From Resistance to Host Response: An Integrative Study of C. difficile Infections

Clostridioides difficile infection (CDI) is a major healthcare challenge, causing severe gastrointestinal illness and significant mortality. Understanding the mechanisms of antibiotic resistance, epidemiology, and immune response in CDI is critical for developing effective treatments and prevention strategies.This dissertation encompasses three complementary studies. The first study investigates the genetic mechanisms underlying cephalosporin resistance in C. difficile strain 630 through differential gene expression analysis. The second study provides a descriptive epidemiological analysis of C. difficile ribotypes in a Las Vegas patient population, highlighting differences between healthcare-associated (HA-CDI) and community-associated (CA-CDI) cases. The third study integrates serum analyte profiling and transcriptomic analysis to explore the differential immune responses in CDI, with a focus on the role of sex hormones. The gene expression analysis identified several putative antibiotic resistance genes, including blaCDD, significantly upregulated in response to cephalosporin exposure, though deletion of these genes did not significantly affect cephalosporin resistance. These findings suggest an intrinsic resistance mechanism in C. difficile. The epidemiological study revealed diverse ribotypes with distinct distributions between HA-CDI and CA-CDI cases, with ribotype 027 being notably prevalent in healthcare settings. The integrative analysis of serum analytes and transcriptomics showed distinct hormone and cytokine profiles correlating with CDI severity and recovery, suggesting that hormonal fluctuations significantly influence immune responses. This multi-faceted approach provides comprehensive insights into the genetic, epidemiological, and immunological aspects of CDI. The findings emphasize the need for alternative therapeutic strategies to combat antibiotic resistance, and continuous surveillance to manage CDI outbreaks. These integrated insights can guide the development of more effective interventions for preventing and treating CDI.