peptidoglycan, flagellin DNA, RNA and others. Upon ligand In addition to NODs, there is a family of NLRs that do not binding, TLRs engage the signaling adaptors MyD88 and TRIF, initiate a transcriptional program, but induce the assembly of a which initiate signaling cascades leading to the activation of large multiprotein signaling complex, called the inflammasome.37 the transcriptional factors NFkB and IRF3 that induce the Assembly of the complex usually also requires an adaptor pro- production of inflammatory cytokines (IL-8, IL-10, pro-IL-1β, tein called ASC (apoptosis-associated speck-like protein with a pro-IL18 and others) as well as a type I IFN response, CARD), which recruits the cysteine protease pro-Caspase-1 to respectively.29 the inflammasome.35 Within this complex pro-Caspase-1 is In vitro, a multitude of TLRs can be activated by Salmonella- activated by dimerization and autoproteolytic cleavage.38 Acti- derived ligands, such as lipoproteins (TLR1/2/6), LPS (TLR4), vated Caspase-1 cleaves the pro-forms of interleukin (IL)-1β and the Salmonella flagellin FliC (TLR5) and CpG-rich repetitive IL-18, leading to production and secretion of the mature elements in Salmonella DNA (TLR9). In addition, TLR2 is cytokines. Caspase-1 activation also initiates a pro-inflammatory known to recognize CsgA, a subunit of the amyloid curly fibers cell-death program called pyroptosis. Pyroptosis is named for that form the biofilm matrix of S. typhimurium.30 TLR4 and “pyro” meaning fire and “ptosis” meaning to fall in Greek, which TLR2 also play an important role in vivo since tlr42/2, tlr22/2 and reflects its hallmark inflammatory outcome.39 Pyroptosis is similar tlr42/2/tlr22/2 mice have increased bacterial burdens in mesenteric to apoptosis in that it is a programmed form of cell death lymph nodes (MLNs) following oral infection.31 Intriguingly, controlled by caspases. Pyroptosis is solely dependent on Caspase- Salmonella virulence seems to actually require TLR sensing. It 1. In contrast to apoptosis, pyroptosis is not a silent form of cell was recently shown that tlr42/2/tlr22/2 mice are sensitive to death. During pyroptosis, there is formation of pores in the cell Salmonella infection, but mice deficient in TLR2, TLR4 and membrane and subsequent release of cellular contents and pro- TLR9 are less sensitive.32 This can be attributed to the fact that inflammatory cytokines, which serve to amplify the inflammatory the SCV in macrophages derived from tlr42/2/tlr22/2/tlr92/2 mice response by signaling the recruitment of other mediators of fails to acidify. Since acidification is an important indicator inflammation. Inflammasome-induced pyroptosis likely benefits for Salmonella ©tosense2the0int1ra-ph2agosomLal aenvinronmdent,ethsehosBtduirinogmsicrobcial iinefectinons cby eelim.inating the intra- Salmonella does not induce the expression SPI-2 virulence genes cellular niche of the pathogen and re-exposing it to extracellular in tlr42/2/tlr22/2/tlr92/2 cells. Thus, although TLRs are clearly immune defenses.40 essential for defense against pathogens, Salmonella has evolved S. typhimurium infections of bone marrow-derived macro- virulence Salmonella mechanisms flagellin that is another are activated PDAMP osensendby in response. oPRRts. In dthei sflagetllinr phages in isenbsor, tissue uthatteinitia.tes culture rapidly activates inflammasome NLRC4, assembly a cytoplasmic and gut, extracellular Salmonella flagellin is detected by enterocytes Caspase-1 activation.41 The activation of the NLRC4 inflamma- expressing TLR5 on their basolateral surface, leading to NFkB some requires the expression of the SPI-1 T3SS and flagellin. activation and a robust IL-8 inflammatory response.33 Although These results led to the hypothesis that the SPI-1 needle complex, Salmonella has mechanisms to dampen this NFkB response, a which is evolutionarily related to the flagellar apparatus, was recent study revealed that enterocytes might have the ability accidentally translocating flagellin into the macrophage cyto- to bypass this effect by transmitting signals to neighboring sol.42,43 However, Salmonellae deficient in flagellin are still uninfected cells to promote NFkB-mediated IL-8 release in capable of inducing a NLRC4 inflammasome response, suggest- response to Salmonella infection.34 ing that there was an additional NLRC4 ligand produced by Once Salmonella has established itself within the SCV, it is Salmonella. Subsequent studies revealed that PrgJ, the needle hidden from many extracellular detection mechanisms. Neverthe- complex rod protein, was also capable of stimulating the NLRC4 less, macrophages and other lymphocytes have evolved mechan- inflammasome.44 isms to recognize the presence of PAMPs in the cytosol.35 The Activated Caspase-1 is a very important mediator of the host NOD-like receptor (NLR) family of PRR is a surveillance system response to Salmonella. Mice lacking Caspase-1 are much more that can detect the presence of PAMPs in the cytosol. NLRs sensitive to Salmonella infection and have higher bacterial burdens contain an N-terminal protein-protein interaction domain [either in systemic organs compared with wild-type mice.45,46 This is due a Caspase Recruitment Domain (CARD) or a Pyrin-like domain at least in part to the production of IL-1β and IL-18, since mice (PYD)], a central nucleotide oligomerization domain (NOD), and lacking either cytokine are also more susceptible to Salmonella a C-terminal Leucine-rich repeat domain (LRR).35 Upon ligand infection than wild-type mice.45 However, NLRC4-deficient mice binding, NLRs multimerize and initiate different signaling harbored comparable bacterial loads as wild-type mice following cascades. For example, NOD1 and NOD2 interact with RIP2 oral infections with wild-type Salmonella.46 The discrepancy kinase, which is a potent activator of NFkB. The contribution between the in vitro and in vivo findings was recently explained of NOD1/2 signaling to the innate immune defense against by our results showing that Salmonellae can also activate Caspase- Salmonella was recently shown by Geddes et al.36 Mice deficient 1 through NLRP3, another cytosolic receptor of the NLR protein in NOD1/2 or RIP2 showed attenuated inflammatory pathology, family.47 Salmonella grown to stationary phase, which results in reduced levels of inflammatory cytokines, and increased coloniza- the downregulation of the SPI-1 T3SS and the expression of the tion of the mucosal tissue. Interestingly, bone-marrow chimeras SPI-2 T3SS, activated two NLRs simultaneously: (1) NLRC4- demonstrated that this was dependent on NOD1/2 signaling in dependent cytokine release was stimulated by SPI-2 T3SS- hemopoietic as well as non-hemapoietic compartments. dependent translocation of flagellin. (2) NLRP3-dependent 66 Gut Microbes Volume 3 Issue 2