Abstract
Clostridium difficile is the leading cause of nosocomial antibiotic-associated diarrhea, known as C. difficile-associated disease and the major etiologic agent of pseudomembranous colitis. In severe cases, C. difficile infection (CDI) can induce toxic megacolon, intestinal perforation and even death. The intestinal epithelial cells are the first tissue to be encountered for the adhesion and colonization of C. difficile, and play as the first physical defense barrier against infection. Despite the well characterized cytotoxicity, few studies investigate the genome-wide interplay between host cells and C. difficile. It has been shown a significant increase of the morbidity and severity of CDI in the past two decades, and the increasing cases in low risk groups also urge us to find other crucial pathogenic mechanisms and virulence factors. Thus, we aim to investigate cross-talk genetic and epigenetic molecular mechanisms between human colorectal epithelial Caco-2 cells and C. difficile during the early-stage (0~60 min) and the late-stage (30~120 min) of infection. In this study, we introduced a systems biology approach to investigate the cross-talk mechanisms during the progression of infection via big data mining, dynamic network modeling, genome-wide data identification method, system order detection scheme and principal network projection method (PNP). We thus focus on how to construct genome-wide genetic-and-epigenetic interspecies networks (GEINs) and then extract host-pathogen core networks (HPCNs) to investigate the progression of underlying host/pathogen cross-talk genetic and epigenetic mechanisms from the early-stage to the late-stage of CDI. Based on our results, we suggest that the cell wall proteins CD2787 and CD0237, which both play an important role in cell adhesion and pathogen defense mechanisms, can be considered as potential drug targets. In addition, the crucial proteins employed by C. difficile for sporulation, including CD1214, CD2629 and CD2643, can also be considered as potential drug targets since the spore-mediated re-infection is an urgent issue to be solved. Finally, we proposed a potential multi-molecule drug containing E64, CD0237-specific IgY and REP3123 for the treatment of CDI due to their inhibitory abilities toward above targets.