key: cord-0715605-zthe1j2s
authors: Lussier, G.
title: Potential detrimental effects of rodent viral infections on long-term experiments
date: 1988
journal: Vet Res Commun
DOI: 10.1007/bf00362802
sha: ff4e235c4c231feb3b56cce9b66fe6fbc36d983a
doc_id: 715605
cord_uid: zthe1j2s

Healthy animals are of paramount importance in obtaining meaningful, reliable scientific results. Viral infections of rodents often have a significant impact on various types of biomedical research. Laboratory animal specialists and researchers must be aware of the possible consequences associated with the use of infected animals. The objective of the paper is a discussion of the frequently encountered viral infections that can complicate or invalidate the interpretation of results by altering the host's response.

Rodent viruses are widespread and have a long history of interfering with biomedical research. Although numerous publications have appeared during the past IO-15 years concerning the effects of rodent viral infections on biomedical data, the literature is scattered in diverse scientific journals. Scientists in general are not well informed of such influences on their research. Therefore, the objective of this article is to review the knowledge published in recent years concerning the possible role of a variety of rodent viruses on long-term experiments Sedai Virus Sendai virus was isolated from mice inoculated with human clinical specimens and was erroneously described as a virus causing fatal pneumonitis in newborn children (Kuroya er a[., 1953) . Subsequently the virus was shown to be indigenous in mice (Fukumi et ai., 1954) . Sendai virus is one of the most prevalent of rodent viruses (Parker & Richter, 1982) . The infection may occur in acute clinical or subclinical forms or may be clinically inapparent and can then only be recognized by serology (Zurcher et al., 1977) .

In addition to being primarily involved in the respiratory system (Ward, 1974; Burek et u/. , 1977; Zurcher et a/. , 1977) . Sendai virus may exert a synergistic effect with bacterial and mycoplasmal infections. Increased severity of lesions has been reported in experimental infections of mice with Haemophhs in@enzo (Degr6 & Glasgow. 1968; Degre. 1970 ) and fusteure/h pezmotropic~ (Jakab, 1974 (Jakab, . 1981 and in mice and rats with Mycoplasma pulmonis (Howard et d., 1978; Schoeb et d., 1985) .

Virus-induced impairment of the functional activity of alveolar macrophages has been reported (Degr6. 1970; Warr & Jakab, 1979) . Sendai virus may cause other subtle and long-lasting effects on humoral and cell-mediated immune responses (Kay et a/., 1979) . It depresses the antibody response to sheep red blood cells (SRBC) in rats , reduces the mitogenic response of lymphocytes to phytohemagglutinin and concanavalin A in mice and rats (Garlinghouse & van Hoosier. 1982) . reduces the severity of adjuvant-induced arthritis in rats, a commonly used model of evaluating antiinflammatory and immunosuppressive drugs (Garlinghouse & van Hoosier, 1978) and accelerates rejection of skin isografts (Streilein e? al., 1981) .

Sendai virus may also interfere with experimental carcinogenesis studies. Regenerative and repair lesions characterized by marked proliferation and squamous metaplasia of bronchial and bronchiolar cells with extension into the alveoli are observed following Sendai infection; these lesions have the appearance of invasive carcinomas (Richter, 1970) . Sendai virus may also have a strong influence on experimental chemical carcinogenesis (Schreiber et al., 1972) . It suppresses the induction of pulmonary adenomas by urethane (Nettesheim, 1974) , reduces the number of lung tumours in lo-chloromethyl-9-chloroanthracene-treated mice and increases the number of lung tumours in 7,12,dimethyl-benz(a)anthracene treatment (Peck et al., 1983) . Interference with the development of leukemia induced by Friend virus has been reported in DBA/2 mice infected with Sendai virus (Wheelock, 1967) . Sendai virus infection of transplantable tumours alters the tumorigenicity of the cells: infection of Ehrlich ascites tumour with Sendai virus produces variants that are less oncogenic (Matsuya et al., 1978) . Similarly, the tumorigenicity of a leukemia cell line was shown to be reduced following persistent Sendai virus infection (Takeyama et al., 1979) . The latter alterations are probably the result of a virus-induced modification of the cell membrane. However, it has recently been shown that Sendai virus is an effective inducer of tumour necrosis factor by blood mononuclear leukocytes (Aderka et al., 1986j suggesting possible implications of the virus in experimental oncogenesis.

Sendai virus infection in pregnant rats results in impaIred fetal developmental and neonatal mortality (Coid & Wardman, 1971) . Infection of pregnant rats in the early stage of gestation results in resorption of embryos, whereas infection at a later stage increases the gestation period and neonatal mortality. The affinity of Sendai virus for fertilized eggs before implantation has been reported in mice with resulting death of embryos and decreased breeding efficiency (Tuffrey et al., 1972) .

