"Investigating mechanisms of neonatal protection from Clostridioides difficile"

Alexa Semon, Orlaith Keenan, Emma Elizabeth Furth,  Babette Zemel, Gary Wu and Joseph Zackular

Clostridioides difficile is an opportunistic enteric pathogen that is classified as an urgent antibiotic-resistant threat by the Centers for Disease Control and Prevention. C. difficile infection (CDI) in adults causes a spectrum of disease including diarrhea, pseudomembranous colitis, toxic megacolon, and death. Remarkably, infants colonized with C. difficile present as asymptomatic, despite being colonized with high burdens of toxigenic strains. The mechanisms governing infant protection from CDI pathology remain unknown. We have established a murine model of neonatal colonization that results in C. difficile burdens and toxin production similar to those seen in human infants. In this model, neonatal mice show 100% survival when given a dose of C. difficile spores that is lethal to adults. Our preliminary results demonstrate that although neonates are protected from lethal infection, they are not truly asymptomatic. We observe a robust recruitment of innate immune cells and evidence of inflammatory cytokine production and damage. These findings begin to expand our understanding of infants' relationship with a ubiquitous enteric pathogen and suggest that age-dependent mechanisms exist which abrogate severe pathology and disease in early life. Because C. difficile colonization occurs during critical timepoint when a beneficial relationship between the host and its resident gut microbiota is established, future directions are targeted at understanding whether early-life C. difficile colonization is consequential to host immune development and the host’s relationship with the intestinal microbiota.