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Infectious Diseases of Mice and Rats (1991)

Chapter: 8. Skin and Joints

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Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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8 Skin and Joints

Overview

Diseases affecting the skin and adnexal structures (e.g., mammary glands) account for many of the clinical abnormalities observed in mice and rats. As a group these diseases can be most perplexing to the clinician and pathologist concerned with rodents. Establishing definitive diagnoses frequently proves difficult or impossible, even in the most capable diagnostic laboratories, because of the complex interactions between some or all of the following: overt pathogens, opportunistic pathogens, host responses, genetic variations of hosts, environmental factors, social interactions, and other, often unknown factors.

A classification of these diseases and conditions is given in Table 12. There are 12 diseases attributed to infectious agents and 6 conditions due to other causes, such as social behavior or environmental factors. In addition to ectromelia virus, other causes of appendage amputations (Mycoplasma arthritidis, Streptobacillus moniliformis, Corynebacterium kutscheri, and "ringtail") are included because of clinical overlap with the pox diseases. Joint diseases, although rare in rodents, have been included here for clinical reasons.

By far the most frequently observed skin conditions are those categorized in Table 12 as "Dermatitis/Alopecias." It should be noted that this category is comprised of a heterogeneous group of conditions represented under both "Infectious Diseases" and "Noninfectious Conditions." The common ectoparasites (mites) and Staphylococcus aureus, a normal inhabitant of the

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×

TABLE 12 Classification of Skin and Joint Diseases/Conditions

I. Infectious diseases

  A. Pox Diseases, Spontaneous Amputations in Some Cases

    1. Mousepox (ectromelia)

    2. Poxvirus disease(s) in rats

  B. Arthritis, Spontaneous Amputations Possible

    1. Mycoplasma arthritidis

    2. Streptobacillus moniliformis

    3. Corynebacterium kutscheri

  C. Dermatitis/Alopecias

    1. Common ectoparasites

    2. Staphylococcus aureus

    3. Pasteurella pneumotropica

    4. Dermatophytosis

    5. Mouse papule virus

    6. Self-mutilation associated with otitis media

  D. Neoplasms

    1. Mouse mammary tumor viruses

II. Noninfectious conditions

  A. Dermatitis/Alopecias

    1. Bite Wounds

      a. Adults (fighting)

      b. Weanlings (hunger ?)

    2. "Whisker trimming," "hair nibbling," and "barbering"

    3. Muzzle alopecia

    4. Hair growth arrest (?)

  B. Spontaneous Amputation Probable

    1. "Ringtail"

skin, are probably the leading causes of skin diseases in mice, while S. aureus alone probably holds that distinction in rats.

Although the diseases caused by poxviruses are extremely important because of high mortality, deleterious effects on research results, and their highly contagious nature, they are relatively infrequent in occurrence or are restricted in geographic distribution. Bacterial arthritis is extremely rare in rodent stocks.

Ectromelia virus
Significance

Low for most research uses of mice. High in those laboratories, such as immunogenetics and tumor biology laboratories, that exchange biologic materials from mice for research purposes.

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×
Perspective

1930: Mousepox was first recognized by Marchal (1930) in England and called "infectious ectromelia". Since that time, mousepox has become the disease name and ectromelia virus has been accepted as the name of the virus.

Recorded major outbreaks of mousepox in the United States are as follows:

1951-1953: Yale University (Trentin and Briody, 1953; Briody, 1955)

1954-1956: Roswell Park Memorial Institute, Buffalo, New York (Shope, 1954; Briody, 1955; Fenner, 1981)

1957-1958: Epizootics in 10 laboratories (Briody, 1959)

1960: Yale University (Bhatt et al., 1981)

1960-1974: National Institutes of Health (NIH), Bethesda, Maryland (Whitney et al., 1981)

1979-1980: NIH and eight other institutions in five states: Utah, Maryland, Missouri, Illinois, and Minnesota (AALAS, 1981; Held, 1981; Whitney et al., 1981).

1981: An enzyme-linked immunosorbent assay (ELISA) for ectromelia virus infection was developed (Collins et al., 1981) and subsequently shown to be far more sensitive and specific than the hemagglutination inhibition (HAI) test that traditionally had been used for serologic diagnosis (Buller et al., 1983).

Agent

Ectromelia virus is a large DNA virus, family Poxviridae, genus Orthopoxvirus. Virions are shaped like ovals or bricks (175 x 290 nm), have a characteristic dumbbell-shaped nucleoid, and are morphologically indistinguishable from vaccinia virus (Fenner, 1982).

Many strains of ectromelia virus have been isolated. The Moscow and Hampstead strains have been studied most extensively. Moscow is the most virulent of the recognized strains. Strains are closely related antigenically. The virus is antigenically related to vaccinia (Fenner, 1982).

Ectromelia virus is cultivable in tissue cultures of several cell types, including HeLa, Vero, and mouse fibroblasts (L929), and on the chorioallantoic membrane of chick embryos (Fenner, 1982).

The virus is quite stable for extended periods under dry conditions at room temperature. It can be preserved for months at room temperature in glycerol and indefinitely at -70°C or by lyophilization (Fenner, 1982). The virus resists dry heat but is rapidly inactivated by moist heat. Heating of serum or other body fluids for 30 minutes at 60°C destroys infectivity (Bhatt and Jacoby, 1987c). Recommended disinfectants include sodium

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×

hypochlorite (100 µg/ml [ppm] available chlorine), vapor-phase formaldehyde (paraformaldehyde, 5-10 g/m3), and iodophores (150-300 µg/ml [ppm]) (Fenner, 1982; Allen et al., 1986; Bhatt and Jacoby, 1986).

Hosts

Mice (Mus musculus). There is one unconfirmed report of the virus being recovered from wild rodents of three genera (Microtus, Apodemus, and Clethrionomys) in East Germany, but wild rodents are not known to serve as reservoir hosts. Some wild mouse species, including Mus caroli, Mus cookii, and Mus cervicolor popaeus, are highly susceptible to experimental infection. Limited replication of the virus and seroconversion occur in members of the genus Rattus after experimental infection (Burnet and Lush, 1936; Fenner, 1981, 1982; Buller et al., 1986).

Epizootiology

Ectromelia virus infections have been reported in many countries. The infection is thought to be enzootic in some institutional mouse colonies in Europe. Periodic epizootics have occurred in the United States since 1950. Some have been traced to imported mice or mouse specimens (Fenner, 1981; Osterhaus et al., 1981).

Ectromelia virus infection has not been reported in commercial barrier colonies in the United States. The infection is most commonly seen in those research laboratories that exchange live mice, mouse tissues, mouse sera, and transplantable mouse tumors (e.g., immunogenetics and experimental oncology laboratories) (Fenner, 1981).

Natural transmission usually is dependent on direct contact and fomites (Wallace and Buller, 1986; Bhatt et al., 1988). Skin abrasions are thought to provide the main route of entry. Aerosol transmission and infection via the respiratory route also is thought to be possible but of relatively little importance (Briody, 1966; Bhatt and Jacoby, 1986; Bhatt et al., 1988). Infected animals begin shedding virus about 10 days after infection when characteristic skin lesions appear (Fenner, 1982).

Persistent infection ("the carrier state") was previously thought to be important in the epizootiology of mousepox. Recovered mice have been reported to shed virus in the feces or from skin lesions for up to 116 days (Gledhill, 1962). However, more recent data indicate that significant numbers of virus particles are shed from infected mice for only about 3 weeks even though the virus can persist for months in the spleen of an occasional mouse (Fenner, 1948c; Bhatt and Jacoby, 1987b). Thus, long-term persistent shedding of virus probably is not as important in the epizootiology of the infection as previously thought (Wallace and Buller, 1985). Cage-to-cage

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×

transmission is low unless favored by husbandry practices, e.g., mixing mice from different cages or handling mice from different cages without changing gloves (Wallace and Buller, 1986; Bhatt and Jacoby, 1987b).

Clinical

Inapparent infection. This form of infection occurs mainly in the highly resistant strains, such as C57BL/6 or C57BL/10. Resistance of these strains to clinical disease (not to infection) has been reported to be due to a single dominant H-2 linked gene (Schell, 1960a,b; Wallace et al., 1985: O'Neill and Brenan, 1987).

