Molecular and genetic dissection of Clostridium difficile spore-mediated transmission to identify points of intervention

Clostridium difficile caused or contributed to the deaths of 8700 hospitalized patients in the UK during 2007, making it the most significant hospital-acquired pathogen. C. difficile is estimated to cost the US health care system 3 Billion USD/year (no current estimates available for UK) representing a serious economic burden that impacts the overall performance and safety of our hospitals {Dubberke, 2009}. C. difficile persists in hospitals by exploiting an infection cycle that is dependent on humans shedding highly resistant and infectious spores. As a result, C. difficile is endemic in many hospitals and outbreaks are difficult to contain, highlighting the compelling need to understand the spore-mediated infection cycle and the factors that lead to C. difficile transmission between individuals. The proposed research will utilize cutting edge genomic and proteomic technologies in combination with in vitro and murine models to study the biology of C. difficile spores, specifically, the signals and molecular processes that lead to the formation of spores and the molecular interactions between spores and the host during colonization. This work has the potential to lead to novel infection control interventions that interfere with C. difficile spore formation and block host colonization by spores.

Clostridium difficile, a major cause of antibiotic-associated diarrhea, produces highly resistant spores that contaminate hospital environments and facilitate efficient disease transmission. To date, most research on C. difficile has focused on the role of their toxins in disease. However, we have a very limited understanding of C. difficile spore biology, especially in the context of structure/function and host-transmission, even though the spores represent a key stage of the infection cycle that can be targeted to improve infection control measures. The proposed research will focus on key questions regarding C. difficile spore-mediated transmission by building upon my research that has led to the development of a novel murine infection and transmission model and the determination of the complete spore proteome. By performing my experiments at the WTSI I have access to cutting edge, high-throughput genomic and proteomic methods that will allow me to address my particular research questions in a multidisciplinary manner. My goals are to characterize spores and identify points of the C. difficile lifecycle can be targeted for prophylactic intervention, such as sporulation-associated signaling pathways, intestinal colonization factors and spore surface proteins. The longer-term goals of my programme are to 1) develop immunomodulatory and rational prebiotic/probiotic methods that suppress C. difficile spore formation and disease within the mammalian intestinal tract and 2) identify spore surface proteins that are critical for host transmission and colonization that can be used for host immunization and potentially diagnosis.