacteria colonize the nasopharynx and spread via the eustachian tube to the middle ear and via the airways to the lungs.
    4. Rabbits with snuffles have a mucopurulent nasal discharge, and characteristically wipe the nose with their front paws, resulting in matted fur on the nose and paws. Contemporary rabbit facilities have SPF animals, and snuffles is becoming unusual
    5. Otitis media can result in progressive torticollis, nystagmus and rolling.
    6. A vaccine is available, but breeders for research laboratories maintain SPF colonies.

9. Respiratory Disease of Subhuman Primates

  1. Measles--caused by a morbillivirus in the family paramyxoviridae.
    1. fever, papular rash and giant cell pneumonia in macaques and some New World species.
    2. Virus invades cells of the respiratory tract, causing necrosis with desquamation or giant cell formation, and serious pneumonia is a frequent complication.
  2. Tuberculosis--Mycobacterium tuberculosis or bovis--a serious disease mainly in captive Old World species.
    1. Clinical signs include cough, anorexia, weight loss and progressive dyspnea.
    2. Lesions are granulomatous nodules in lungs and bronchial lymph nodes.
    3. Captive macaques and New World species are routinely tested (eyelid) at least twice annually.
    4. Although many precautions are taken with this zoonotic disease, the greatest likelihood is spread of infection from human asymptomatic carriers to the colony primates.
  3. Pneumonyssus simicola--the lung mite, which causes pulmonary acariasis.
    1. Nearly all rhesus are infected, resulting in multiple discrete cystic nodules throughout the lungs.
    2. Sections of mites can be found in airways on histopath, and mite pigment accumulates in pulmonary macrophages.

10. References

  • Castleman WL, et al. Pathogenesis of bronchiolitis and pneumonia induced in neonatal and weanling rats by parainfluenza (Sendai) virus. Am J Path 129: 277-286, 1987.
  • Confer AW et al. Intranasal vaccination of rabbits with Pasteurella multocida A:3 outer membranes that express iron-regulated proteins. Am J Vet Res 62: 697-702, 2001.
  • Furuta T, Fujita M, et al. Fatal spontaneous pneumocystosis in nude rats. Lab An Sci 43:551-556, 1993.
  • Schoeb RE, Juliana MM, et al. Effect of viral and Mycoplasma infections, ammonia exposure, vitamin A deficiency, host age, and organism strain on adherence of Mycoplasma pulmonis in cultured rat tracheas. Lab An Sci 43:417-424, 1993.
  • Shoji-Darkye Y, Itoh T, and Kagiyama N. Pathogenesis of CAR bacillus in rabbits, guinea pigs, Syrian hamsters, and mice. Lab An Sci 41:567-571, 1991.
  • Wojcinski ZW, Perry DH. Sialodacryoadenitis virus-associated lesions in the lower respiratory tract of rats. Vet Path 23" 278-286, 1986.