Clinical disease. Highly variable, ranging from less than 1% to nearly 100%, depending on many factors such as strain of mouse, strain of virus, length of time infection has been present in the colony, and husbandry practices (Briody et al., 1956; Briody, 1966). The spectrum includes:

  1. Minimal enzootic disease. The disease can smolder for long periods in small subpopulations (e.g., 2-4% of cages or total mice within a room) with little spread of infection, few if any clinical signs, and negligible mortality (Werner et al., 1981).
  2. Explosive epizootic disease. May result in sudden morbidity and mortality affecting 80-90% of a colony. This form of the disease most often has been seen in the more susceptible strains, including A, CBA, C3H, DBA/2, and BALB/c, as a result of the first introduction of the infection into a colony (Briody et al., 1956; Briody, 1966; AALAS, 1981; Bhatt and Jacoby, 1986; Wallace and Buller, 1986).

Clinical manifestations can include any or all of the following: variable (<1% to >80%) mortality; ruffled hair coat; hunched posture; facial edema; conjunctivitis; swelling of the feet; cutaneous papules, erosions, or encrustations mainly on face, ears, feet, or tail; or necrotic amputation (ectromelia) of limbs or tails (Werner et al., 1981; Fenner, 1982).

Pathology

All mice are probably equal in susceptibility to infection, but clinical disease and mortality are virus- and mouse strain-dependent (Bhatt and Jacoby, 1986, 1987a). In general, mice of the A, CBA, C3H, DBA/2, and BALB/c strains are highly susceptible, the AKR and SJL strains are moderately susceptible, and the C57BL/6 and C57BL/10 strains are highly resistant to disease (Briody et al., 1956; Briody, 1966; AALAS, 1981; Wallace and Buller, 1985, 1986; Wallace et al., 1985; Bhatt and Jacoby, 1986, 1987a; Buller et al., 1987a).

The incubation period is 7 to 10 days. Virus ordinarily enters via the

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×

skin. There is local replication and extension to regional lymph nodes via lymphatics, where replication also occurs, resulting in a mild "primary viremia" as virus escapes into the blood via efferent lymphatics. Virus is taken up by splenic and hepatic macrophages, and extensive multiplication occurs in these target organs (sometimes with death due to diffuse splenic and hepatic necrosis), resulting in a massive "secondary viremia." Virus from the secondary viremia localizes in a wide variety of tissues, especially the skin (basal cells), and in the conjunctiva and lymphoid tissues. A primary lesion (frequently on the head) may appear at the site of skin inoculation about 4-7 days post infection. Foot swelling and secondary (generalized) rash (pocks) may appear 7-10 days post infection. Skin lesions heal rapidly (within 2 weeks), leaving scars on survivors (Fenner, 1948a,b, 1949).

In acute mousepox there is severe necrosis of the liver, spleen, lymph nodes, Peyer's patches, and thymus. Jejunal hemorrhage often results from mucosal erosions. Inclusions may be present in the cytoplasm of hepatocytes and other infected cells. Characteristic large eosinophilic cytoplasmic inclusions may be present in skin lesions. Necrotic amputation of limbs (ectromelia) and tails can be seen in mice that survive the acute disease (Roberts, 1962a,b, 1963; Allen et al., 1981).

Diagnosis

Inapparent infections and low prevalence of enzootic disease may create major problems in establishing a diagnosis of mousepox. In the former, there may be no reason to suspect the infection. In the latter, extensive testing may be necessary to identify the low percentage of infected mice in a large population (Wallace et al., 1981; Werner et al., 1981).

Diagnosis of acute disease is based on the presence of typical lesions, with confirmation by: (a) demonstration of characteristic large virus particles in affected tissues by using transmission electron microscopy, or (b) serologic testing of survivors of acute disease (Allen et al., 1981; Bhatt and Jacoby, 1986). Differential diagnosis of the hepatic and splenic lesions should consider infections due to Salmonella enteritidis and Streptobacillus moniliformis. Differential diagnosis of skin lesions should exclude fight wounds, bite lesions of the type in mice described by Les (1972), and loss of limbs due to bacterial infections such as Streptobacillus moniliformis or Mycoplasma arthritidis (Freundt, 1959).

Serologic testing is of special value because of the feasibility of testing large numbers of animals rapidly in the event of a suspected outbreak. The enzyme-linked immunosorbent assay (ELISA) is particularly useful for this purpose in unvaccinated mice because it is sensitive and specific. The ELISA has been reported to give false-positive results in NZW and NZB

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×

mice. The hemagglutination inhibition (HAI) test is relatively insensitive but has the advantage that it does not give positive reactions in testing sera from mice that have been vaccinated with the IHD-T strain (Collins et al., 1981; Buller et al., 1983).

The indirect immunofluorescence assay (IFA) for many years was considered the most sensitive and specific procedure for serologic testing, but the impracticality of maintaining live antigen in the laboratory limited its usefulness for research purposes (Christensen et al., 1966). Recently, the ELISA was found to be 10-fold more sensitive than the IFA (Buller et al., 1983).

Biologic materials, such as cells and blood, can be screened for mousepox (and other agents) by injecting the tissue into known pathogen-free mice followed by serologic testing. Alternatively, virus isolation may be attempted using BS-C-1 and other cell lines (Bhatt and Jacoby, 1986). Failure of skin lesion development at the site of vaccination with vaccinia virus by scarification of tail skin is considered suggestive of prior infection with mousepox (Fenner, 1982).

Control

Institutions that must receive mice, mouse tissues, or tumors from sources other than commercial barrier facilities should have a disease surveillance program for quarantine and testing of incoming mice and mouse tissues for infectious agents, including ectromelia virus. This approach constitutes the only practical way by which laboratories with a high risk of introducing ectromelia virus can effectively avoid the periodic disastrous consequences of mousepox outbreaks (Small and New, 1981).

In the past, accepted practice for eradicating mousepox required disposal of mouse colonies and all infected biologic materials (e.g., tumors and sera), plus rigorous decontamination of rooms and equipment (AALAS, 1981). Cesarean derivation of infected mouse stocks was not considered an acceptable alternative since it may not eliminate the virus; intrauterine infection is known to occur in mice infected during pregnancy (Fenner, 1982). More recently, it has been suggested that quarantine and cessation of breeding may be successful in eliminating ectromelia virus (Bhatt and Jacoby, 1987b).

Vaccination with a live virus vaccine, the IHD-T strain of vaccinia adapted to growth in embryonated eggs, may be useful in eliminating the infection from small, closed colonies where all offspring can be vaccinated at around 6 weeks of age (Tuffery, 1958; Trentin and Ferrigno, 1959; Flynn, 1963a). Vaccination can protect mice from fatal mousepox, but does not prevent infection or virus transmission (Wallace and Buller, 1986; Bhatt and Jacoby, 1987d). Vaccination with the IHD-T strain causes seroconversion and resultant

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×

false positive ELISA and IFA test results, but not to the HAI test because the vaccine does not stimulate production of HAI antibody (Collins et at., 1981; Buller et al., 1983). Immunodeficient mice are highly susceptible to infection with the IHD-T strain and must be protected when vaccinating.

Interference with Research

Mousepox is one of the most feared diseases of mice because of (a) the potential for explosive outbreaks in which mortality can approach 100%, (b) known major effects on research results, and (c) known serious problems of detection once latent infection becomes established in a mouse population (AALAS, 1981).

Manipulations that have been reported to promote mousepox epizootics include: experimental infection with tubercle bacilli, x-irradiation, administration of various toxic chemicals, shipment, tissue transplantation, castration, and tumors (Briody, 1959). In addition:

  1. Mousepox infection can alter phagocytic response (Blanden and Mims, 1973). Conversely, procedures that decrease phagocytosis may increase susceptibility to mousepox, e.g., large doses of endotoxin or splenectomy (Schell, 1960b).
  2. Intraperitoneal injection of Freund's adjuvant enhances the severity of experimental mousepox (McNeill and Killen, 1971).
  3. C57BL/6 mice infected experimentally with LP-BM5 murine leukemia virus had increased susceptibility to ectromelia virus, possibly due to inability to generate an ectromelia virus-specific cytotoxic T cell response (Buller et al., 1987c).
  4. Ectromelia virus can replicate in vitro in lymphoma and hybridoma cell lines from mice. Potentially, passage of such contaminated cell lines in mice can introduce the virus into mouse colonies (Buller et al., 1987b; Wallace and Buller, 1986).
Poxvirus(es) in Rats
Significance

Unknown.

