Caspase-11 and NLRP3 exacerbate systemic Klebsiella infection through reducing mitochondrial ROS production

Klebsiella pneumoniae is a Gram-negative bacterium and the third most commonly isolated microorganism in blood cultures from septic patients. Despite extensive research, the mechanisms underlying K. pneumoniae-induced sepsis and its pathogenesis remain unclear. Acute respiratory failure is a leading cause of mortality in systemic K. pneumoniae infections, highlighting the need to better understand the host immune response and bacterial clearance mechanisms.

To investigate the impact of K. pneumoniae infection on organ function and immune response, we utilized a systemic infection model through intraperitoneal injection in mice. Bacterial loads in key organs were quantified, and lung injury was assessed. Survival analysis was performed in wild-type (WT) and gene deficient mice. Mitochondrial damage and reactive oxygen species (ROS) production, as well as cytokine levels were measured in macrophages isolated from these mice to evaluate their contribution to bacterial clearance capacity.

Our findings demonstrate that K. pneumoniae systemic infection results in severe lung injury and significant bacterial accumulation in multiple organs, with the highest burden in the lungs. Deficiency of caspase-11 or NLRP3 led to prolonged survival, a reduction in pulmonary bacterial load, increased blood oxygen levels, and decreased IL-6 levels in the lungs compared to WT controls. Furthermore, caspase-11- and NLRP3-deficient macrophages exhibited elevated mitochondrial ROS production in response to K. pneumoniae, which correlated with more effective bacterial clearance.

These results suggest that caspase-11 and NLRP3 contribute to K. pneumoniae-induced sepsis by impairing mitochondrial function and reducing ROS production in macrophages, thereby compromising bacterial clearance. The observed reduction in lung injury and increased survival in caspase-11- and NLRP3-deficient mice indicate that targeting these pathways may offer potential therapeutic strategies to improve host defense against systemic K. pneumoniae infection.