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Public Service Announcement
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Public Service Announcement
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Background: Tyzzer's disease has recently been confirmed in two mice of a single strain within one production room at The Jackson Laboratory, Bar Harbor ME. For most current infromation refer to www.jax.org/jaxmice. The following text is provided as a public service announcement to educate the professional and scientific community on this disease.
Tyzzer's Disease in Laboratory Mice
History: Tyzzer's disease was first documented in a report by Ernest Tyzzer, in which he described a fatal outbreak of disease among Japanese Waltzing mice in 1917. It has subsequently been documented in a wide variety of mammals, including rodents, lagomorphs and non-human primates. There is a single human case report.
Etiology: Tyzzer's disease is caused by infection with an apparently obligate intracellular, spore-forming bacterium that is now classified as Clostridium piliforme (previously Bacillus piliformis). It's geographic distribution is worldwide. Although this bacterium has a wide host range, there appears to be considerable antigenic diversity and strong, but not absolute, species specificity. Thus, infection of mice is most likely to take place through exposure to a mouse or rodent isolate.
Transmission: Clostridium piliforme is transmitted as an environmentally-resistant spore through oro-fecal contact. Experimentally infected animals appear to shed the organism in feces for 1-2 weeks. Spores can remain viable in contaminated bedding for 1-2 years, and mice readily become infected upon exposure to contaminated bedding or fecal material. Transplacental transmission has been demonstrated experimentally in mice.
Clinical Signs: As with all infectious diseases in mice, disease susceptibility varies with genetic background of the mouse, immune status of the mouse, and virulence of the pathogen. Clinical signs and disease can also vary depending upon whether infection of the colony is epizootic or enzootic. Thus, infected mice can be subclinically infected, or may experience high mortality. There is some evidence that T cell deficient mice may be more prone to severe disease. Subclinical infections are the norm, but subclinically infected animals effectively transmit infection, and if carriers are subjected to stress, they may develop clinical disease. Disease is typically most apparent among weaning age mice. Clinical signs are nonspecific, and include hunched, dehydrated animals with starry coats, unformed feces and acute death.
Necropsy Findings: The most obvious gross finding is multifocal hepatitis, characterized as pinpoint pale foci to larger areas of necrosis up to a few mm in diameter. Not all mice develop hepatic lesions, and lesions may be missed grossly. Microscopic features consist of focal acute coagulation necrosis, with a peripheral zone of reactive inflammation. Hepatocytes in these peripheral regions contain pathognomonic fascicles of elongated filamentous bacteria within their cytoplasm (and occasionally nucleus). Organisms are poorly discernable on H&E, but are readily apparent with Giemsa, PAS or silver stains. The primary target organ of C. piliforme is intestine. Enteric lesions can be subtle and segmental, involving (usually) terminal small intestine, cecum and colon. Enteric lesions consist of enterocyte exfoliation into the gut lumen or crypt lumina, edema of the lamina propria, and varying degrees of necrosis of the muscularis. In acute lesions, inflammatory cells may be sparse. More severe lesions consist of mucosal ulcerations. Special stains will reveal pathognomonic fascicles of bacteria in the cytoplasm of enterocytes. Concerted examination will reveal filamentous bacteria in smooth muscle cells, but they tend to be few in number. In addition, focal necrotizing myocarditis may be present with demonstrable organisms, but this appears to be the most variable component of Tyzzer's disease in the mouse. Figures illustrating the diagnostic features of intestinal and liver lesions are available at:
Differential Diagnosis: Focal hepatitis combined with enteritis can be caused by a number of other infectious agents in the mouse. These include Corynebacterium kutscheri, Salmonella, Helicobacter, mouse hepatitis virus, ectromelia virus, and Cryptosporidium (in immunodeficient mice).
Definitive Diagnosis: Confirmation of active infection is performed by PCR of tissues or feces, but the lesions containing the typical intracellular bacteria are accurately diagnostic for skilled pathologists. A number of retrospective serologic assays are available. Serologic assays are best used for colony surveillance, and currently available antigens are fraught with problems of cross-reactivity (false positive reactions). C. piliforme can be grown in vitro using a number of cell cultures, but this is not used for diagnostic purposes.
Control: The most effective means of elimination is aggressive depopulation and disinfection of the affected animal rooms, equipment, washing areas, etc. Wild and feral rodent control is mandatory. Mice can be quarantined and re-derived, with the caveat that transplacental transmission can potentially take place. Thus, embryo transfer or in vitro fertilization with sperm are the safest approaches. In any disease outbreak, attention must be paid to amending the practices and conditions that allowed the outbreak to occur in the first place.
Caution: In situations in which the source of infection is via imported animals from other institutions, it may not be wise to universally condemn all animals from such sources, as infection is likely to be isolated to specific rooms or production areas.
References:
Percy DH, and Barthold SW. 2001. Pathology of Laboratory Rodents and Rabbits. Iowa State University Press, Ames
Riley LK, and Franklin CL. 1997. Tyzzer's disease, rat, mouse, and hamster. In: T.C. Jones, J.A. Popp, and U. Mohr (eds). Monographs on Pathology of Laboratory Animals: Digestive System.
For more information about the Mutant Mouse Regional Resource Center Program, contact:
http://www.mmrrc.org/index.html
Prepared by S.W. Barthold
date: 03/15/2002