The first strain of MHV, strain JHM, was isolated from the central nervous system of a spontaneously paralyzed mouse (Cheever et al., 1949) . MHV is now considered as a common contaminant of mouse colonies where the infection is often subclinical (Parker et al., 1965; Carthew & Verstraete, 1978; Gannon & Carthew, 1980; Lussier & Descoteaux, 1986) . However, MHV may induce different types of disease in several mouse strains (Virelizier & Allison, 1976) . Most strains, including strain C57BL, are fully susceptible and die in a few days with hepatitis. Mice of the A strain are fully resistant, develop a mild disease, clear the virus efficiently and survive (Le Prevost et al., 1975) . Mice with intermediate susceptibility, including strain C3H, become carriers and develop a progressive neurologic disease lasting for weeks or months (Virehzier et al., 1975) . Other strains of MHV may cause enteritis (Broderson et al., 1976) . Infectious agents or numerous physical factors may act synergistically with MHV to produce a fulminant disease in colonies where MHV had previously been clinically inapparent (Fox et al., 1977; Kraft, 1982) .

MHV may alter various parameters of the immune response including either decreasing or enhancing the humoral response to SRBC, depending on experimental condititions (Virelizier et al., 1976) . Furthermore, persistently infected mice show a marked and long-lasting immunosuppression (Virelizier et al., 1976) . Infection of mice before antigen administration leads to immunosuppression, whereas simultaneous infection with virus and antigen results in immunostimulation (Virelizier et ul., 1976; Tamura er ui., 1978) . The presence of interferon correlated with these modifications, interferon peaking before antigen is associated with immunodepression, whereas interferon secretion after antigen is associated with immunostimulation (Virelizier et ul., 1976) . MHV has been shown to alter host resistance to experimental infection with encephalomyocarditis virus (EMC) and to reduce the protective effects of exogeneously administered inteferon against EMC infections (Dempsey et uZ., 1986) .

MHV infection modifies numerous enzyme systems; it increases certain hepatic enzymes while it decreases several others (Ruebner ef ul., 1965; Paradisi et ul., 1972; Budillon ef uZ., 1972) .

In susceptible strains, MHV-3 induces histological modifications of the thymus characterized by a rapidly progressing destruction of the cortex (Virelizier et ul., 1976) .

Numerous strains of MHV reduce ability of mice to seroconvert to pneumonia virus of mice (PVM) and convert Sendai-virus-susceptible DBA/2 mice to a resistant phenotype (Carraro et uZ., 1984) ; antibody titers to PVM in MHV-infected mice are lower than in uninfected animals.

Numerous macrophage alterations caused by naturally occurring MHV have been reported (Boorman et uZ., 1982; Dempsey et ul., 1986) . These include increased number of cells, cytoplasmic vacuolations, increased vacuolated membranes, increased erythrophagocytosis and altered macrophage ectoenzyme phenotypes.

Cerebral damage leading to hydrocephalus has been induced in rats following intracerebral inoculation of strain A59 of MHV. However, anomalies were not detected following inoculation of nine other strains of MHV (Hirano ef uZ., 1980).

PVM was isolated by Horsfall and Hahn (1940) by serial passages of mouse lung in mice during attempts to isolate viruses from cases of human respiratory disease. Serial intranasal passage of lung tissue infected with PVM may result in interstitial pneumonia on the second or third transfer (Tennant et ul., 1966) . High incidence of hydrocephalus has also been produced following intracerebral inoculation of newborn mice (Lagace-Simard er ul., 1980).

LDV has been well reviewed (Riley, 1974; Rowson & Mahy, 1975) . The virus was orginally detected as a contaminant of transplantable mouse tumours (Riley et ul., 1960) . The mouse is the only susceptible host to LDV in which the infection is non-lethal and life-long. Laboratory mouse colonies are not often found to be infected, but LDV is a contaminant of most transplantable tumours and other biological materials maintained by passages in mice (Riley er ul., 1960 (Riley er ul., ,1978 Rowson & Mahy, 1985) . The infection may then be introduced inadvertently into a mouse colony. Infected mice exhibit a fivefold to tenfold elevation in plasma levels of LDH (Riley et u/., 1960; Riley, 1974) and increased levels of a certain number of other plasma enzymes (Plagemann etul., 1962) . The level of enzyme activity in the plasma, however, is not directly related to the level of viral infectivity (Motycka et uf., 1976) . Impaired functioning of the enzyme clearance mechanism by macrophages has been incriminated as the cause of increased enzyme level (Bailey er ul., 1964; Notkins, 1965; Mahy ef ul., 1965u,b) . The functional capacity of the reticuloendothelial system as measured by carbon clearance is markedly depressed (Notkins & Scheele. 1964) .

