Identifier

etd-04102013-190507

Degree

Doctor of Philosophy (PhD)

Department

Veterinary Medical Sciences - Pathobiological Sciences

Document Type

Dissertation

Abstract

Bacterial pneumonia and sepsis are two important causes of mortality in the world. Emergence of multidrug resistant bacteria has necessitated the development of new treatment and/or prevention strategies to augment host immune defense. In this context, the innate host defense is critical in clearing pathogenic bacteria from the host. Early neutrophil recruitment is a critical step in a multistep requence leading to bacterial clearance. Pattern recognition receptors (PRRs) play a critical role in the innate immune system. Receptor interacting protein 2 (RIP-2) is an adaptor for the nod-like receptors (NLR) NOD1 and NOD2. Nucleotide oligomerisation domain 2 (NOD2) is an intracellular PRR that is shown to be important for host defense against intracellular bacterial pathogens. However, the role of NOD2 and RIP-2 during Gram-negative bacterial pneumonia and polymicrobial sepsis has not been explored. Thus, we hypothesize that the NOD2/RIP-2 axis is critical for host defense during bacterial pneumonia and sepsis/septic peritonitis. To test this hypothesis, we infected NOD2(NOD2-/-), RIP-2(RIP-2-/-) deficient mice intratracheally (i.t) with E. coli (106 CFUs/mouse) and Klebsiella pneumoniae (103 CFUs/mouse). We observed that NOD2/RIP2 signaling is critical for the host defense during gram-negative pneumonia and poly microbial sepsis. The NOD2/RIP2 axis regulates neutrophil recruitment via IL-17A production. We also found that NOD2/RIP-2 signaling is essential for the production of IL-6 and activation of STAT3. We demonstrated that RIP-2 regulates inflammasome activity that is independent of NOD2 signaling. Taken together, these data demonstrate that the NOD2/RIP-2 axis plays a critical role in neutrophil-mediated host defense through IL-17A production and by inflammasome activation. In cecal ligation puncture (CLP) induced sepsis, RIP2-/- mice show increased mortality with higher bacterial burden in the peritoneum and systemic organs compared to WT controls. We found reduced neutrophil influx IL-17A and IL-1beta levels in the peritoneum of RIP2-/- mice after CLP. Furthermore, we also observed increased systemic inflammation accompanied by vital organ damage in the knockout mice. As a whole our data suggest a critical role of RIP2 in neutrophil recruitment, along with IL-17A and IL-1beta during sepsis.

Date

2013

Document Availability at the Time of Submission

Release the entire work immediately for access worldwide.

Committee Chair

Jeyaseelan, Samithamby

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