Perspective

Two large outbreaks of a highly fatal poxvirus disease occurred in laboratory rats in the USSR during 1973 and 1974 (Marennikova and Shelukhina, 1976; Marennikova et al., 1978b). A poxvirus disease with symptoms resembling mousepox was reported in Romania in 1976 (Iftimovici et al.,

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×

1976). More recently, rat tissues received from the USSR, but originating in Czechoslovakia, were found to contain poxvirus. The animals from which the tissues were obtained had a clinically inapparent poxvirus infection (Kraft et al., 1982). Whether these reports concerned the same or different viruses is unknown.

Agent

Poxvirus (or perhaps more than one virus). Possibly a virus of wild rodents, Turkmenia rodent poxvirus, that is related to cowpox virus but that is distinctly different from mousepox virus (Marennikova et al., 1978a). The strain isolated from rats in the USSR was designated 012-Moscow 73 (Krikun, 1977; Marennikova et al., 1978b; Kraft et al., 1982).

Hosts

Laboratory rats and wild rodents, Felidae (zoo animals fed infected rats), and humans (Marennikova and Shelukhina, 1976; Marennikova et al., 1978b). Laboratory mice are highly susceptible to experimental infection (Majboroda and Lobanova, 1980; Majboroda et al., 1980).

Of 40 personnel exposed to infected rats, four became ill. Symptoms included headache, fatigue, cough, rhinitis, tickling in the throat, and digestive upset. Two of the four had a rash on the head, shoulders, knees, and back of the hands (Marennikova et al., 1978b).

Epizootiology

Infections in rats have been reported only in animals from the USSR and Eastern Europe. Wild rodents might serve as reservoir hosts in the USSR. Outbreaks of disease in the USSR were explosive, possibly associated with the entry of wild rodents into animal facilities.

Clinical

Infection can be inapparent (Kraft et al., 1982) or occur as an epizootic with 50% mortality (Marennikova and Shelukhina, 1976; Marennikova et al., 1978b). Disease in rats during epizootics occurred in three forms: pulmonary, dermal, and mixed pulmonary and dermal.

  1. Pulmonary form. Rats became anorexic, extremely dyspneic, and moribund, with death occurring uniformly by the third or fourth day of clinical signs.
  2. Dermal form. Relatively mild. Partial anorexia; papular rash on tail, paws, and muzzle, with transition to dry crusts in 1-2 days; sometimes partial amputation of the tail and possibly also the paws; and deaths occurring rarely.
Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×
  1. Mixed form. Symptoms were transient, lasting only two to three days. Suckling rats were most susceptible. Adults most often had the dermal form of the disease and survived (Marennikova et al., 1978b).
Pathology

Lesions seen in the pulmonary form are severe interstitial pneumonia and pulmonary edema with serous or hemorrhagic pleural effusion. In addition to pox lesions and occasional spontaneous amputation of feet and tail, rats with the dermal form of the disease also had focal pneumonia and sometimes mucosal exanthema involving the mouth, nasopharynx, and rectum (Marennikova et al., 1978b).

Kraft et al. (1982) studied a group of rats received from Czechoslovakia via the USSR that had inapparent infection. They found desquamative lesions containing poxvirus virions in the nasal mucosa.

Diagnosis

Definitive information is lacking. The hemagglutination inhibition test or enzyme-linked immunosorbent assay for mousepox might be useful. Virus isolation and characterization are essential.

Control

Definitive information is lacking, but until proven otherwise, measures comparable to those used for mousepox should be employed. Great caution should be used when importing rodents from Eastern Europe and the USSR.

Interference with Research

No data are available. Probably similar to mousepox in mice.

Mycoplasma arthritidis
Significance

Uncertain. Subclinical infection may be very common in rats and mice.

Perspective

Experimental models of arthritis: Most of the recent literature on this agent concerns laboratory models of arthritis produced by inoculating large

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×

doses of Mycoplasma arthritidis intravenously or into the footpad of rats and mice (Lindsey et al., 1978b; Cole and Cassell, 1979; Cole and Ward, 1979). It must be emphasized that these models are highly artificial and may have little relevance to the understanding of the host-parasite relationships in the natural infection.

Natural infections in rats: Natural infections of M. arthritidis in rats have been reported infrequently since 1938, with the organism having one of the following four roles:

  1. Incidental infection has been reported (sometimes in association with Mycoplasma pulmonis) in various sites, including the nasopharynx (Ito et al., 1957; Ward and Cole, 1970; Stewart and Buck, 1975), middle ears (Preston, 1942; Stewart and Buck, 1975; Eamons, 1984), the lung (Cole et al., 1967), a paraovarian abscess (Preston, 1942), the submaxillary gland (Klieneberger, 1938), and multiple organs (Davidson et al., 1983).
  2. Subclinical infection has been a complicating factor in studies of experimental arthritis (Pearson, 1959; Mielens and Rozitis, 1964; Cole et al., 1969).
  3. As a contaminant of transplantable tumors M. arthritidis has caused polyarthritis and/or abscesses at the injection site in recipient rats (Woglom and Warren, 1938; Howell and Jones, 1963).
  4. M. arthritidis has been a cause of spontaneous polyarthritis in wild (Collier, 1939) and laboratory (Findlay et al., 1939; Preston, 1942; Ito et al., 1957) rats.

Thus, the literature contains less than a dozen reports of natural arthritis due to M. arthritidis in rats, with the most recent such report appearing in 1969.

Natural infections in mice: Natural infections of M. arthritidis in mice were first reported in 1983 (Davidson et al., 1983). In that study the organism was isolated from the nasal passages, the conjunctiva, and the uterus and by laryngo-tracheo-bronchial lavage from approximately 10% of otherwise pathogen-free mice and rats housed in the same room. No gross or microscopic lesions attributable to M. arthritidis were found in either host.

Agent

M. arthritidis is a bacterium, class Mollicutes, order Mycoplasmatales, family Mycoplasmataceae (sterol-requiring mycoplasmas). It is Gram negative, lacks a cell wall, pleomorphic, and may occur in filaments 2 to 30 µm long. It will grow on conventional horse serum-yeast extract mycoplasma medium, usually under facultatively anaerobic conditions at pH 7.8, 37°C, and 95% relative humidity. M. arthritidis requires arginine and usually produces "fried egg" appearance when grown on solid medium. For specific methods of cultural isolation, see Cassell et al. (1983a).

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×

Determination of the species is based on biochemical and serologic tests (Razin and Freundt, 1984). The type strain is ATCC 19611 (NCTC 10162, PG6). Virulence factors of M. arthritidis have not been defined (Razin and Freundt, 1984). The organism can be preserved indefinitely by lyophilization or freezing at -70°C.

Hosts

Rats and mice are considered the natural hosts. A few isolates have been obtained from monkeys and humans, but their significance is unknown (Razin and Freundt, 1984).

Epizootiology

Current evidence suggests that subclinical (often noncultivable) infection occurs in many contemporary rats and mice, including cesarean-derived, barrier-maintained stocks (Thirkill and Gregerson, 1982; Davidson et al., 1983, Lindsey et al., 1986b). The preferred host sites and natural history of these infections are poorly understood.

Clinical

The infection is usually subclinical and noncultivable.

Pathology

Lesions usually are not present in subclinical infections (Davidson et al., 1983). The pathology of experimental arthritis due to M. arthritidis in rats and mice has been reviewed by Lindsey et al. (1978b).

Diagnosis

For rodent health surveillance the ELISA (Horowitz and Cassell, 1978; Cassell et al., 1981, 1983b) should be performed, followed by Immunoblot (Minion et al., 1984) on positive sera for differentiation of M. arthritidis and M. pulmonis antibodies. Adult breeding stock should be tested repeatedly by using the ELISA because only a few animals with subclinical infection usually seroconvert, and some do so only transiently. Few animals within a population may be infected, and very few organisms may be present in any host site. Isolation of the organism from such animals with subclinical infection may require culture of tissue homogenates from multiple organ sites, which is not practical in most instances (Cassell et al., 1983a). In the rare event of clinical arthritis, the organism should be cultured from joint exudates (Cassell et al., 1983a).

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×
Control

Definitive information is not available. However, major attention should be directed toward selection of M. arthritidis-free breeding stocks through intensive, repetitive testing by ELISA of small populations of breeders over many months, followed by strict barrier maintenance. If valuable stocks infected with M. arthritidis are to be rederived, it might be helpful to place breeders on an extended course of tetracycline treatment prior to cesarean derivation. Only known M. arthritidis-free stocks should be used as foster parents. The mode(s) of transmission are unknown.

