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.

Grant Number: 1F31AI191739-01
NIH Institute/Center: NIH
Principal Investigator: Amber Bahr