Ausschuss für Hygiene

Host species:

• • laboratory mice
  • one report about an epidemic outbreak in a gerbil colony (de la Puente-Redondo, 1999)
  • one report of an outbreak in a guinea pig colony (Ocholi 1988)

Organotropism:

• • etiologic agent of transmissible murine colonic hyperplasia (TMCH)
  • large bowel (descending colon is most affected)

Clinical disease:

• • infection in most adult mice is subclinical and self-limiting (Barthold 1978)
  • suckling mice, adult animals of some inbred strains (Barthold 1977, Itoh 1988, Silverman 1979),  Han:NMRI mice (Bieniek 1976) and transgenic lines (Maggio-Price 1998) are more susceptible and demonstrate clinical signs
  • clinical signs are nonspecific and include ruffled coat, weight loss, depression, stunting, perianal fecal staining, pasty dark feces and dehydration
  • variable incidence of rectal prolapse in mice of all ages is indicative of infection (Brennan 1965, and others)
  • mice that recover may be refractory to reinfection (Barthold 1980)
  • streptomycin in the drinking water may influence the severity of the disease (necrosis, colitis) (Luperchio 2000)
  • age, host genetic background, diet and indigenous microbiota influence disease expression (Luperchio 2001)
  • mucosal hyperplasia is more severe in outbred NIH Swiss mice as compared with C3H/HeJ, C57BL/6J and DBA/2J mice (Barthold 1977)
  • moderate hyperplasia in C3H/HeJ mice (Barthold 1977)
  • least degree of hyperplasia in C57BL/6J and DBA/2J mice (Barthold 1977)
  • commercial diets effect the baseline colon morphology and presumably the epithelial cell turnover rate – the dietary constituents responsible for this effect are unknown (Barthold 1977)
  • germfree CF1 and C3H mice are highly susceptible, germfree C57BL/6 and NC mice are susceptible, and germfree BALB/c are resistant to infection (Itoh 1988)
  • CD4^-/- or TCR-β^-/- mice develop polymicrobial sepsis and end-organ damage (abscesses) and succumb during acute infection (Bry 2004)

Pathology:

• • colitis
  • hallmark pathologic lesion: colonic hyperplasia with limited inflammation and epithelial cell hyperproliferation in the descending colon (Barthold 1978)
  • characterized by crypt elongation, increased mitotic activity, mucosal thickening, variable mucosal inflammation, crypt abscesses, occasional erosions and ulcers, healing and goblet cell hyperplasia (Barthold 1978, National Research Council 1991)
  • necrosis of the colonic mucosa and severe colitis most notably in suckling mice (Luperchio 2000)
  • grossly thickened and rigid distal colon, devoid of formed feces
  • cecum is often empty and contracted
  • with increasing severity of disease, the entire colon, and less frequently, the cecum and ileum may be involved
  • animals of some inbred strains and transgenic lines develop lesions as severe as those seen in suckling mice: neutrophil infiltration of mucosa and submucosa, mucosal erosions and necrosis (Barthold 1978)
  • mucosal hyperplasia is dependent on the host immune response (Higgins 1999)
  • infection generates a predominately lymphocytic infiltrate, characterized by CD4⁺ T cells situated near the proliferative epithelial crypts (Higgins 1999)
  • innate immunity can mediate acute responses to infection, but T and/or B lymphocytes mediate most of the tissue pathology and inflammation in the later stages of infection (Vallance 2002)
  • bacteremia and extra-intestinal infection are not hallmarks of infection, though recovery of bacteria from blood and liver and spleen has been reported (Luperchio 2001)
  • B cell-deficient (MuMT^-/-) or B and T cell-deficient (recombinase-activating gene 2^-/-) mice develop severe pathology in the colon and internal organs and deteriorate rapidly during acute infection (Bry 2004)
  • inflammatory and crypt hyperplastic responses in RAG1^-/- mice are transient and infection is often fatal (Vallance 2002)
  • RAG1^-/- mice respond to infection primarily with a granulocytic infiltration of the colonic mucosa (Vallance 2002)
  • hyperplastic responses do not occur in interferon (IFN)-γ receptor-deficient mice (Higgins 1999)
  • depletion of IFN-γ prevents crypt hyperplasia (Artis 1999)

Morbidity and mortality:

• • little morbidity and mortality in most adult mice, while mortality or runting is seen in weaning-age mice (Barthold 1978, Barthold 1977)
  • increased level of mortality accompanied by a high incidence of rectal prolapse in outbred Swiss-Webster mouse (Ediger 1974)
  • high mortality in T-cell receptor αβ transgenic mice (Maggio-Price 1998)
  • wild-type mice clear the infection; T and/or B lymphocytes are required to clear the infection (Vallance 2002)
  • only limited mortality in most inbred and outbred strains
  • severity of hyperplasia does not correlate with mortality: C3H/HeJ mice did not develop more severe hyperplasia as compared to outbred Swiss-Webster mice, but C3H/HeJ mice exhibited 45% mortality while no mortality was observed in Swiss-Webster mice (Luperchio 2001)
  • C57BL/6 mice depleted of CD4⁺ T cells are highly susceptible to infection and develop severe colitis (Vallance 2003)
  • LPS-hyporesponsive C3H/HeJ mice experience more rapid and extensive bacterial colonization than SCID mice – high bacterial load is associated with accelerated crypt hyperplasia, mucosal ulceration and bleeding, together with very high mortality rates (Vallance 2003)
  • immunodeficient mice (mice lacking IL12, IFN-γ, TNF receptor or both T and B lymphocytes) are more susceptible to infection than immunocompetent mice (Goncalves 2001, Simmons 2002, Vallance 2002, Vallance 2003) and infection is often fatal in former mice

Zoonotic potential:

• none

Interference with research:

Physiology

• • experimental stress can evoke more severe disease in infected mice
  • increase in total cellular β-catenin accompanied by an increase in nuclear β-catenin concentrations; elevated levels preceded crypt elongation (Sellin 2001)
  • increased transcription of EGR-1 with subsequent activation of the MEK/extracellular signal-regulated kinases (de Grado 2001)
  • increase in production of keratinocyte growth factor, which induces cell proliferation (Higgins 1999; Bajaj-Elliott 1998)

Immunology

• mice with deficiencies in cell-mediated immunity or mice lacking T and B cells are more susceptible to infection with C. rodentium (MacDonald 2003)
• colonic hyperproliferation is associated with cytokinetic alterations (Barthold 1979)
• increase of IL-10 secretion and inhibition of IL-2 and IL-4 secretion by mitogen-stimulated murine spleen cells (Malstrom 1998)
• variable effect on IFN-γ secretion, whereas the effect of enteropathogenic Escherichia coli lysates is inhibitory (Malstrom 1998)
• suppression of lymphocyte activation in vitro (Klapproth 2000)
• highly polarized Th 1 immune response, characterized by increased levels of IL-12, IFN-γ and TNF-α mRNA (Higgins 1999)
• infected IL-12p40^-/- and IFN-γ^-/- mice mount anti-Citrobacter serum and gut associated IgA responses and strongly express inducible NO synthase (iNOS) in mucosal tissue, despite diminished serum nitrite/nitrate levels (Simmons 2002)
• up-regulated expression of the mouse β-defensins (mBD)-1 and mBD-3 in colonic tissue in C57BL/6 mice; in contrast, only up-regulated expression of mBD-3 in IL-12- and IFN-γ-deficient mice (Simmons 2002)

Oncology

• • C. rodentium-induced hyperplasia can alter chemical carcinogenesis in the large bowel (Barthold, 1977, 1980)
  • hyperplastic state of the colon serves as a promoter for colon tumorigenesis (Barthold 1977)
  • transient hyperplastic state increases susceptibility to the carcinogenic effect of 1,2-dimethylhydrazine (DMH) in NIH Swiss mice
  • DMH administration concomitant with hyperplasia reduces the latency period for early neoplastic lesions, however hyperplasia has no effect on already established tumors
  • hyperplastic lesions may be confused with neoplasia because associated cytokinetic alterations share several common features with those observed in neoplasia (Barthold, 1979; Pullinger 1960)
  • increase in cellular concentrations of cyclin D1 and c-Myc (proteins maintaining proliferation status

References:

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Vallance, B. A., W. Deng, L. A. Knodler, and B. B. Finlay. 2002. Mice lacking T and B lymphocytes develop transient colitis and crypt hyperplasia yet suffer impaired bacterial clearance during Citrobacter rodentium infection. Infect. Immun. 70: 2070-2081.

Authors: P. Kirsch / H. Meyer