Host pathogen interactions during Acinetobacter baumannii infection

Abstract

Acinetobacter baumannii is an emerging nosocomial, opportunistic pathogen with growing clinical significance. A. baumannii has an exceptional ability to rapidly develop drug resistance and is frequently responsible for ventilator-associated pneumonia in clinical settings. In order to develop an effective treatment strategy, understanding host-pathogen interactions during A. baumannii infection is crucial. Pattern-recognition receptors activate the downstream multi-component inflammasomes complex leading to the development of inflammatory responses and the recruitment of innate immune effectors against a pathogen. However, the mechanism of inflammasome activation and pro-inflammatory secretion in A. baumannii infection remains elusive. This thesis details the role of inflammasome activation in A. baumannii infection. This study focuses on the systemic infection model using intraperitoneal injection to model the acute clinical lethality. Surprisingly, only the A. baumannii strain, which induces mice lethality induces the secretion of IL-1b and IL-18 into the plasma, suggesting a potential hyper-activation of inflammasome. I demonstrated how A. baumannii escapes canonical inflammasome activation and triggers detrimental non-canonical type I IFN-Capsase 11 pathway. I demonstrated that mice deficient in the non-canonical pathways, Ifnar1-/- and Caspase-11-/-, both exhibited protection against the infection and lower bacteria burden. Furthermore, this study is also the first study to show that GBP1 is critical for the development of fatal hyper inflammation, as in Gbp1-/- mice, improved survival was observed along with reduced systemic inflammatory cytokines. Overall, my work demonstrates that a fine balance between protective and hyper-inflammation is mediated via Caspase-11-IL1 pathway to protect the host against multidrug resistant A. baumannii mediated severe infection and might serve as a basis for potential intervention strategies. Show more