Investigating Microbial and Host Factors that Modulate Severity of \u3ci\u3eClostridioides difficile\u3c/i\u3e Associated Disease

Clostridioides difficile is recognized as one of the most important pathogens in hospital and community healthcare settings. The clinical outcome of infection of toxigenic C. difficile infection (CDI) ranges from asymptomatic colonization to fulminant pseudomembranous colitis and death. In recent studies, it has been suggested that a high proportion of nosocomial CDI cases are transmitted from asymptomatic carriers which might be acting as infection reservoirs. Understanding what causes the different responses to infection could lead to the development of novel prevention and treatment strategies. Although several explanations have been proposed to explain variations in susceptibility, understanding of the exact mechanisms that underlie the spectrum of variation in CDI disease severity remains limited and further research is needed to determine what factors are responsible for these variations. In this work, we establish different human microbiota- associated (HMA) mouse models. By analyzing innate immune responses to CDI, we demonstrate that these models reproduce differences in disease severity during infection observed in human patients. These differences were largely based on mouse strain (C3H/HeN and C57BL/6J) and independent from C. difficile burden or toxin activity. Altogether, our HMAmouse models demonstrated the potential to study interactions between microbiome, pathogen and host inflammatory responses in the context of CDI. Advisor: Jennifer Auchtun