Evasion of innate immunity by Yersinia pseudotuberculosis: LPS biosynthesis genes play a key role in inhibiting the antimicrobial effects of chemokines and other antimicrobial peptides (P1241)

Abstract

Host defense peptides, including antimicrobial chemokines, play an essential role in protecting a wide variety of organisms from bacterial infection. In an effort to identify bacterial genes involved in resistance to antimicrobial chemokine mediated cell death we performed random transposon mutagenesis on a population of Yersinia pseudotuberculosis. Through the use of a novel flow cytometric assay these mutant bacteria were then screened for mutations which led to increased binding to the antimicrobial chemokine to the bacterium. Using this strategy we have screened thousands of mutant bacteria and identified several genes that when mutated lead to increased antimicrobial chemokine binding to and killing of bacteria. These genes, which when interrupted lead to increased susceptibility to antimicrobial chemokine mediated cell death, fall into several functional categories including efflux pups, transcriptional regulators and LPS biosynthesis related genes. Understanding how chemokines and other host defense peptides recognize and bind bacteria and how bacteria evade the antimicrobial activity of host defense peptides, could lead to novel drug targets that enhance the innate immune system. In short, the therapeutic use of AMCs to fight infections may be significantly enhanced by simultaneously targeting processes, such as lipopolysaccharide biosynthesis, that are required for resistance to these peptides.