Interference with Research

Subclinical M. arthritidis infections can be activated to complicate experimental arthritis in rats (Pearson, 1959; Mielens and Rozitis, 1964; Cole et al., 1969).

M. arthritidis infection can cause spontaneous polyarthritis in rats (Collier, 1939; Findlay et al., 1939; Ito et al., 1957; Preston, 1942).

Transplantable tumors of rats can become contaminated with M. arthritidis, resulting in arthritis and/or abscesses at the injection site in recipients (Woglom and Warren, 1938; Klieneberger, 1939; Jasmin, 1957; Hershberger et al., 1960; Ward and Jones, 1962; Howell and Jones, 1963; Amor et al., 1964).

Experimental infections of rodents with M. arthritidis can be complicated by preexisting, latent infection with this mycoplasma (Thirkill and Gregerson, 1982).

Experimental infection of rats with M. arthritidis has been shown to increase susceptibility to experimental pyelonephritis (Thomsen and Rosendal, 1974).

Experimental infections of M. arthritidis in mice have been found to induce interferon production (Rinaldo et al., 1974; Cole et al., 1976b), activate T and B lymphocytes (Cole et al., 1977, 1981, 1982; Naot et al., 1977), suppress humoral and cellular immune responses (Kaklamanis and Pavlatos, 1972; Eckner et al., 1974; Cole et al., 1976a), and alter macrophage function (Dietz and Cole, 1982).

M. arthritidis is a frequent contaminant of rodent cell cultures (Barile, 1973).

Streptobacillus moniliformis
Significance

Low.

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×
Perspective

This organism was a common commensal of wild and laboratory rats (and an occasional pathogen of humans, mice, and other species) before the era of widespread cesarean derivation and barrier maintenance of laboratory rodents. There have been relatively few reports of the infection in the United States since 1960, including approximately a dozen cases of rat-bite fever in humans (Anderson et al., 1983).

Agent

Streptobacillus moniliformis is a bacterium of uncertain taxonomic position. It is a Gram-negative bacillus, which measures 0.1-0.7 x 1.0-5.0 µm, and occurs singly or in long, filamentous chains. It often has spherical, oval, fusiform, or club-shaped swellings. S. moniliformis requires serum, ascitic fluid, or blood for growth and is nonhemolytic. It is negative for catalase, oxidase, nitrate reduction, and indole production. S. moniliformis can form "cotton balls" or "fluff balls" in broth and can produce L-form variants (Savage, 1984).

Synonyms: Streptothrix muris ratti, Nocardia muris, Actinomyces muris, Haverhilia multiformis, Asterococcus muris, and many others.

Hosts

The natural host is the rat, with most common isolation sites being the nasopharynx, middle ear, respiratory tract, and subcutaneous abscesses (Freundt, 1959; Savage, 1972, 1984). Mice, guinea pigs, turkeys, humans, and others can contract the infection from rats, especially from rat bites (Harkness and Ferguson, 1982). In humans, cases resulting from bites have been referred to as "rat-bite fever" and cases occurring in milk-borne epidemics have been referred to as "Haverhill fever."

Epizootiology

The organism is a commensal of the nasopharynx in wild and conventionally reared laboratory rats (Strangeways, 1933; Klienebrerger, 1935). It has not been reported from cesarean-derived, barrier-maintained rats or mice (Van Rooyen, 1936; Weisbroth, 1979).

Epizootic disease has occurred in laboratory mice (Levaditi et al., 1932; Mackie et al., 1933; Freundt, 1956) and wild mice (Williams, 1941) and is most likely to be seen in mice housed near infected rats (Freundt, 1959).

Transmission is by rat bites, aerosols, and fomites.

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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Clinical

Rats harbor infection in the nasopharynx without clinical signs. The organism is not known to cause natural disease in rats.

In mice, early signs have included conjunctivitis, photophobia, cyanosis, diarrhea, anemia, hemoglobinuria, emaciation, and high mortality. In survivors septicemia apparently clears in a few weeks, but infection persists around joints for about 6 months (Savage et al., 1981). During the chronic phase of infection there may be diffuse swelling and reddening of limbs or tail, with the development of chronic arthritis, deformity and ankylosis, or amputation (ectromelia) at any stage in the evolution of joint disease. With the occurrence of spinal lesions, posterior paralysis, kyphosis, and priapism can occur. Abortions and stillbirths also have been reported (Levaditi et al., 1932; Mackie et al., 1933; Williams, 1941; Freundt, 1956, 1959; Sawicki et al., 1962).

In humans, the incubation period is usually 3 to 10 days, followed by abrupt onset of fever, chills, vomiting, headache, and myalgia. There is a maculopapular rash that is most pronounced on the extremities. Arthritis occurs in about two-thirds of cases, and other complications such as endocarditis and focal abscesses occur in some untreated cases. The recommended treatment is penicillin, administered for a minimum of 7 days (Roughgarden, 1965; Anderson et al., 1983).

Pathology

In mice, the early lesions are those associated with septicemia, particularly focal necrosis of spleen and liver, splenomegaly, and lymphadenopathy. Subsequently, arthritis of varying stages and severity predominate (Lerner and Silverstein, 1957; Lerner and Sokoloff, 1959). There may be spontaneous amputation of limbs and tails (Levaditi et al., 1932; Mackie et al., 1933; Williams, 1941; Freundt, 1956, 1959).

Diagnosis

Cultural isolation and identification of the organism (Martone and Patton, 1981) are essential, along with exclusion of other infectious agents and disease processes. Differential diagnosis should rule out mousepox and bacterial septicemias such as those caused by Corynebacterium kutscheri and Salmonella enteritidis.

Control

Mice and rats from stocks that have been cesarean derived, barrier maintained, and regularly monitored for rodent pathogens by a comprehensive

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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health surveillance program should be used. Housing mice and unmonitored rats in the same room should be avoided.

Streptobacillus moniliformis is considered rare in contemporary laboratory rats and mice. This is perhaps one of the most striking achievements of cesarean-derivation, barrier-maintenance methodology (Weisbroth, 1979).

Interference with Research

S. moniliformis is unlikely to be found to interfere with research results because it is rare in contemporary rodents. Nevertheless, it can cause high mortality in mice and is a serious zoonotic infection in people.

Common Ectoparasites

The comprehensive text Parasites of Laboratory Animals (Flynn, 1973a), lists approximately 4 flea, 4 lice, 24 mite, and numerous tick parasites of mice and rats. However, an important distinction is made between the prevalence of ectoparasites among animals in nature and those in the laboratory. For laboratory populations, Flynn (1973a) lists as being common only four types of mite for mice (Myobia musculi, Myocoptes musculinus, Radfordia affinis, and Psorergates simplex) and one type of mite for rats (R. ensifera). Weisbroth (1982) states that P. simplex has not been reported in the past decade and can be regarded as rare. For the same reason R. ensifera can also be considered rare (unpublished observations of members of the ILAR Committee on Infectious Diseases of Mice and Rats). Thus, only three mites (M. musculi, M. musculinus, and R. affinis), all of which are parasites of mice, can be accepted as common ectoparasites in contemporary laboratory settings (Kunstyr and Friedhoff, 1980; Weisbroth, 1982).

Myobia musculi
Significance

Moderate.

Perspective

Myobia musculi is considered the more pathogenic of the common mites of laboratory mice.

Agent

Myobia musculi is a fur mite, order Acarina. Adult Myobia musculi, which can be seen with a hand lens, appear pearly white and elongate

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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(about twice as long as wide). Males and females have the same general appearance. The males measure 285-320 µm long x 145-175 µm wide. The females measure 400-500 µm long x 285-300 µm wide. The first pair of legs is very short, closely associated with the mouth parts, and modified for clasping hair. The second, third, and fourth pairs of legs have tarsi that end in a claw-like structure known as an empodium (Flynn, 1955, 1963e, 1973a).

Life Cycle

The life cycle includes egg, larval, nymphal, and adult stages. The eggs are oval and about 200 µm long and are usually seen either attached to the base of hairs or inside mature females. Eggs hatch in about seven days, and completion of the entire life cycle requires about 23 days (Flynn, 1973a; Friedman and Weisbroth, 1977; Weisbroth, 1982).

Hosts

Mice. Rarely, rats and other laboratory rodents.

Epizootiology

Mites can be seen anywhere on the body but are most numerous alongside the hair bases and in the more densely furred areas (i.e., over the head and back). Transmission is by direct contact (Weisbroth, 1982).

