S-23 : Innate immune sensing of bacteria and bacterial virulence by the cytosolic inflammasome complex

Abstract

Inflammasomes are large cytoplasmic complexes that mediate caspase-1 activation, cytokine maturation and macrophage inflammatory death. We demonstrate that the NAIP family of NOD-like proteins (NLRs) are cytosolic receptors for various bacterial products and activate caspase-1 through another NLR protein NLRC4. In mice, NAIP5 directly recognizes flagellin while NAIP1 and NAIP2 are receptors for the needle and rod subunit of bacterial toxin-injecting type III secretion system (T3SS), respectively. Human NAIP (hNAIP) is the ortholog of mouse NAIP1 and also recognizes the T3SS needle protein derived from a wide range of bacterial pathogens including Salmonella typhimurium, enterohaemorrhagic Escherichia coli, Shigella flexneri and Burkholderia spp. Ligation of the NAIPs by the corresponding ligands promotes their physical association with NLRC4, resulting in caspase-1 activation and anti-bacteria defense. We further discover that Pyrin, another candidate pattern recognition receptor encoded by the familial Mediterranean fever disease gene MEFV, forms an inflammasome complex in response to bacteria or bacterial toxin-induced inactivating modifications of host Rho proteins. These include glucosylation by Clostridium difficile cytotoxin TcdB, adenylylation by FIC-domain bacterial effectors, ADP-ribosylation by Clostridium botulinum C3 toxin as well as deamidation by Burkholderia cenocepacia, which all occur in the switch I region in Rho-subfamily GTPases. Loss of the Pyrin inflammasome causes elevated intra-macrophage growth of B. cenocepacia and diminished lung inflammation in mice. The two inflammasome pathways not only play an important role in restricting bacterial infections but also serve as a mechanism for distinguishing pathogenic bacteria from non-pathogenic ones such as commensals.