Aging impairs the cellular immune response to acute C. difficile infection

Abstract Clostridium difficile (C. difficile) is a spore-forming bacterium that produces enterotoxins that damage the intestinal epithelium. The incidence of C. difficile infection (CDI) increased significantly over the last two decades, particularly among those ≥65 years of age. The objective of this study was to determine the role of age in immune responses to C. difficile infection in mice, utilizing strains of varying virulence. We have shown that mice infected with C. difficile strain VPI 10463 (VPI) exhibit more severe disease compared to C. difficile strain 630. Thus, to examine an age-related effect on immune responses in CDI, young mice (2–3 months old) and aged mice (22–24 months old) were rendered susceptible with cefoperazone and then infected with either C. difficile strain 630 or VPI. Cecum and colon were harvested during peak disease severity (day 2–4 post-infection) and processed to assess intestinal immune cell profile by flow cytometry. We found that CD45+ immune cell infiltration occurs early in the cecum of mice infected with VPI, but not in 630, regardless of age. Of the CD45+ immune cells in the cecum and colon of VPI-infected mice, the majority were CD11b+ myeloid cells. While young mice infected with C. difficile strain VPI showed a robust increase in cecal eosinophils, there was a significant lack of an eosinophil response in aged counterparts. In summary, C. difficile strain 630 did not elicit an early cellular intestinal immune response and this was independent of age. Furthermore, aged mice demonstrated a significantly decreased local cellular immune response to C. difficile VPI 10463 infection compared to young mice, suggesting a role for age-associated immune responses in CDI outcomes in older patient populations.