Differential activation of NLRP3 inflammasome by Acinetobacter baumannii strains

Abstract

Acinetobacter baumanniiis an emerging nosocomial, opportunistic pathogen with growing clinical significance globally.A.baumanniihas an exceptional ability to rapidly develop drug resistance. It is frequently responsible for ventilator-associated pneumonia in clinical settings and inflammation resulting in severe sepsis. The inflammatory response is mediated by host pattern-recognition receptors and the inflammasomes. Inflammasome activation triggers inflammatory responses, including the secretion of the pro-inflammatory cytokines IL-1β and IL-18, the recruitment of innate immune effectors againstA.baumanniiinfection, and the induction programmed cell death by pyroptosis. An important knowledge gap is how variation among clinical isolates affects the host’s innate response and activation of the inflammasome duringA.baumanniiinfection. In this study, we compared nineA.baumanniistrains, including clinical locally-acquired isolates, in their ability to induce activation of the inflammasome and programmed cell death in primary macrophages, epithelial lung cell line and mice. We found a variation in survival outcomes of mice and bacterial dissemination in organs among three commercially availableA.baumanniistrains, likely due to the differences in virulence between strains. Interestingly, we found variability amongA.baumanniistrains in activation of the NLRP3 inflammasome, non-canonical Caspase-11 pathway, plasmatic secretion of the pro-inflammatory cytokine IL-1β and programmed cell death. Our study highlights the importance of utilising multiple bacterial strains and clinical isolates with different virulence to investigate the innate immune response toA.baumanniiinfection.