One special characteristic of the virus is its site of replication that appears to specifically favour the antigen-presenting macrophages (Porter et ul., 1969; Schlesinger et ul., 1976; Rowson & Mahy, 1975; Inada & Mims, 1985 . LDV infection causes numerous immunological perturbations. When the virus is given shortly before the antigen, it has an apparent adjuvant action on the humoral immune response. (Notkins et al., 1966; Mergenhagen et ul., 1967; Michaelides & Simms, 1977,198O; Isakov et ul., 1982; Rowson & Mahy, 1985) . In chronically infected mice, the humoral response is depressed (Oldstone et al., 1974; Riley et ul., 1976) . LDV infection stimulates interferon production and activates NK cell activity (Koi et ul., 1981) . LDV has also been shown to affect lymphocyte circulation (Chang & Turk, 1977) . The infection increases the levels of circulating immunoglobulins (Notkins et ul., 1966; Notkins, 1971) ; the increase is mainly in the IgG 2a subclass (Michaelides & Simms, 1977) . LDV infection depresses the cellmediated response (Howard eta/., 1969; Inada & Mims, 1986 ). An increase in spleen and lymph node mass and a slight transitory fall in thymus weight have been recorded (Riley & Spackman, 1974 Rowson & Mahy, 197.5; Stauber et ul., 1975) . Histological examination of the lymphoid tissue may reveal hyperplasia of the germinal centers and a reduction in the concentration of lymphocytes in the thymus-dependent areas (Snodgrass & Hanna, 1970; Snodgrass et ul., 1972; Proffitt et al., 1972) . Thymic atrophy can be prevented by adrenalectomy, suggesting the effect is steroid-mediated (Fritzmaurice et ul., 1972) . The virus persists in the circulation in the presence of excess neutralizing antibody. The deposition of circulating virus-antibody complexes in the kidneys of LDVinfected animals may lead to the development of an immune-complex type of glomerulonephritis Oldstone & Dixon, 1971) .

LDV plays a role in the progress of a variety of neoplastic conditions. Tumour development may be stimulated or depressed. Several investigators have reported suppression of the growth of certain transplantable tumors in LDV-infected mice (Notkins, 1965; Bailey et al., 1965; Riley, 1966 Riley, , 1974 Riley et al., 1978) . However, tumour enhancement and normal tumour growth have also been observed in LDV-infected animals (Turner et al., 1971; Michaelides & Schlesinger, 1974) . The timing of the LDV infection appears to be a critical factor in its effect on the growth of tumours. Mice are more susceptible to tumour formation during acute infection (Michaelides & Schlesinger, 1974) , while chronic infection inhibits or delays tumour formation Brinton-Darnell & Brand, 1977; Michaelides & Schlesinger, 1974; Isakov et al., 1978 Isakov et al., ,1982 Henderson et ul., 1979; Theiss el ul., 1980; McDonald, 1983; Johnson & Shin, 1983) . Minor alterations in timing or dose of tumour cells can alter the results. The growth-enhancing effect of the acute infection may be related to the depression of cellmediated immunity.

As an example of the confusion that LDV can cause in an experiment, splenectomy had been reported to protect BALB/c mice against tumour formation when animals were inoculated with syngeneic methylcholanthrene-induced tumour cells (Chang & Turk, 1977) . However, it was subsequently discovered that the tumour had become infected with LDV and that splenectomy had no effect on tumour induction following inoculation with LDV-free tumour cells (Henderson et al., 1979) .

A fatal paralytic neurological disease characterized by an inflammatory destruction of motor neurons is observed in LDV-infected mice immunosuppressed by aging or by immunosuppressive agents (Duffey et ul., 1976; Nawrocki et ul., 1980; Martinez et ul., 1980; Bentley et,al., 1982) ; the only strains of mice susceptible are C58 and AKR.

LCMV was first isolated from a nntient with acute awntic-m~nindtk (Armctrnmm J& Lillie, 1934) . LCMV was one of the first viruses to be recognized as a latent infection in mice (Traub, 1935) ; it is a pantropic virus that infects the central nervous system and causes persistent infection in mice and other rodents (Parker er uf., 1976) . Wild mice are considered as a natural reservoir of the virus and laboratory mice are easily infected from wild mice. Hamsters are also highly susceptible to LCMV. Although not widespread in laboratory rodent colonies, when present, LCMV can interfere with experimental results and poses a health hazard for humans. LCMV has also been found to be a contaminant of many mouse transplantable tumours (Collins & Parker, 1972; Pike, 1979; Bhatt er ul,, 1986) . Infection in the adult mouse may result in death or, depending on the strains of mouse and the route and dose of virus, may be followed by immunity and clearance of the virus. Mice infected neonatally develop a persistent non-clinical infection that is maintained through successive generations. As the mouse ages, there is development of immune complex disease characterized by glomerulonephritis, arteritis, and widespread interstitial lymphoid infiltration (Hotchin, 1962; Oldstone & Dixon, 1970; Kajima 8~ Pollard, 1970) . In certain strains of mice, persistent infections affect the synthesis of growth hormone (Oldstone et ul., 1982) . Infected animals undergo significant decrease in body weight and become defective in glucose metabolism.

Immunological research may be compromised when persistently infected mice are used. LCMV replicates in mononiiclear~ cells of blood and lymphoid tissue: B-lymphocytes, T-lymphocytes, and macrophages contain replicating virus (Doyle & Oldstone, 1978) . Depression of humoral and cell-mediated immune responses of infected mice have been reported (Mims & Wainwright, 1968) . LCMV can ameliorate the z'n vivu growth of transplantable tumours (Jungblut & Kodza, 1963; Nadel & Hans, 1956; Youn & Barski, 1966) . Enhanced activity of NK cells correlates with decreased receptivity for syngeneic stem cells in bone marrow and spleen (Thomsen et al., 1986) . Rejection of skin grafts prepared from syngeneic donor mice chronically infected with LCMV has been observed (Holtermann & Majde, 1971 ). LCMV causes a marked activation of NK cells and macrophages (Welsh, 1978; Blanden & Mims, 1973; Thomsen etal., 1986) and stimulates the production of interferon (Ronco et ul., 1981) .

