Modeling mucosal immunity and gut microbiota interactions during Clostridium difficile infection
Viladomiu, M., A. Leber, R. Hontecillas. V. Abedi, S. Hoops, and J. Bassaganya-Riera (2015) Modeling mucosal immunity and gut microbiota interactions during Clostridium difficile infection, American Association of Immunologists Annual Meeting, New Orleans, LA
Clostridium difficile is a facultative pathogen associated with antibiotic-induced infections which result in an exuberant inflammatory response, leading to nosocomial diarrhea, colitis and even death. We have previously reported novel evidence supporting a role of T cells in modulating host responses to C. difficile. Specifically, T cell alteration towards a pro-inflammatory phenotype due to lack of PPARγ resulted in increased disease symptoms and colonic pathology, which correlated with the abrogation of T cell regulatory (Treg) responses and shift towards a Th17-driven cellular response. To better understand the role of T cells during C. difficile infection from initiation through expansion to resolution, we built a computational model of the cellular host response to the bacterium. In line with our experimental findings, the model demonstrates a crucial role of Th17 effector and Treg responses, as well as an important contribution from commensal bacteria populations in the clearance of C. difficile and colonic pathology. Simulation results predict that proper clearance of infection with reduced damage to the epithelium is possible through a shift in the relative populations of Th17 and Treg cell subsets or through an accelerated regrowth of beneficial commensal strains. Our modeling provides novel insights on the mechanisms regulating C. difficile-associated immunopathology and show the path towards safer and more effective therapeutic interventions.