Biochemical dissection of bacterial virulence and macrophage innate immunity

Abstract

Many bacterial pathogens use a type III secretion system to inject virulent effector proteins into host cells. These effectors often use sophisticated biochemical strategies to manipulate host signal transduction pathway. I will present our work on three bacterial effector families, each of which defines a novel enzymatic posttranslational modification, and their functions in infection. The OspF effector from Shigella flexneri employs a MAPK phosphothreonine lyase activity to block host MAPK signaling and IL‐8 production. The CHBP/Cif family of effectors from Burkholderia pseudomallei and Enteropathogenic E. coli (EPEC) catalyze deamidation of Gln‐40 in ubiquitin and NEDD8, inactivating host ubiquitin pathway and many related cellular processes. NleE from EPEC and Salmonella typhimurium carries out a novel cysteine methylation modification on key ubiquitin‐chain sensory proteins in host NF‐kB pathway, blocking NF‐kB‐mediated inflammatory response during infection. On the host side, the inflammasome complex is believed to be important for macrophage innate immune defense against bacterial infection. I will also discuss our recent identification and characterization of the NAIP family of NOD‐like proteins (NLRs) that serves as inflammasome receptors for bacterial flagellin and also the type III secretion apparatus, which plays an important role in restricting various bacterial infections.