DESCRIPTION (provided by applicant: Antimicrobial activity of apolipoprotein A-I It has been well established that the human serum protein apolipoprotein A-I (apoA-I) plays a central role in the transport and metabolism of cholesterol. However, it has become increasingly clear that the protein plays an important role in innate immunity as well. We propose to investigate the binding of apoA-I to bacterial membranes. Initial studies have shown that apoA-I binds to lipopolysaccharides of the outer membrane and negatively charged phospholipids of the inner membrane. Lysine residues play a critical role in this binding interaction. We aim to understand the molecular basis for the antimicrobial properties of apoA-I. The binding of apoA-I to a variety of LPS from different bacterial sources including truncated LPS versions, and phospholipids from in inner membrane, will be investigated in detail. This will provide key insight into the binding mechanism. Since neutralization of lysine residues inhibits antimicrobial properties, we will use a naturally occurring modification caused by acrolein. This agent is abundantly present in cigarette smoke targeting lysine residues in serum proteins. Upon modification by acrolein, binding to lipopolysaccharides, negatively charged phospholipids, and the inhibition of bacterial growth will be determined. The proposed studies aims to better understand how apoA-I recognizes bacterial membrane surfaces thereby providing protection against gram-negative infection. The knowledge obtained by this study has the potential to result in improved ways to manage bacterial sepsis for which no effective treatment exists.

PUBLIC HEALTH RELEVANCE: Antimicrobial activity of apolipoprotein A-I Apolipoprotein A-I is an exchangeable apolipoprotein well known for its anti-atherogenic properties. It has become clear that the protein also plays a role in innate immunity and exerts antimicrobial properties. The proposal aims to understand the molecular basis of the antimicrobial activity. Knowledge obtained from our studies into this novel role of apolipoprotein A-I may lead to improved ways to treat gram-negative bacterial sepsis.