LCMV may persist in fi cells of the islets of Langerhans of certain strains of mice resulting in metabolic and pathologic findings resembling those of type II diabetes mellitus (Oldstone et al., 1984; Rodriguez et uZ., 1985) .

Immunopathologic destructive lesions of the cerebellum have been reported following inoculation of suckling rats (Monjan et uf., 1974) .

Parvoviruses that can infect rodents include Kilham rat virus (RV), Toolan rat (H-l) virus and minute virus of mice (MVM). Although experimental infection can be established in a number of other species, the rat is the only natural host for RV and H-l viruses and the mouse is the only natural host for MVM (Kilham & Margolis, 1970; 1971) .

RV was first identified in rat embryo tissue cultures inoculated with materials from tumour-bearing rats (Kilham & Oliver, 1959) . The infection is common in laboratory and wild rats (Kilham, 1966; Robey et al., 1968; Robinson et ul., 1971) . RV is apparently species-specific during naturally occurring infections but can produce cerebellar hypoplasia or skeletal deformities in experimentally infected hamsters and cats (Kilham, 196lu, 196lb; Bear & Kilham, 1962; Kilham & Margolis, 1965) . In adults, RV produces usually a latent infection, but the virus can be activated by immunosuppression to cause hemorrhagic encephalopathy (El Dadah et ul., 1967) . Similar lesions accompanied by cerebellar necrosis can be induced experimentally by intracerebral or parenteral inoculation of suckling rats (Cole ef al., 1970; Margolis 8~ Kilham, 1970) . RV has been isolated as a contaminant of murine leukemia virus preparations (Kilham & Maloney, 1964) and of transplantable tumours (Kilham & Oliver, 1959; Lum & Schreiner, 1963) . The virus can replicate in rat lymphocytes and has been shown to inhibit the lymphoproliferative response to mitogens or allogeneic lymphoid cells (Campbell et al., 1977) and to alter the natural cytotoxicity of rat spleen cells to lymphoma target cells (Darrigrand et al., 1984) .

H-l virus is an antigenically distinct rat parvovirus (Moore 1962 ) first isolated from a human tumour cell line that had been passaged in rats (Toolan et al., 1960; . H-l virus can cause neurological and skeletal aberrations and fetal resorption in experimentally inoculated rodents but it is believed to be nonpathogenic in naturally infected rats (Kilham & Margolis, 1969; Toolan, 1960) . H-l virus can contaminate transplantable tumours and established cell lines (Toolan, 1961; hallauer et al., 1971) . The virus also reduces the incidence of fibrosarcomas induced in hamsters by 7,12,dimethylbenzanthracene (Toolan et al., 1962) . MVM was originally isolated as a contaminant of the mouse adenovirus (Crawford, 1966) and is considered only moderately pathogenic for mice. However, the virus is highly prevalent in mouse colonies (Parker et al., 1970~; Lussier & Descoteaux, 1986) and is a frequent contaminant in transplantable mouse tumours and leukemia stocks (Parker ef al., 1970~; Collins & Parker, 1972) . The infection can be introduced into a colony through inoculation of contaminated cell lines or biological materials. Experimental inoculation of MVM induces lethal infections in suckling rats and runting in mice. The virus is pathogenic for hamsters causing a lethal infection (Kilham & Margolis, 1970) . A variant of MVM has been isolated from a murine T lymphoma cell line that differs from the prototype virus in being selectively lytic to T cells in v&o (Bonnard et al., 1976; Bloom, 1984) . MVM alone or as a contaminant of biological material has been reported to suppress or completely inhibit cell-mediated immune responses of mice (Bonnard et al., 1976; Herberman et al., 1977) .

Reovirus 3 produces hepatitis, enteritis, encephalitis, and pancreatitis in affected animals (Seamer, 1967) and can adversely affect research directed at these organs. Reovirus 3 has also been shown to influence DNA replication in vim (Jasney et al., 1980) . If the latter effect is also observed in viva, the subtle effect of the infection would be more significant.

Reovirus 3 may also play an important role in the host response to environmental carcinogens and may act as an immunostimulant. The incidence of pulmonary adenomas following urethane administration is markedly reduced when the mice are exposed to reovirus 3 (Theiss et al., 1978) . Reovirus 3 also significantly affects the therapeutic value of 1,3-bis-(2-choretyl)-1 nitrosourea (BCNU) in the experimental model using transplantable EL4 lymphoma cells (Kollmorgen et al., 1975; . Similar results have been shown when reovirus 3 was used to protect mice from the A-10 murine mammary adenocarcinoma (Sansing et al., 1977) .

Two pathologically distinct strains of MAdV have been described. The FL strain isolated as a contaminant of the Friend's leukemia virus and the K87 strain isolated from the feces of normal mice (Hashimoto er al., 1966) . The FL strain causes acute fatal disease in suckling mice and a generalized persistent, inapparent infection in adult mice with viruria lasting for months or years (Heck et al., 1972'; Van der Veen & Mes, 1973) . In contrast, MAd K87 produces only an intestinal infection in neonatal or older mice without observable signs of disease (Sugiyama et al., 1967) . Immune spleen cells from mice infected with MAdV strain FL were shown to be cytotoxic to target mouse embryo cells or lymphoid cells infected with MAdV (Inada & Uetake, 1978) . It has been postulated that a virus-induced surface antigen may be recognized as a new antigen which may serve as a target site for cell-mediated immunity (Inada & Uetake, 1978) .