The dynamics of mite populations on the host are very complex and are influenced by factors that include grooming, mouse strain susceptibility, and host immune responses. Athymic nude (nu/nu) and other furless mice are not susceptible to infestation (Weisbroth, 1982).

Clinical

The general appearance of infested mice is not directly related to the size of the mite populations present. Infestations are commonly subclinical. Clinical signs include scruffiness, pruritis, patchy alopecia, self-trauma, ulceration of the skin, and pyoderma. Close inspection often reveals varying amounts of bran-like material (hyperkeratotic debris) and mites on the skin and around the base of the hairs (Csiza and McMartin, 1976; Weisbroth, 1982).

Pathology

Mice of the C57BL strains and their congeneic sublines are particularly susceptible to severe skin disease caused by M. musculi, presumably because

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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of their propensity to develop hypersensitivity to mites (Friedman and Weisbroth, 1975; Csiza and McMartin, 1976; Weisbroth et al., 1976; Weisbroth, 1982).

Lesions vary from mild to severe. Initially there is mild hyperkeratosis, but this often progresses to severe hyperkeratosis with fine bran-like material on the skin over virtually all of the body but particularly abundant over the dorsum, head, and shoulders. In more advanced cases, there is patchy alopecia and chronic, ulcerative dermatitis distributed most frequently asymmetrically in the shoulder and neck regions. Secondary bacterial infection commonly leads to suppurative and granulomatous inflammation. Hyperplasia of regional lymph nodes, splenic lymphoid hyperplasia, and increased serum immunoglobulins are common. Chronic infestation can cause secondary amyloidosis (Galton, 1963; Csiza and McMartin, 1976; Weisbroth et al., 1976; Weisbroth, 1982).

Diagnosis

The diagnosis is made by demonstrating and identifying the mites, while excluding other causes of dermatitis such as fungi (ringworm) or Staphylococcus aureus. Mites can be demonstrated by using a stereoscopic microscope or hand lens to examine the pelage, particularly over the back and head. Alternatively, mice can be killed and placed either on black paper and left at room temperature or in tape-sealed Petri dishes and refrigerated for an hour. As the body cools, the mites leave it and can be collected from the paper or Petri dish. The mites are mounted under a coverslip on glass slides with immersion oil and identified microscopically on the basis of anatomic features (Flynn, 1955, 1963e, 1973a; Wagner. 1969; Weisbroth, 1982).

For preservation of mites, Hoyer's solution is recommended. Hoyer's solution is made by mixing the following, in sequence, at room temperature: 50 grams of distilled water, 30 grams of gum arabic, 200 grams of chloral hydrate, and 20 grams of glycerine (Flynn, 1963e).

Control

Cesarean derivation and barrier maintenance are the most effective methods for eradication of mite infestations (Weisbroth, 1982). Treatment with insecticides is not recommended because they can alter experimental results.

Interference with Research

Infestations of M. musculi have been found to cause secondary amyloidosis (Galton, 1963; Weisbroth, 1982). In addition, mite-infested mice should be

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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considered undesirable for behavioral studies because behavioral patterns are likely to be altered by hypersensitivity to the mites.

Myocoptes musculinus and Radfordia affinis

These two mites will not be discussed in detail because they are generally similar to Myobia musculi in morphology, epizootiology, life cycle, diagnosis, and control. Myocoptes musculinus causes lesions similar to but usually milder than those caused by Myobia musculi, whereas Radfordia affinis is not recognized as a significant pathogen. It must be emphasized that mite infestations of mice usually are due to more than one mite species. M. musculinus and R. affinis also are identified by characteristic morphologic features of the adults (Flynn, 1973a; Weisbroth, 1982).

Interference with Research

Mite infestations due to M. musculinus have been found to reduce the contact sensitivity of mice to oxazolone (Laltoo and Kind, 1979).

Other Ectoparasites

Readers desiring more in-depth coverage and information on the less common species of ectoparasites of mice and rats should consult comprehensive reference works on the subject (Baker et al., 1956; Pratt and Littig, 1961; Pratt and Wiseman, 1962; Owen, 1972; Flynn, 1973a; Hsu, 1979; Weisbroth, 1982).

Staphylococcus aureus
Significance

Low.

Perspective

This organism is considered one of the more important causes of naturally occurring skin lesions in mice and rats.

Agent

Staphylococcus aureus is a Gram-positive, coagulase-positive, coccus bacterium, family Micrococcaceae. It occurs in grape-like clusters, is facultatively anaerobic and usually produces yellow pigment when grown on

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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blood agar. S. aureus produces many extracellular enzymes and toxins. It is one of the hardiest of non-spore-forming bacteria. Species subtypes are identified by bacteriophage typing and biochemical reactions (Oeding, 1983).

Hosts

Mice, rats, people, and many others.

Epizootiology

It commonly colonizes nasopharynx, lower digestive tract, fur, and skin of conventionally reared, as well as barrier-reared rodents. It can also be readily cultured from cages, room surfaces, and personnel.

The epizootiology of pathogenic types in animals is poorly understood. Human carriers may be an important source of infection for rodent colonies and vice versa (Blackmore and Francis, 1970).

Many rodent colonies have infection without overt disease. Pathogenesis probably is dependent on many factors including phage type(s) present, traumatic injuries of skin or mucosal surfaces, host factors, and sanitation.

Clinical

A variety of clinical syndromes have been attributed to Staphylococcus aureus, including the following:

  1. Ulcerative dermatitis in rats. Intensely pruritic, moist eczematous lesions, usually 1-2 cm in diameter, occur on lateral surfaces of the shoulders and neck. Lesions appear to be initiated or aggravated by scratching with the ipsilateral rear foot. Pruritis associated with sialodacryoadenitis virus infections of Harderian or salivary glands may play a role (Ash, 1971; Fox et al., 1977b; Wagner et al., 1977).
  2. Ulcerative dermatitis in mice. Moist eczematous lesions on face, neck, ears, and forelegs. In one facility 10-50% of VM/Dk mice were affected beginning around 8 months of age. The lesions were rarely seen in mice of several other strains in the facility (Taylor and Neal, 1980).
  3. Facial abscesses in immunocompetent mice. Multiple abscesses and botryomycotic granulomas occur in deeper tissues of the face, including the orbital tissues, facial muscles, peridontium, and mandibles. In one facility the C57BL/6Bd strain was the most affected of several strains present. Another outbreak involved the BSVS strain (Shultz et al., 1973; Clarke et al., 1978).
  4. Orbital and facial abscesses in athymic (nulnu) mice. Purulent lesions of varying size occur commonly around the eyes and on the face (ILAR, 1976b).
Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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  1. Tail lesions in rats. Raised, yellow pustules occur on the proximal one-third of the tail, progressing to draining abscesses and sometimes sloughing of the tail (Hard, 1966).
  2. Preputial gland abscesses. Preputial glands are firm and enlarged to a few millimeters in diameter. Many strains are affected, but C3H/HeN has the highest incidence (Needam and Cooper, 1976; Hong and Ediger, 1978a).
  3. Self-mutilation of penis. Young male C57BL/6N mice develop this condition when first placed in cages with females for harem breeding. The sheath swells so that it can be impossible to protrude the penis. The penis of affected males may be mutilated severely so that the os penis often protrudes from the surface. Acute balanoposthitis is associated with accumulation of purulent exudate containing S. aureus in the sheath. Disease may be related to aggressive breeding activity of young males with traumatic injury of the penis (Hong and Ediger, 1978b; J. R. Lindsey, Department of Comparative Medicine, University of Alabama at Birmingham, unpublished).
  4. Traumatic pododermatitis in rats. Exercise on circular activity wheels causes abrasions and lacerations with secondary staphylococcal pododermatitis of the hind feet (Morrow et al., 1977).
  5. Pathology

    The primary mechanism of host defense against S. aureus is complement-mediated killing by polymorphonuclear leukocytes (Verhoef and Verbrugh, 1981; Quie et al., 1983). Thus, suppurative inflammation is a hallmark of S. aureus tissue invasion. In ulcerative dermatitis there is destruction of the epidermis, and the underlying dermis contains pustules, abscesses and, eventually, chronic or granulomatous inflammation. The other clinical syndromes are similar, differing mainly in location and stage of infection. Large numbers of organisms are usually present and can be demonstrated readily in Gram-stained sections or imprints.

