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

Yuqi Zhou ¹ Zhuodong Chai ¹ Ankit Pandeya ¹ Ling Yang ¹ Yan Zhang ¹ Guoying Zhang ¹ Congqing Wu ² Zhenyu Li ¹ Yinan Wei ^1*

• ¹ Texas A and M University, College Station, United States
• ² University of Kentucky, Lexington, Kentucky, United States

Gram-negative bacterium Klebsiella pneumoniae is the third most commonly isolated microorganism in blood cultures from septic patients and can cause serious epidemics and endemic nosocomial infections. Despite intensive investigation, pathogenesis and mechanism of K. pneumoniae-induced sepsis remains elusive. Using a systemic infection model through intraperitoneal injection, we found that K. pneumoniae induced severe lung injury and a high level of bacteria accumulated in all key organs, especially in the lung. Deficiency of caspase-11 or NLRP3 led to prolonged survival, a reduction of the pulmonary bacterial load, increase in the blood oxygen levels, and reduction of the pulmonary IL-6 level compared to the WT counterparts in vivo. Caspase-11 or NLRP3-deficient macrophages produced elevated levels of mitochondrial ROS compared to wild type cells in response to K. pneumoniae, correlated with more effective K. pneumoniae clearance. Our data suggest that the acute respiratory failure is the main cause of death following K. pneumoniae systemic infection. Upon activation by K. pneumoniae, Caspase-11 and NLRP3 impair mitochondria function, leading to reduction in ROS production in macrophages, thereby reducing their capacity in bacteria clearance.