NLRP3 inflammasome plays an important role in the innate immune response to Acinetobacter baumannii infection

Abstract

Abstract Acinetobacter baumannii is an emerging multi- or pan-drug resistant nosocomial and community associated bacterium that is increasingly becoming a serious health threat world-wide. Pneumonia, bacteremia, urinary tract infections, and wound infections are some of the important clinical manifestations of A.baumannii infection. However, the innate immune pathways leading to various clinical outcomes associated with A. baumannii infections are not fully characterized yet. We identified that A. baumannii invades and survives within host cells and hypothesized that intracellular innate immune receptors might play a role in the host defense to A. baumannii infection. Inflammasomes are intracellular multiprotein complexes that play critical roles in innate immunity. But whether inflammasome pathway plays any role in the pathogenesis of A. baumannii infection is not studied yet. Through in vitro and in vivo murine pneumonia infection models, we demonstrate that the most extensively studied inflammasome, NLRP3, is an important player in the host defense and inflammatory response associated with A. baumannii infection. We show that A.baumannii infection primes as well as activates the NLRP3 inflammasome assembly in mouse bone marrow-derived macrophages. A.baumannii infection induced IL-1β/IL-18 production is entirely dependent upon ASC/NLRP3/Caspase-1 axis. A.baumannii activates NLRP3 inflammasome by various overlapping mechanisms such as ROS generation/Potassium ion imbalance. Thus we identified a previously unrecognized role for inflammasome components in the host innate immune response to A. baumannii infection and this information may provide alternative therapeutic approaches to tackle A. baumannii infections.