    Cell-mediated immunity can be important in host defense against S. aureus and in the pathogenesis of some rodent lesions associated with this agent. Experimentally delayed hypersensitivity to S. aureus can easily be induced in mice (Johnson et al., 1961; Taubler, 1968; Taubler and Mudd, 1968; Easmon and Glynn, 1975, 1977, 1979; Adlam and Easmon, 1983). Although not proven, it may be that hypersensitivity to S. aureus plays a role in the ulcerative dermatitis associated with this agent in mice and rats.

    The preputial abscesses in C3H/HeN mice reported by Hong and Ediger (1978a) apparently result from ascending infection in the ducts of the preputial glands. Purulent exudate fills the ducts and glands and may dissect through the gland wall, resulting in subcutaneous abscesses in the pubic area. From the ventral surface these appear as small lumps (1-3 mm) underneath the skin. Organisms other than S. aureus, specifically, enteric bacteria, also

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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have been observed to produce this lesion in C3H/HeN mice (J. R. Lindsey, Department of Comparative Medicine, University of Alabama at Birmingham, and J. E. Wagner, Veterinary Medical Diagnostic Laboratory, University of Missouri, Columbia, unpublished).

Diagnosis

The diagnosis of S. aureus is dependent upon isolation and identification of the organism and exclusion of other agents (e.g., dermatophytes and mites) as possible causes of lesions.

Control

General methods of control are improved sanitation, frequent sterilization of cages and other equipment, assurance of proper operation of cage washers, elimination of equipment that causes injury to the skin, and reduction in the number of animals per cage. In the case of self-mutilation of the penis in mice, reduction of the number of females per male in harems is helpful.

Interference with Research

Infections of S. aureus may require culling of breeders or may disrupt studies, particularly in older animals. Even more important may be alterations in host immune responses, e.g., it has been shown experimentally that injection of killed S. aureus into mice inhibits contact sensitivity to oxazolone by activating suppressor B cells (Benedettini et al., 1984). The occurrence of renal abscesses caused by S. aureus in rats has been observed following prolonged immunosuppression with corticosteroids (Simmons and Simpson, 1977).

Dermatophytes
Significance

Low.

Perspective

Laboratory mice and rats occasionally have been found to serve as inapparent carriers of dermatophytes and, rarely, have been reported to have clinical dermatomycosis (ringworm or favus). Very few infected colonies have been incriminated as sources of dermatophyte infection for people (Dolan et al., 1958; MacKenzie, 1961; Brown and Suter, 1969; Refai and Ali, 1970; Kunstyr, 1980; Fox and Brayton, 1982).

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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Agent

Fungi, class Deuteromycetes (Fungi Imperfecti), genera Trichophyton and Microsporum. Trichophyton mentagrophytes is the most common cause of inapparent infection and reported dermatomycosis in mice and rats. Other dermatophytes that have been isolated from the fur of mice and rats include Trichophyton ajelloi, T. schoenleini, T. terrestre, Microsporum gallinae, M. gypseum, and M. cookei (Georg, 1960; Dvorak and Otechenasek, 1964; Emmons et al., 1977; Weisbroth, 1979; Kunstyr, 1980; Fox and Brayton, 1982; Williford and Wagner, 1982).

Hosts

Mice, rats, people, and numerous others (Georg, 1960).

Epizootiology

Dermatophytes are not reported in cesarean-derived, barrier-maintained rodent stocks. Other animals and people probably are major reservoirs of infection for mice and rats. Organisms are parasites of keratin, i.e., hair and superficial layers of skin (Georg, 1960; Emmons et al., 1977).

Clinical

Inapparent infections are thought to be more common than clinical disease, but both are rare (Dolan and Fendrick, 1959; Davies and Shewell, 1965; Feuerman et al., 1975; Fishman et al., 1976; Balsari et al., 1981). Clinical disease appears to have been observed in mice (Booth, 1952; Blank, 1957; Cetin et al., 1965; Reith, 1968; Fishman et al., 1976) far more frequently than in rats (Povar, 1965).

Lesions consist of irregularly defined areas of alopecia with a scaly to crusty appearance and occasional pustules at the edges. Lesions are most common on the head near the mouth and eyes, but can be seen anywhere on the body (Georg, 1960).

Pathology

Uncomplicated lesions can be very subtle, with only thickening of the stratum corneum seen in sections stained with hematoxylin and eosin. Special stains such as periodic acid-Schiff or Gridley's fungus stain are valuable in demonstrating the organisms. Severe cases may have hypertrophy of the epidermis with varying degrees of acute and chronic inflammation in the dermis (Georg, 1960).

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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Diagnosis

For detection of asymptomatic carriers, the fur of several animals can be brushed while the animals are held over opened plates of culture medium and then the plates can be cultured for dermatophytes (Mackenzie, 1961). For clinical cases, hair can be plucked or skin scrapings can be taken from the periphery of lesions and mounted onto slides in 10% potassium hydroxide for visualization of hyphae and endospores. Definitive diagnosis is dependent on culture and identification of organisms by using Sabouraud's or other dermatophyte medium (Georg, 1960; Emmons et al., 1977).

Control

Where feasible, infected stocks should be destroyed and replaced by dermatophyte-free stock after thorough sterilization and disinfection of facilities and equipment. Cesarean derivation of valuable stocks may be desirable. Treatment of affected animals is not recommended.

For prevention of infection, barrier maintenance is effective. Rodents should be housed well away from laboratory animal species known to be more frequently infected, e.g., cats and dogs (Kunstyr, 1980).

Dermatophyte infections of mice and rats do not represent important zoonoses. The most common of these infections, T. mentagrophytes infection in mice, has been reported as a source of infection for humans in only six instances (Fox and Brayton, 1982), and these occurred in the 1950s and 1960s before cesarean-derivation and barrier-maintenance methods were in common practice.

Interference with Research

There are no known examples of dermatophyte infections interferring with research in contemporary mice and rats.

Pasteurella pneumotropica
Significance

Low.

Perspective

1948-1950: Jawetz (1948, 1950) and Jawetz and Baker (1950) published papers that seemed to implicate Pasteurella pneumotropica as an ubiquitous respiratory tract pathogen of major importance in mice.

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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1973: Moore et al. (1973) reported on a stock of gnotobiotic rats maintained in isolators and found that they were monocontaminated with P. pneumotropica, suggesting that the organism might normally inhibit the gastrointestinal tract.

1974: Jakab (1974) reported on the first in a series of studies in which mice experimentally infected with Sendai virus showed decreased clearance of intranasally inoculated P. pneumotropica. Although this and subsequent studies by Jakab and associates (Jakab, 1981) were entirely experimental, they possibly gave further impetus to the belief that P. pneumotropica is a respiratory pathogen.

1980s: More than 3 decades after the reports of Jawetz (1948, 1950) and Jawetz and Baker (1950) P. pneumotropica has not been incriminated as being responsible for outbreaks of respiratory disease in mice, i.e., their findings have not been confirmed in a natural outbreak. Perhaps their experimentally infected mice also had Sendai virus and/or Mycoplasma pulmonis infections. The gross and microscopic lesions they described were compatible with murine respiratory mycoplasmosis. Also, their mice were stated to have natural Chlamydia trachomatis infection and spontaneous pulmonary consolidation (Jawetz, 1950).

Agent

Pasteurella pneumotropica is a Gram-negative, coccobacillus bacterium, family Pasteurellaceae, measuring 0.5 x 1.2 µm. It is nonhemolytic. Colonies on sheep blood agar are convex, measuring 0.5-1.5 mm at 24 hours, and gray or yellow in color. Oxidase, urease, and catalase are produced, and nitrate is reduced to nitrite (Carter, 1984).

Hosts

Mice, rats, hamsters, guinea pigs, and many others.

Epizootiology

P. pneumotropica can be isolated from a high percentage (up to 95%) of healthy animals in some colonies and from feces of gnotobiotic rats (Moore et al., 1973; Sparrow, 1976; Saito et al., 1978). It can be isolated from numerous organs: respiratory tract, oral cavity, intestine, uterus, urinary bladder, skin, and conjunctiva (Jawetz, 1948, 1950; Hoag et al., 1962; Heyl, 1963; Wheater, 1967; Kunstyr and Hartman, 1983). Transmission is probably by contact and fomites.

