Clostridium difficile is now the most common cause of hospital-acquired infections in the United States. This Gram-positive, spore-forming, strict anaerobe most commonly infects antibiotic- treated hosts, though community-acquired infections are on the rise for unknown reasons. To survive outside a host, C. difficile produces dormant spores. Spores are metabolically dormant forms of bacteria that are resistant to many harsh conditions (e.g., many cleaning agents, heat, radiation and antibiotics). In a host, C. difficile spores germinate in response to bile acids. Following C. difficile spore germination, the vegetative cells produce the toxins that trigger the host?s inflammatory response and that cause the primary symptoms of disease. Remarkably, the effectors of C. difficile infection (e.g., toxin receptor abundance and inflammation) exhibit strong circadian rhythms. These rhythms are generated by molecular circadian clocks found in virtually every mammalian cell, and which rely on transcriptional feedback loops to coordinate the rhythmic expression of about 10-15% of the genome. The circadian nature of the host physiology suggests that the normal host circadian rhythms may impact the efficiency with which C. difficile infects, colonizes and causes disease. In this exploratory application, the effects of host circadian biology on the ability of C. difficile to colonize and on the host?s inflammatory response to C. difficile infection will be explored.
This proposal addresses the need to consider host circadian rhythms during Clostridium difficile infection. Virtually every mammalian cell harbors a molecular circadian clock, which relies on transcriptional feedback loops to coordinate the rhythmic expression of about 10-15% of the genome. Because of the impact circadian rhythms have on host gene expression and host physiology, hosts may be more susceptible to or respond differently to C. difficile infection at different times of day.