MAdV strain FL persists in the kidneys of infected mice for months, producing infiltrates and moderate tubular damage for a considerable period (Wigand, 1980) . Virusinduced lesions in the kidneys predispose to the development of frank pyelonephritis following Escherichia coli inoculation (Ginder, 1964) . MAdV strain FL significantly alters experimental scrapie disease in mice causing significant acceleration of clinical signs of scrapie (Ehresmann & Hogan, 1986) .

MCMV infection has adverse effects upon several parameters of the host defense mechanisms including antibody response to a variety of antigens (Osborn & Me&ark, 1967; Osborn et al., 1968; Booss & Wheelock, 1975; Tinghitella & Booss, 1979) . Similarly, marked suppression of the host's ability to respond to stimulation with T and B cell mitogens has been described Booss & Wheelock, 1975 , 1977a Selgrade et al., 1976; Kelsey et al., 1977 Kelsey et al., , 1978 Cruz & Warier, 1978; Wu & Ho, 1979; Sell et al., 1985) . The induction of interferon by multiple agents (Osborn & Medearis 1966 ,1967 Kelsey et al., 1977; Stringfellow et al., 1977) and the inversion of the helper to suppressor T-lymphocyte subsets ratio has been reported (Sell et al., 1985) . Skin graft survival is significantly prolonged in MCMVinfected recipient mice Lang et al., 1976) . In certain strains of mice, sublethal MCMV infection induces an early suppressive phase and a later enhanced phase of T cell reactivity to foreign histocompatibility antigens (Grundy & Shearer, 1984) . Zn vitro T cell lysis of EL4 tumour cells by splenocytes was significantly suppressed in BALB/c mice grafted with EL4 ascites allograft if the animals had previously been infected with MCMV (Hamilton et al., 1978 (Hamilton et al., , 1979 . Mice infected with MCMV have temporarily increased rates of carbon clearance compare to uninfected controls , a signficant reduction in neutrophil migration (Howard et al., 1982; Bale et al., 1983; Lineaweaver et al., 1984) and defective neutrophil functions (Leung & Hashimoto, 1986) . Activation of the reticula-endothelial system by MCMV has been reported (Schleupner et al., 1979) . MCMV has also been shown to cause alterations of the respiratory function (Shanley et al., 1982; Reddehase et al., 1985) , to potentiate bacterial, fungal, and viral infections (Hamilton et al., 1976; Bale et al., 1982; Howard et al., 1982; Leung & Hashimoto, 1986) , and to affect the breeding efficiency of infected colonies (Baskar et al., 1985) . Pre-existing or concurrent MCMV infection enhances resistance to development of pulmonary tumour nodules after intravenous inoculation of syngeneic mammary tumour cells; while MCMV infection during tumourigenesis may enhance tumour growth and shorten survival time (Olsen et al., 1976) .

Peritoneal macrophages harvested from mice infected previously with MCMV were tumouricidal in vitro for a syngeneic mammary tumour cell line and have shown antiviral activity by repressing replication of vaccinia virus in cell cultures (Schleupner et al., 1979) .

Macrophages harvested from MCMV-infected mice showed augmented phagocytosis of yeast particles in vitro (Schleupner et al., 1979) . On the other hand, enhanced protection against Wisteria monocytogenesh has been demonstrated in infected mice (Schleupner et uf., 1979) .

Rats are susceptible to MCMV after intraperitoneal inoculation (Smith et ul., 1986) . MCMV infection in rats is associated with transient reversals of T helper/suppressor cell ratios and alterations of immune cell functions as detected by spleen cell proliferation (Smith et ul., 1986) .

RCMV was first isolated by Rabson et al. (1969) from salivary glands of wild roof rats shown to contain characteristic cytomegalovirus inclusions. Encephalitis has been induced in suckling rats by intracerebral inoculation of the virus (Kilham & Margolis, 1975; Priscott & Tyrell, 1982) . RCMV has been used as a model for studying the immunopathology of persistent and reactivating infection in immunocompromised rats (Bruggeman et al., 1983; . The virus has an immunosuppressive effect on the immune response to SRBC (Bruggeman et al., 198.5 ). It has also been shown to induce enhanced levels of chemiluminescence emitted during phagocytosis of zymozan particles, and to enhance the host's capacity to kill Stuphylococcus uureus (Hendrix et ul., 1986) .

