Type I IFN dependent and independent mechanisms of protection in <i>C. difficile</i> infection
Abstract
Abstract Clostridium difficile infection (CDI) is increasingly prevalent in individuals in health care settings and in the community. C. difficile is a gram positive, anaerobic bacteria that forms spores resistant to common disinfectants. Upon infection, C. difficile spores germinate, divide and produce damaging toxins resulting in intestinal inflammation. While inflammatory mediators are known to affect disease severity, the role of type I IFN signaling in CDI has not been characterized. We hypothesized that type I IFN signaling was important for innate protection in CDI. IFNAR-deficient mice succumbed to CDI more rapidly than wild type mice. Since type I IFNs can reduce inflammasome activity, we assessed IL-1β expression in multiple tissues, and discovered that IFNAR mice expressed more IL-1β protein, and less insulin-like growth factor (IGF) transcripts in response to CDI. To investigate a potential treatment, we treated mice with the type I IFN-inducing dsRNA mimetic, polyIC. PolyIC treatment delayed onset of symptoms in survival studies. Surprisingly, the protective effect of polyIC was not a result of IFNAR signaling; treatment increased IGF and decreased IL-1β in both wild type and IFNAR-deficient mice. Finally, treating wild type mice with recombinant type I IFN also reduced disease severity. These findings suggest direct type I IFN signaling protects from CDI and treatment with polyIC may protect mice via a pathway independent of IFNAR signaling. Considering that recombinant type I IFN is already used clinically and novel treatment options for CDI are needed, further investigation of innate immune pathways may present new treatment options for this emerging infection.