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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Clinical

This agent has been associated with a wide range of clinical manifestations and disease processes in laboratory rodents, including the following:

In mice:

  1. Conjunctivitis (Wagner et al., 1969; Needham and Cooper, 1975)
  2. Panophthalmitis (Weisbroth et al., 1969)
  3. Dacryoadenitis (Wagner et al., 1969; Needham and Cooper, 1975)
  4. Subcutaneous and cervical abscesses (Weisbroth et al., 1969; Wilson, 1976; Moore and Aldred, 1978)
  5. Bulbourethral gland infections (Sebesteny, 1973)
  6. Respiratory disease? (Hoag et al., 1962; Goldstein and Green. 1967; Brennan et al., 1969a,b; Saito et al., 1978)
  7. Uterine infections (Hoag et al., 1962; Brennan et al., 1965; Blackmore and Casillo, 1972; Ward et al., 1978)
  8. Otitis media (Harkness and Wagner, 1975)

In rats:

  1. Ophthalmitis (Roberts and Gregory, 1980)
  2. Conjunctivitis (Hill, 1974b; Young and Hill, 1974; Moore, 1979)
  3. Subcutaneous abscesses (Van der Shaaf et al., 1970)
  4. Mastitis (Hong and Ediger, 1978c)
  5. Respiratory disease? (Burek et al., 1972)
Pathology

P. pneumotropica is an opportunist that most frequently causes lesions of the skin and adnexal structures. Lesions caused by P. pneumotropica usually are characterized by suppurative inflammation. Eye lesions of rats attributed to P. pneumotropica in past reports could have been caused by sialodacryoadenitis virus, with P. pneumotropica present merely as an opportunist or incidental inhabitant.

Diagnosis

Many colonies of mice and rats have P. pneumotropica infections of the upper respiratory tract, digestive tract, conjunctiva, and other sites but no demonstrable disease. Diagnostic efforts must discriminate between P. pneumotropica infection and P. pneumotropica-induced disease, and rule out other possible causative agents and disease processes.

Pasteurella spp., Actinobacillus spp., Haemophilus spp., and Yersinia spp., which are commonly found in mice and rats, give similar reactions in

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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many biochemical tests. Therefore, extensive biochemical testing is required to accurately identify these organisms (Hooper and Sebesteny, 1974; Lentsch and Wagner, 1980; Simpson and Simmons, 1980; Ackerman and Fox, 1981: Kunstyr and Hartman, 1983: Carter, 1984; Wullenweber-Schmidt et al., 1988).

Control

Since this agent is usually an opportunist, control of important primary pathogens and other factors that compromise host defenses may be more important than efforts to control P. pneumotropica infection. Cesarean derivation and maintenance in a gnotobiotic isolator may be necessary to exclude the organism completely. Antibiotic therapy has been attempted in a few instances (Gray and Campbell, 1953; Moore and Aldred, 1978), but it has limited value.

Interference with Research

Lesions due to P. pneumotropica in the skin and adnexal tissues can interfere with research involving those organs.

Mouse Papule Virus
Significance

Very low.

Perspective

Knowledge of this agent is limited to a single report in which a group of mice with skin lesions resembling those of mousepox was described (Kraft and Moore, 1961).

Agent

The agent is an unclassified virus. It is ether sensitive and heat labile and can pass through a filter of 450 nm pore size. Inclusions found in skin lesions were considered suggestive of poxvirus etiology. Sera from infected animals were negative by the hemagglutination test for antibodies to vaccinia virus. No isolates of the agent are available for further study (L. M. Kraft, Moffett Field, Calif., personal communication, 1985).

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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Hosts

Mice.

Epizootiology

Unknown.

Clinical

Papular skin lesions are characterized as areas of edema and hyperemia, with central indentation or dimple formation, randomly distributed over the body, including the feet and tail. Subsequently, there is keratinization and scab formation, followed by healing without scar formation. Lesions are most noticeable in nursing mice prior to the appearance of hair (Kraft and Moore, 1961).

Pathology

Raised papules are seen scattered over the entire body, particularly in neonatal mice before growth of hair. Microscopically, acidophilic, intracytoplasmic inclusions are present in the epidermis, and the dermis has variable infiltrates of neutrophils, lymphocytes, and histiocytes (Kraft and Moore, 1961).

Diagnosis

Diagnosis of a suspected occurrence of the disease should include isolation, characterization, and identification of the agent; fulfillment of Koch's postulates; and characterization of the clinical and pathological aspects of both the natural and experimental disease.

Control

Unknown.

Interference with Research

There are no known examples in which this agent interferes with research.

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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Mouse Mammary Tumor Virus
Significance

Infections of different mouse strains with variants of this agent provide a large assortment of valuable models for experimental viral carcinogenesis.

Perspective

1933: Workers at the Jackson Laboratory (Little, Bittner, Green, and Murray) announced the discovery of a nonchromosomal influence of maternal origin that played a decisive role in the development of mouse mammary cancer (Gross. 1970).

1936: This "influence" was reported to be a virus transmitted through the mother's milk (Bittner, 1936; Visscher et al., 1942).

1959: DeOme et al. (1959) developed an assay for premalignant changes in the mouse mammary gland based on the outgrowth pattern of transplanted cells in mammary fat pads free of mammary rudiments.

1974: Lasfargues et al. (1974) successfully grew the virus in vitro.

1976: The ubiquity of the mouse mammary tumor virus (MMTV) provirus in cellular DNA of GR (substrain not given) mice was demonstrated through molecular hybridization studies (van Nie and Hilgers, 1976).

1979: Inbred strains of mice were shown to have different MMTV proviruses (Cohen and Varmus, 1979).

Agent

MMTV is a medium-sized RNA virus, family Retroviridae. It is the prototype of a morphologically distinct subclass of retrovirus, type B, that is characterized by an eccentric location of the nucleocapsid within the viral envelope (Bernhard, 1958; Bentvelzen and Hilgers, 1980; Schlom, 1980).

Four major variants of the virus have been identified. MMTV-S (S for standard; the Bittner virus) is transmitted through the milk to nursing young and is highly oncogenic. MMTV-L (L for low oncogenic) is transmitted through germ cells and is weakly oncogenic. MMTV-P (P for pregnancydependent) is transmitted through both milk and germ cells and is highly oncogenic. MMTV-O (O for overlooked) is considered an endogenous virus in the genome of most mice (Bentvelzen and Hilgers, 1980; Medina, 1982).

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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Hosts

Mus musculus (laboratory and wild). Similar viruses have been reported in other species, including Mus cervicolor, Mus cookii. and Mus caroli (Bentvelzen and Hilgers, 1980; Teramoto et al., 1980).

Epizootiology

Mouse strains such as C3H, DBA/2, and A readily express MMTV-S, and the virus can be demonstrated in a variety of locations throughout the body, especially in mammary tissue and milk. Molecular studies indicate that other mouse strains have proviral copies in their cellular DNA (van Nie and Hilgers, 1976). MMTV proviruses can influence the incidence of malignancy, but most are cryptic, having no discernible effect (Traina-Dorge and Cohen, 1983).

Foster nursing experiments have demonstrated that transmission of MMTVS occurs via ingestion of infected milk, and results in a high incidence of mammary tumors early in life (6-12 months) when the associated genetic and hormonal factors are also present (Bittner, 1936; Medina, 1982; Traina-Dorge and Cohen, 1983).

Clinical

Mammary tumors in female mice can be located on virtually any part of the body (ventral, lateral, and dorsal surfaces) from the chin to the pelvic region. A variable frequency of metastases to distant sites occurs, but the lungs are the most common site (Dunn, 1959; Medina, 1982).

Pathology

Current theory holds that the virus initially induces "hyperplastic alveolar nodules," which are preneoplastic lesions. The average latency period from infection to tumor expression is 6-9 months. The development of tumors is enhanced by administration of estrogen to male and female mice, forced breeding, and administration of carcinogens (e.g., 3-methylcholanthrene and 7,12-dimethylbenzanthracene). Glucocorticoid hormones appear to promote mammary tumor production through the induction of intracellular MMTV RNA (Ringold, 1983). Susceptibility to MMTV is controlled by host genetic factors, i.e., it is strain dependent (Medina, 1982; Michalides et al., 1983; Traina-Dorge and Cohen, 1983).

Mammary tumors usually are circumscribed, round to nodular, gray to white masses located in the subcutaneous tissue. They can become very large. Ulcerations and hemorrhages are common in large tumors. Most

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×

mammary tumors are adenocarcinomas of Dunn's histologic types A or B (Dunn, 1959). Type A tumors are characterized by uniform acini lined by a single layer of cuboidal cells, while type B tumors are variable in the extent of differentiation, but usually consist of irregular cords and sheets of cells. Other types include adenocarcinomas of types C, Y, L, and P; carcinomas with squamous cell differentiation; and carcinosarcomas. Other histologic types are rare (van Nie, 1967; Sass and Dunn, 1979).

