Age-associated defects impair the optimal development of a protective immune response to Clostridium difficile in the context of infection in a novel aged murine model

Clostridium difficile infections (CDI) is a major source of mortality in the US, especially among the elderly. Protection against CDI is mediated by anti-toxin host antibodies (Ab). Although it is known that elderly mount an impaired anti-toxin response, it is yet to be determined whether their lower Ab levels are due to defective germinal center (GC) priming during acute CDI that leads to defective B cell proliferation and maturation. To test our hypothesis, we developed an antibiotic mucosal spore challenge CDI model and infected young (4mo.) and aged (u003e18mo.) mice with UK1 hypervirulent C. diff spores. By day 4 post-infection 100% of the aged had succumbed to infection compared to only 10% of young mice. Following a sublethal spore challenge a significant decrease of total PD1 + CXCR5 + Tfh cells was detected in aged compared to young at Day 12 and 21 PI ( p p + PNA + CXCR5 + B cells in our aged cohort ( p p = 0.02). The frequency of toxin-specific IgG, IgM and IgA ASC, and serum and mucosal toxin-specific Ab were markedly reduced in the aged. Our data suggests aged mice are more susceptible to CDI due to a defect in early GC formation, leading to an impaired antigen-specific Ab response. Overcoming this could prevent age-associated recurrence and severe CDI.