INFECTIONS OF LABORATORY MICE: EFFECTS ON RESEARCH
Laboratory mice are host to a large spectrum of over 60 different infectious agents that may, under some circumstances, be pathogens. Many of these agents have been eliminated from contemporary mouse colonies but may re-emerge periodically.
Declaring an infectious agent a pathogen in the laboratory mouse can be a challenge. Some agents produce no discernible pathology, even in immunodeficient mice (e.g., astrovirus); some are opportunistic pathogens (e.g., Pseudomonas); and others (e.g., mouse hepatitis virus) can be overtly pathogenic in naive neonatal mice or immunodeficient mice, and yet produce minimal or no signs when enzootic within a population or when infecting genetically resistant mice. These features create a challenge for educating the investigator about the significance of infectious agents in the mouse and convincing institutional officials of the need to provide core support for surveillance and diagnostic programs that ensure the health and welfare of research animals, as well as protecting the research investment. There are 3 major reasons for being concerned about infectious agents in the mouse: jeopardy of unique colonies, zoonotic risk, and effects on research. Effects on research are significant and varied, and there is growing documentation of infectious agents obscuring phenotypes in GEMs.This text emphasizes all known naturally occurring infections of laboratory mice that have the potential for producing either lesions in mice or effects upon research, even those that have largely disappeared from contemporary mouse populations. This is because of the expanding use of immunologically deficient mice, burgeoning (and overcrowded) mouse populations, variable or inadequate microbial control practices, infestation of animal facilities by feral mice, and the re-emergence of rare infectious agents due to unrestricted traffic of GEMs among institutions.
Microbial quality control is often a casualty in the face of financial austerity, imposed by declining National Institutes of Health budgets, rising husbandry costs, and increasingly onerous government and institutional regulations. All of these factors are contributing to the re-emergence of infectious disease among laboratory mice.Disease expression is significantly influenced by age, genotype, immune status, and environment of the mouse. Genetic manipulation has introduced additional and often unexpected variables that may influence disease expression. Under most circumstances, even the most pathogenic murine viral agents cause minimal clinical disease. However, under select circumstances, the same agents can have devastating consequences. Genetically immunodeficient mice and infant mice less than 2 weeks of age that have not benefited from maternal immunity are highly susceptible to viral disease. Mouse strain genetic background, including H-2 haplotype, is an important factor in host susceptibility, with growing nuances contributed by experimentally induced gene alterations. Different viruses, and different strains of virus, vary considerably in their contagiousness and virulence, which impacts sampling size for surveillance and recognition of disease. Housing methods, including ventilated cages and microisolator cages, complicate detection and significantly influence the contagion dynamics within a population. Infectious agents can be introduced to mouse colonies through feral mice, unrestricted traffic of personnel, biologic material, including transplantable tumors, ES cells, and iatrogenic introductions of mouse pathogens when used as models for human disease.
Investigation of host-agent epizootiology by the astute diagnostician must encompass all of these factors. Animals submitted for necropsy should be accompanied by thorough clinical history, including microbial surveillance data of the colony, accurate nomenclature, genetic background, and genetic manipulation.
Mice must be carefully selected to provide maximal opportunity for diagnosis. Clinically ill animals or live cagemates of deceased or ill mice are optimal, since they would be most likely to have active infections or lesions. Diagnosis of infections in a rodent colony should not be solely dependent upon gross and microscopic pathology. A useful adjunct is serology, but this should never be used alone for diagnosis. Mice may be seronegative if actively infected with acutely cytolytic viruses, such as mouse hepatitis virus (MHV), and will be seropositive during or following recovery. Conversely, mice may be seropositive yet actively infected with a second strain of the same agent, as is the case with MHV. Young mice can be seropositive due to passively derived maternal antibody but not actively infected with the agent in question. Some virus infections, such as Sendai virus, induce immune-mediated disease. Thus, mice may not become clinically ill until a week or more into infection. Therefore, positive seroreactivity would be confirmatory in clinically ill mice infected with Sendai virus. These examples underscore that seroconversion to an agent does not imply a cause and effect relationship with disease, unless epizootiology, pathology, and serology are considered collectively. Finally, molecular methods of detection are increasing in use but must be accompanied by appropriate positive and negative controls, and positive results must always be confirmed by sequencing or other methods.
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