The role of PCSK9 in clearance of bacterial lipids and the development of anti-PCSK9 treatment for sepsis

Sepsis, which is characterized as an uncontrolled inflammatory response to severe infection, is the leading cause of death in intensive care units. In Canada, sepsis led to a total of 13,500 deaths in 2011, which translates to approximately one in 18 deaths in Canada involving sepsis. Despite this pressing medical need, there are currently no effective treatments for sepsis. 

It is well established that bacterial lipids, such as lipopolysaccharide (LPS) in Gram-negative bacteria and lipoteichoic acid (LTA) in Gram-positive bacteria, induce aberrant inflammatory response in sepsis and they associate with various lipoprotein fractions in the blood. Recent research has revealed that septic patients with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) loss-of-function mutations have better survival rates due to increased bacterial lipid clearance. It is likely that inhibition of PCSK9 leads to enhanced clearance of bacterial lipids and thus an improved chance of survival. 

Dr. Leung will characterize the role of PCSK9 in these two major pathways of bacterial lipid clearance by utilizing a novel in vivo imager to monitor the distribution of fluorescently-tagged LPS and LTA in mice. He will assess the therapeutic potential of PCKS9 inhibition by examining the ability of anti-PCSK9 monoclonal antibodies to clear bacterial lipid-laden LDL and VLDL through the LDLR and VLDLR pathways, respectively. 

Dr. Leung’s research will address a current knowledge gap in the role of lipoprotein pathways in the clearance of inflammatory bacterial lipids from circulation.