Two antigenically related coronarviruses, SDAV and RCV, which share a common antigen with MHV (Bhatt et al., 1972) , have been isolated from rats. Sialodacryoadenitis is a common, naturally occurring, highly infectious non-fatal disease that is characterized by inflammation of lacrymal and salivary glands as well as of upper and lower respiratory tracts. Ocular lesions including keratoconjunctivites, cornea1 ulceration, anterior synechiae, exudate in the anterior chamber, and secondary bacterial infections often develop late in the disease (Weisbroth & Peress, 1977) . These lesions make infected animals unsuitable for research in which the eye is the target organ (Innes & Stanton, 1961; Lai et ul., 1976) . SDAV virus has been shown to be infectious for mice, causing interstitial pneumonia; it is transmitted from mouse to mouse and is detected most readily in the trachea and lung (Bhatt et al., 1977) . The main importance of the infection in mice appears to be the serologic cross-reaction between SDAV and MHV. Unless one is aware of SDAV and its cross-reaction with MHV, it may be difficult to distinguish serologically between the two infections in a mouse colony (Bhatt et ul., 1977) . In contrast to SDAV, RCV is primarily pneumotropic, causing little or no sialodacryoadenitis (Parker et ul., 197Ob) .

SDAV and RCV may have a significant impact in certain types of experiments. For instance, lesions of the upper respiratory tract may predispose rats to other respiratory pathogens and may interfere with anesthesia or inhalation in toxicology research (Parker et al., 197Ob; Jacoby et al., 1979) . Decreased breeding efficiency has been reported in female rats exposed to SDAV early in pregnancy (Utsumi et al., 1980) ; this may affect reproductive research and teratology studies.

K virus was first isolated as a contaminant of the mouse mammary tumour virus (Kilham, 1952) and has been found to be different from poiyomavirus, another member of the papovavirus family (Bond et ul., 1978) . The virus is known to infect weanling or adult mice without producing overt disease and is endemic in many wild mouse colonies (Halt, 1959; Rowe et ul., 1961) . However, inoculation of newborns with biological material containing K virus may produce a fatal illness characterized by a severe interstitial pneumonia (Fisher & Kilham, 1953; Kilham &Murphy, 1953; Greenlee, 1979) . Infection in weanling mice with K virus enhances the acute hepatic necrosis and inflammation produced by subsequent infection with MHV (Tisdale, 1963) .

The virus was first identified by Stewart (1960) and Eddy (1960) . It normally causes an inapparent infection of mice; however, inoculation of the virus causes a variety of tumours in numerous species including suckling mice, rats, guinea pigs, rabbits, and ferrets (Eddy, 1969) . Polyomavirus can be transmitted to the fetuses when the mother is infected at various stages throughout gestation (McCance & Mims, 1977) . The virus persists at low levels for long periods in organs such as the kidney (Rowe et ul., 1960) and can be reactivated (McCance & Mims, 1979) . Neonatal thymectomy enhances its tumourigenicity in newborn and adult hamsters (Defendi & Roosa, 1965) . A wasting disease has been reported in infected nude mice (Sebesteny et d., 1980) .

MTV was first described as a contaminant of mouse mammary tumour homogenates (Rowe & Capps, 1961) . Neonatal infection of mice with MTV induces a non-fatal disease characterized by extensive but temporary necrosis of the thymus which is maximal 10 to 14 days after infection (Rowe & Capps, 1961; Cross et ul., 1979) . In addition to the severe histological lesions produced in the thymus, MTV induces profound suppression of a number of immunologic functions mediated by thymus-derivated cells (Cohen et ul., 1975; Morse et ul., 1976) . Spleen cells have markedly diminished reactivity to T cell phytomitogens and to allogenic cells and are incapable of effecting a primary in vitro or in viva response to a T-dependent antigen (Cohen et ul., 1975) . Infection with MTV results in a profound reduction in the direct graft-versus-host reactivity of thymocytes (Cross et ul., 1976) . Responses to B cell mitogens and to a T-independent antigen appear unimpaired (Cohen et ul., 1975; Cross et ul., 1976; Morse et ul., 1976) .

These numerous examples of alterations of research data stress the need for monitoring rodent colonies as well as transplantable tumours and murine viral stocks. If experiments are performed with infected animals or with contaminated materials they may lead to erroneous conclusions. This problem is particularly important in immunology, toxicology and experimental pathology. Therefore, health of experimental animals is absolutely essential to the production of accurate reproducible research and test results. Consequently, it is imperative that investigators pay considerable attention to the viral profile of their research animals. 

Tumor necrosis factor induction by Sendai virus

Effect of murine cytomegalovirus infection on

Pathology of a pneumotropic virus recovered from C3H mice carrying the Bittner milk agent

Adverse effects of mouse hepatitis virus on ascites myeloma passage in the BALB/cJ mouse

Biological synergism between the LDV-virus and Eperythrozoon cccoides. Studies on the mechanism

A pneumotropic virus from mice causing hemagglutination

Prevalence of indigenous viruses in laboratory animal colonies in the United Kingdom 1978-1979

Studies on adjuvant-induced arthritis, tumours transplantability, and serologic response to bovine serum albumin in Sendai virus infected rats

The suppression of lymphocytic mitogenesis in Sendai virus infected rats

Increased susceptibility of mice infected with mouse adenovirus to Escherichia coli-induced pyelonephritis

Pathogenesis of K virus infectoin in newborn mice

The effect of cytomegalovirus infection on the host response to foreign and hapten-modified self histocompatibility antigens

Parvoviruses as contaminants of permanent human cell lines. Archiv fuer die gesamte Virusforschung

Viral infection-homograft interactions in a murine model

Effects of murine cytomegalovirus infection on the immune response to a tumour allograft

