915. Aging predisposes mice to acute symptomatic disease and prolonged weight loss in a murine model of Clostridium difficile infection
Session: Poster Abstract Session: Bacterial Pathogenesis
Saturday, October 22, 2011
Room: Poster Hall B1
Handouts
  • Pawlowski_IDSA 2011.pdf (659.3 kB)
  • Background:  C.difficile infection (CDI) incidence, severity, and mortality, particularly in the aging population, has been increasing, corresponding with the emergence of the hypervirulent NAP1/BI C. difficile strain. We have previously shown that aged germ free and conventional mice exposed to a BI strain exhibit striking differences in the severity of C.difficile infection. We therefore performed further experiments to demonstrate age related differences in a murine model of C.difficile infection.

    Methods:  Aged (16 mo, N=16) and young (3 mo, N=16) C57BL/6 mice from the National Institutes on Aging were exposed to clindamycin continuously and orally infected with 1x107  viable cells of a C.difficile BI strain. Mice were monitored for weight loss and symptoms and stool analyzed for C.difficile burden using quantitative PCR and toxin A/B using ELISA. Colon and cecal segments were processed and analyzed for histopathology and ceca were tested for mucosal cytokine production utilizing Luminex bead technology.  

    Results: Both aged and young mice developed acute symptomatic CDI with aged mice displaying significantly greater and more persistent weight changes as compared to young mice through day 15 (p≤0.05).  Aged and young mice maintained elevated and comparable stool concentrations of C. difficile and toxin throughout the 15-day period. Histopathologic changes were equal and present in both aged and young mice, with the highest degree of damage at day 2 post-infection. Ceca from aged mice displayed significantly greater elevations in the pro-inflammatory cytokines IL-1β, MCP-1, and IL-17 post infection (p≤0.05), with decreased IL-10 levels early in infection, and increases in IL-10 and IFN-γ concentrations later in infection (p≤0.05).

    Conclusion: Our findings indicate that aging predisposes mice to more severe symptomatic CDI with greater acute and persistent weight loss despite similar fecal toxin levels, shedding of C.difficile, and  histopathologic changes. Infection in aged mice however, is associated with significantly greater mucosal pro-inflammatory cytokine responses and reduced early anti-inflammatory cytokines, suggesting that poorer regulation of inflammation with aging may be leading to more severe symptomatic disease.

     


    Subject Category: B. Bacterial pathogenesis, studies in animal models, molecular pathogenicity

    Sean Pawlowski, MD1,2, Glynis L. Kolling, PhD2, Gina M. Calabrese, BS2, Rosemayre S. Freire2, James Platts-Mills, MD3, Cirle AlcantaraWarren, MD2 and Richard Guerrant, MD2, (1)Colorado Infectious Disease Associates, Denver, CO, (2)Division of Infectious Disease and International Health, University of Virginia, Charlottesville, VA, (3)Division of Infectious Disease and International Health, University of Virginia, Charlottesville, CO

    Disclosures:

    S. Pawlowski, None

    G. L. Kolling, None

    G. M. Calabrese, None

    R. S. Freire, None

    J. Platts-Mills, None

    C. AlcantaraWarren, None

    R. Guerrant, None

    Findings in the abstracts are embargoed until 12:01 a.m. EST Thursday, Oct. 20 with the exception of research findings presented at IDSA press conferences.