Sepsis-induced inflammasome impairment facilitates development of secondary A. baumannii pneumonia

Acinetobacter baumannii has become one of the most critical pathogens causing nosocomial pneumonia. Existing animal models of A. baumannii pneumonia are not relevant to the majority of critical care patients. We aimed to develop a novel model of secondary A. baumannii pneumonia in post-sepsis mice.

A two-hit model of sepsis induced by cecal ligation and puncture followed by A. baumannii pneumonia on day 5 was established. In addition, the two-hit model was established in humanized mice. A period of 2 h of mechanical ventilation followed by observation was used in additional experiments. Lung histopathology, bacterial cultures, and cellular infiltration were analysed as well as markers of the inflammasome activity in vivo and ex vivo.

A. baumannii infection caused mortality and loss of body weight and temperature in post-sepsis mice. Increased lung bacterial burden and dissemination together with signs of enhanced inflammatory injury were observed in post-sepsis mice but not control mice that were challenged with A. baumannii. Post-sepsis mice were unable to mount inflammasome activation in response to secondary pneumonia to the level of control mice. Transfer of wild-type but not capsase-1 KO alveolar macrophages was able to restore the pulmonary protection against A. baumannii. Mechanical ventilation exacerbated the pathological response to pneumonia in post-sepsis mice but enhanced inflammasome signalling in non-sepsis mice with pneumonia.

We established a novel model of A. baumannii pneumonia that revealed sepsis-induced impairment of inflammasome activation in alveolar macrophages is critical for the control of secondary A. baumannii pneumonia.