Synergistic effect on mortality in mice with murine cytomegalovirus and Pseudomonas aeruginosa, Staphyloccus aureus, or Candida albicans infections

A new mouse virus apparently related to the adenovirus group

Adenovirus isolated from the faeces of mice. I. Isolation and identification

Effect of murine cytomegalovirus on cell-mediated immunity

Effects of cytomegalovirus infection on mouse neutrophil chemotaxis and random migration

Cell-mediated immunity to murine cytomegalvirus

Cytomegalovirus-induced immune suppression

IL Cell-mediated immunity. C/inicu~ &

Cytomegalovirus-induced immune suppression. I. Humoral immunity

Inhibition of cellular immune reactions in mice infected with lactic dehydrogenase virus. iVuture

The biology of lymphocytic choriomeningitis infection: Virus induced immune disease

Pattern of infection and selective loss of la positive cells in suckling and adult mice inoculated with lactic dehydrogenase virus

Live lactate dehydrogenase-elevating virus (LDV) induces suppressor T cells that inhibit the development of delayed hypersensitivity to LDV

Cell-mediated immunity assayed by 5rCr release test in mice infected with mouse adenovirus

Acute disease of the submaxillary and harderian glands (Sialo-dacryoadenitis) of rats with cytomegaly and no inclusions bodies

The mechanism of modulation of humoral immune responses after infection of mice with lactic dehydrogenase virus

An immunoregulatory factor associated with spleen cells from tumor-bearing animals. I. Effect on tumor growth and antibody production

Viral diseases

Effect of sequential inoculations of Sendai virus and Pasteurellupneumotropica in mice

Interactions between Sendai virus and bacterial pathogens in the murine lung: A review

Effects of reovirus infection on the spatial and temporal organization of DNA replication in L cells

Lack of correlation of growth attenuation of murine lymphoma caused by in vitro passage with loss of lactate dehydrogenase virus

Interference between lymphocytic choriomeningitis virus and the leukemia-transmitting agent of leukemia L2C in guinea pigs

Ultrastructural pathology of glomerular lesions in gnotobiotic mice with congenital lymphocytic choriomeningitis (LCM) virus infection

Short-and long-term effects of natural infection with parainfluenza type I virus (Sendai)

Alterations of host defense mechanisms by murine cytomegalovirus infection

Correlation of the suppression of mitogen responsiveness and the mixed lymphocyte reaction with the proliferative response to viral antigen of spienic lymphocytes from cytomegalovirus-infected mice

Isolation in suckling mice of a virus from C3H mice harboring Bittner milk agent

Mongoiisim associated with rat virus (RV) infection in hamsters. Virofogy

dehydrogenase-elevating virus as the etiological agent of genetically restricted, age-dependent polioencephalomyehtis of mice

Reduced tumorigenicity by addition in vitro of Sendai virus

TransplacentaI transmission of polyoma virus in mice

Reactivation of polyoma virus in kidneys of persistently infected mice during pregnancy

Biockina of cell-mediated immunitv to Molonev murine sarcoma virustransformed cells by lactate dehydrogenase virus-antibody complex

Adjuvanicity of lactic dehydrogenase virus: Influence of virus infection on the establishment of immunologic tolerance to a protein antigen in adult mice

Effect of acute or chronic infection with lactic dehydrogenase virus (LDV) on the susceptibility of mice to plasmacytoma MOPC-315

Immune response in mice infected with lactic dehydrogenase virus. I. Antibody response to DNP-BGG and hyperglobulinaemia in BALB/c mice

Immune response in mice infected with lactic dehydrogenase virus. Antibody response to a T-dependent and a T-independent antigen during acute and chronic LDV infections

The immunodepressive action of lymphocytic choriomeningitis virus in mice

Pathogenesis of cerebellar hypoplasia produced by lymphocytic choriomeningitis virus infection of neonatal rats: protective effect of immunosuppression with anti-lymphoid serum

Characteristics of certain viruses isolated from transplantable tumors

Neonatal infection with mouse thymic virus: effects on cells regulating the antibody response to type III peneumococcal polysaccharide

Gel chromatography of serum from mice infected with a virus elevating-lactate: NAD oxidoreductase activity-an attempt to separate viral and enzymatic activities

Effect of the virus of lymphocytic choriomeningitis on the course of leukemia in guinea pigs and mice

Etiologic role of lactic dehydrogenase virus infection in an age-dependent neuroparalytic disease in C58 mice

Review and introduction remarks: Multifactorial respiratory carcinogenesis

Lactic dehydrogenase virus

Enzymatic and immunologic alterations in mice infected with lactic dehydrogenase virus

Elevated gamma-globulin and increased antibody production in mice infected with lactic dehydrogenase virus

Impaired clearance of enzymes in mice infected with the lactic dehydrogenase agent

Persistent lymphocytic choriomeningitis viral infection

Virus-anti-viral antibody complexes and associated chronic disease following transplacental infection

Lactic dehydrogenase virus-induced immune complex type giomerulonephritis

Virus-induced alterations in homeostasis: Alterations in differentiated funciions of infected cells in vivo

Virus persists in 8 cells of islets of Langerhans is associated with chemical manifestations of diabetes