Mice of many strains develop humoral and cellular immune responses to MMTV, indicating that mice infected early in life are not immunologically tolerant (Bentvelzen and Brinkhof, 1980).

Diagnosis

Mouse mammary tumors appear as nodules or masses of varying size in the subcutaneous tissue. They are diagnosed and classified on the basis of histopathologic characteristics (Dunn, 1959; Sass and Dunn, 1979).

Detection and characterization of MMTV requires test procedures normally available only in specialized viral oncology laboratories. Some of the more common procedures are nucleic acid hybridization, immunologic assays for viral antigens, and bioassays for infectivity in different strains of mice (Medina, 1982). A better alternative for investigators whose studies require the presence or absence of MMTV or specific MMTV proviruses may be to obtain mice with the desired characteristics from either the National Institutes of Health (Dr. S. Potkay, Chief, Veterinary Resources Branch, Division of Research Services, Building 14A, Room 103, National Institutes of Health, Bethesda, MD 20205) or the National Cancer Institute (NCI) (Dr. J. G. Mayo, NCI-Frederick Cancer Research Facility, Biological Testing Branch, P.O. Box B, Frederick, MD 21701).

Control

For most studies, control of MMTV is not required. The most practical method of control is through selection of mouse strains. Foster nursing on mouse strains that are free of the virus has been used to eliminate MMTV-S.

Interference with Research

MMTV infection in mice is an extremely valuable model of mammary cancer, especially for studies of the interactions of the virus, hormones, genetics, and carcinogens. It is the only known animal model of virus-induced mammary cancer. The infection also can be a complicating factor in experimental carcinogenesis studies.

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×

Concurrent infection of mice with the lactic dehydrogenase-elevating virus and MMTV-S reduces the incidence of virus-induced mammary tumors (Riley, 1966).

Self-Mutilation Associated with Otitis Media

Harkness and Wagner (1975) reported on a single incident in which a small percentage of adult mice in a colony exhibited violent scratching of the external ears and adjacent tissues. Histologic sections of the external ears showed ulceration and acute inflammation of the ear pinnas, external canals, and adjacent tissues. The mice also had purulent otitis media from which Mycoplasma pulmonis, Pasteurella pneumotropica, and other agents were isolated. The skin condition was considered secondary to the otitis media.

Noninfectious Skin Conditions Important In Differential Diagnosis

Bite Wounds in Adult Mice and Rats

Fighting can be a serious problem in some strains of mice (Wimer and Fuller, 1966). It is usually worst among mature males but also occurs among females in some strains. Some of the most notorious fighters are mature males of the BALB/c, SJL/J, and HRS/J strains, which generally must be housed one per cage. Bite wounds can appear anywhere on the body, but they usually are most concentrated on the rump and lumbar regions, with few or none on the shoulders or head. The characteristic pattern of open and healing wounds along dorsal surfaces of the trunk is virtually diagnostic (Scott and Fredericson, 1951; Fredericson and Birnbaum, 1954).

Among male mice housed in groups, the submissive cage mates, which are bitten most frequently, often develop anemia and splenomegaly and have a much greater incidence of amyloidosis than do dominant males (Page and Glenner, 1972). In one colony of SW (Swiss Webster) mice, complication of bite wounds by group G streptococci reportedly caused necrotizing dermatitis and 35% mortality (Stewart et al., 1975).

Skin lesions caused by fighting also can occur in old male rats, but fighting among rats is usually of little consequence compared with that among mice. Housing in compatible groups or singly usually results in dramatic healing of bite wounds within a few days in both rats and mice.

Bite Wounds in Weanling Mice

This syndrome was first reported in C3H/HeJ and C3HeB/FeJ mice, occurring usually at 5-8 weeks of age (Les, 1972). It was associated with

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×

the housing of weanling mice in groups of 40 per cage and sometimes affected all mice in a cage. Lesions varied from small red foci to encrusted excoriations up to 3 mm in diameter on the tail skin. Some tails became swollen, and the part distal to some lesions sloughed. As healing occurred, the lesions became small white scars readily visible on the tails of pigmented C3H mice. Koopman et al. (1984) have confirmed these observations for C3H/He mice.

A similar, if not identical, condition has been seen in weanling mice of the BALB/c strain (Cox et al., 1977). In addition to lesions on tails, these mice also had the lesions on their feet and ears. Using histologic methods, these investigators demonstrated that the dermis beneath the lesions regularly contained fragments of keratinized epithelium from the skin surface, suggesting that the skin lesions were bite wounds inflicted by cage mates. A major difference between C3H/He and BALB/c mice with this condition is that healing results in small but prominent white foci of scarring on the tails of pigmented C3H/He mice but leaves almost imperceptible scars on the tails of albino BALB/c mice.

The cause of this condition is unknown. Les (1972) and Koopman et al. (1984) have suggested that "social stress" plays a role. However, the cause may simply be hunger resulting from the sudden separation of weanlings from their dams, the simultaneous crowding of weanlings into large groups where access to food and water is limited, and/or poor palatability of food (e.g., due to hardness of the pelleted diet). Control is accomplished by housing smaller numbers of weanlings per cage (i.e., avoiding crowding). The major importance of the condition is that it be recognized as a distinct entity that can be readily differentiated from mousepox by clinical and pathological features.

"Whisker-Trimming," "Hair-Nibbling," and "Barbering"

These are descriptive terms that have been applied to an assortment of patterns of alopecia associated with social behavior in mice. C57BL/6, C57BL/10, C3H, and SW mice have been the most studied, and heredity is thought to play a role. The dominant cage mate chews off the whiskers or hair of other cage mates giving the affected area a smoothly shaved appearance. The sites affected most are the whiskers and hair of the face, head, neck, and back. Usually, hair chewing occurs without injury to the underlying skin, although chronic hair chewing can result in thickening and increased pigmentation of the epidermis or even formation of foreign body granulomas in the dermis. If such chronically chewed mice are separated from the more dominant mouse, the regrowth of hair may be sparse and unpigmented, often with residual partial alopecia (Hauschka, 1952; Long, 1972; Thornburg et al., 1973).

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
×
Muzzle Alopecia

Small patches of alopecia are located on the lateral surfaces of the muzzle. They can result from mechanical trauma associated with repeatedly inserting the muzzle through holes in the cage cover or between metal rods forming the food hopper (but is probably more often due to whisker-trimming by cagemates). Histologically, the affected skin may show hyperkeratosis, acanthosis, and mild inflammation (Litterst, 1974).

Hair Growth Cycling Arrest

Mice are known to grow hair in distinct patterns or cycles (Borum, 1954; Chase, 1954; Chase and Eaton, 1959; Argyris, 1963). Occasionally, one may see an entire litter of runted mice about weaning age with complete loss of hair on the torso. A small tuft of hair remains at the base of the tail and normal-appearing hair is present on the head and legs. Such mice generally have severe systemic disease (e.g., mouse hepatitis virus infection) and, presumably, are experiencing a temporary arrest of normal hair growth cycling (J. R. Lindsey, Department of Comparative Medicine, University of Alabama at Birmingham, unpublished).

"Ringtail"

This condition has been reported in mice (Nelson, 1960), laboratory rats (Njaa et al., 1957; Flynn, 1959; Totton, 1958), and the South African white-tailed hamster (Stuhlman and Wagner, 1971). It is characterized by the appearance of concentric rings around the tail, frequently followed by sloughing of all or part of the tail. The feet also may be swollen and reddened. The cause is thought to be environmental conditions of low (less than 40%) relative humidity and high (more than 80°F) temperature.

Suggested Citation:"8. Skin and Joints." National Research Council. 1991. Infectious Diseases of Mice and Rats. Washington, DC: The National Academies Press. doi: 10.17226/1429.
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This new edition—a must for all researchers who use these lab animals—provides practical suggestions for breeding, keeping, and identifying pathogen-free laboratory rodents. It contains three informative sections. The first, Principles of Rodent Disease Prevention, summarizes methods for eliminating infectious agents. It offers information on pathogen terminology; pathogen status of rodents; and breeding, transporting, isolating, testing, and diagnosing rodents. The second section, Individual Disease Agents and Their Effects on Research, describes the diagnosis and control of each infectious agent, and the last section, Diagnostic Indexes: Clinical Signs, Pathology, and Research Complications, contains informative tables covering all the diseases listed in the volume, arranged to help in the diagnosis of infected animals.

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