Interferons and eosinophils promote liver injury during Ehrlichia-induced shock - Project Summary As our immune system is activated by infection to clear pathogen mechanisms are activated to both boost/stimulate and quell our immune response to promote effective antimicrobial effector functions, but also limit tissue damage. Therefore, an overactive and toxic immune response to an infection can enhance local tissue damage, which may also contribute to bacterial dissemination into the bloodstream. During a systemic infection, host defense against the spread of pathogen via the bloodstream requires a highly coordinated immune response in which the liver plays a pivotal role due its intrinsic ability to detect, capture, and clear circulating microbes as well as produce acute phase proteins. Despite these inherent antimicrobial mechanisms, numerous bacteria circumvent these defenses, establish infection in the liver, and cause liver damage and dysfunction. Infection-associated liver dysfunction is a strong independent risk factor for infection-induced mortality, however the underlying mechanisms that contribute to infection-induced liver injury are not clear. Therefore, the overarching objective of this proposal is to define components of the host’s immune response that contribute to liver damage/dysfunction during a severe bacterial infection. An excessive or ill-timed interferon (IFN) response has been implicated in hyperinflammation and tissue damage in numerous infectious diseases, but how interferons are regulating the intrahepatic immune response has not been investigated. Ixodes ovatus ehrlichia (IOE) is an obligate intracellular hepatotropic bacteria that causes severe liver injury and fulminant septic shock in C57BL/6 mice. Previous work in our lab demonstrated that mice deficient in type I IFN or both type I and II IFN signaling are protected from IOE-induced mortality demonstrating a fundamental role for type I IFNs in pathology. Therefore, the primary goal of this proposal is to understand the IFN-dependent mechanisms that contribute to immune dysregulation and infection-induced mortality. Our central hypothesis of this proposal is that IOE-induced mortality is primarily attributed to type I and II IFN- dependent immune-mediated liver damage and dysfunction whereby hepatocyte cell death and eosinophilic degranulation exacerbates hepatic and systemic inflammation. We propose two aims: in Aim 1 we will investigate the cell drivers and mechanisms within the non-hematopoietic and hematopoietic compartments required for IFN-dependent liver damage during IOE infection; in Aim 2 we will explore the role of eosinophils in driving liver dysfunction and damage during infection. Collectively, our studies will investigate novel cellular mechanisms contributing to infection-induced liver damage and further define how infection-induced mortality is attributed to liver dysfunction/damage.