Chronic virus infection and immune responsiveness. II. Lactic dehydrogenase virus infection and immune response to non-viral antigens

Alteration of murine host defense mechanisms to mammary tumors (MT) by cytomegalovirus (CMV) (Abstract no. 69)

Immunosuppression during acute murine cytomegalovirus infection

Studies of relationship between mouse cytomegalovirus and interferon

Suppression of interferon and antibody and multiplication of Newcastle disease virus in cytomegalovirus infected mice

Histochemistry of glutamic-oxaloacetic transaminase in mouse liver during MHV-3 infection

Minute virus of mice. II. Prevalence, epidemiology, and occurrence as a contaminant of transplanted tumors

Rat coronavirus (RCV): A prevalent naturally occurring penumotropic virus of rats. Archiv fuer die gesamte Virusforcshung

Lymphocytic choriomeningitis virus infection in fetal, newborn, and young adult Syrian hamsters. (Mesocricetus auratus)

Viral diseases of the respiratory system

Virus studies with germ free mice. I. Preparation of serologic diagnostic reagents and survey of germ free and monocontaminated mice for indigenous murine viruses

Inlluence of Sendai virus on carcinogenesis in strain A mice

Laboratory-associated infections: incidence, fatalities, causes, and prevention

Plasma lactic dehydrogenase-elevating agent of mice: Distribution in tissues and effect on Iactic dehydrogenase isozyme patterns

Plasma lactic dehydrogenase-elevating agent of mice: Effect on levels of additional enzymes

Deposition of immune complexes in the kidneys of mice infected with lactic dehydrogenase virus

Immunofluorescence assay for antigen and antibody in lactic dehydrogenase virus infection of mice

The isolation and partial characterization of a cytomegalovirus from the brown rat, Rattus norvegicus

The combined action of Rauscher leukemia virus and lactic dehydrogenase virus on mouse lymphatic tissue

Isolation and growth of rat cytomegalovirus in vitro

Interstitial murine cytomegalovirus pneumonia after irradiation: characterization of cells that limit viral replication during established infection of the lungs

Application of infectious agents to the study of lung cancer. Studies on the etiology and morphogenesis of metaplastic lung lesions in mice

Spontaneous mammary tumors: Decrease in incidence in mice infected with an enzyme-elevating virus. 5&nce

Persistence and other characteristics of the lactate dehydrogenase-elevating virus (LDH virus)

Antibody-producing cells: virusinduced alterations of response to antigen

Transmissible agent associated with 26 types of experimental mouse neoplasms

Modifying effects of a benign virus on the malignant process and the role of physiological stress on tumor incidence

Melanoma enhancement by viral induced stress

The LDV virus: An interfering biological contaminant

Studieson the natural infection of rats with the Kilham rat virus

Seroepidemiological study of rat virus infection in a closed laboratory colony

Virus persists in beta cells of islets of Langerhans and infection is associated with chemical manifestations of diabetes. 11. Morphological observations

Lymphocytic choriomeningitis in the nude mouse

A new mouse virus causing necrosis of the thymus in newborn mice

Growth curves of polyoma in mice and hamsters

Lactic dehydrogenase virus

Lactate dehydrogenase-elevating virus

Viral hepatitis in mice. Changes in oxidative enzymes and phosphatases after murine hepatitis virus (MHV-3) infection

Evaluation of time and dose in treating mammary adenocarcinoma with immunostimulants

Lactic dehydrogenase virus replicates in somatic cell hybrids of mouse peritoneal macrophages and SV40-transformed human fibroblasts

Activation of reticuloendothelial cells following infection with murine cytomegalovirus

Exacerbation of murine respiratory mycoplasmosis in gnotobiotic F344/N rats by Sendai virus infection

Induction of lung cancer in germfree, specific-pathogen-free and infected rats by N-nitrosoheptamethyleneine: Enhancement by respiratory infection

Some virus infections of mice

Demyelination and wasting associated with polyomavirus infection in nude (nu/nu) mice

Effects of murine cytomegalovirus on the in vitro responses of T and B cells to mitogens

T-lymphocyte subpopulations and function during murine cytomegalovirus infection

The pathogenesis of pneumonitis due to murine cytomegalovirus

Mouse cytomegalovirus is infectious for rats and alters lymphocyte subsets and spleen cell proliferation

Experimental infection with mouse adenovirus in adult mice. Archiv fuer die gesamte Virusforschung

Modulators of the immune system

Correlation of persistent mouse hepatitis virus (MHV-3) infection with its effects on mouse macrophage cultures. Archives of ViroZogy, SO

Neuropathological effects of persistent infection of mice by mouse hepatitis virus

The role of circulating interferon in the modifications of immune responsiveness by mouse hepatitis virus (MHV-3)

Naturally occurring Sendai virus disease of mice

 Kilham, L., 196lb. Rat virus (RV) 117-135 Kilham, L. & Margohs. G., 1965 . Cerebellar disease in cats induced by inoculation of rat virus. Science, 148,244-24.5 Kilham, L. & Margohs. G., 1969 . Transplantable infection of rats and hamsters induced by oral and parenteral inoculations of H-I and rat viruses (RV). Teratology, 2, 111-123 Kilham, L. & Margolis, G., 1970