phagocytes or when it spreads to new host cells (Fig. 2C). dependent on Caspase-1 expression in stromal but not lymphoid Consistent with this idea, it has been shown recently that cells, suggesting that SopE-induced Caspase-1 activation hap- Salmonellae constitutively expressing flagellin are released from pened in gut epithelial cells and not mucosa resident lymphocytes. host cells via NLRC4/Caspase-1-induced pyroptosis and are Although these results suggest that T3SS effector proteins could subsequently removed by neutrophils.40 In addition, Salmonella possibly activate Caspase-1 directly, the significance of these replicate extracellularly after depletion of neutrophils.70 Although results for infections with wild-type Salmonella is still unclear. neutrophils are important for host defense against Salmonella, The effector-less mutant strain expressing SopE should be infiltrating neutrophils are also a major cause of tissue damage compared with wild-type bacteria or to a SopE single deletion in the mucosa, which is sometimes associated with necrosis in mutant in the same analyses. In addition, several wild-type strains large areas of the terminal ileum and colon.53 This tissue damage of Salmonella lack SopE, yet are still able to induce activation of leads to a loss of epithelial barrier function, resulting in an Caspase-1. However, the notion that Caspase-1 could also be increase in inflammation and contributing to diarrhea. In active in stromal cells in the gut was recently strengthened by the addition, neutrophils might contribute to diarrhea by stimulating discovery of the NLRP6 inflammasome.76 Unlike other NLRs, chloride secretion from epithelial cells.71 Thus, although neutro- NLRP6 is highly expressed in the epithelial cells of the intestine, phil recruitment prevents the systemic spread of the infection, it while its expression is low in lymphoid cells. NLRP6 seems to be might nevertheless be a key determinant for the development of involved in gut homeostasis through Caspase-1 mediated IL-18 gastroenteritis. secretion.76 The ligand activating NLRP6 remains undiscovered Active induction of inflammation by S. typhimurium. so far, but it is hypothesized that it could be a bacterial PAMP Although S. typhimurium cannot resist the onslaught of neutro- indicating epithelial cell integrity. Interestingly, IL-18 is an phils in intestinal tissue, the pathogen appears to be custom-built important trigger of intestinal inflammation during Salmonella to bloom in the lumen of the inflamed intestine, because its infections, yet if Salmonellae activate NLRP6 in the gut and if numbers in this niche increase dramatically during inflammation. they do this actively by its T3SSs remains to be determined. Above, we have ©discussed2the 0diff1erent 2mechaLnismasSnalmodnellaes Bioscience. has evolved to gain this advantage allowing it to survive and Summary and Outlook replicate in the inflamed gut despite diarrhea and nutrient restriction.72 Considering the significant growth advantage that In recent years, there has been a rapid increase in our under- Salmonella surprising if gains Salmonella from intestinal would inflammation, Dactivoely innduceohostt it would not indnatei be smecthanrismisbof standing and appreciation uthe tinenate.immune of the importance, system. This function includes and immune pathways to cause inflammation. Indeed, the W.D. establishing the molecular basis for the detection of extra- and Hardt and J.E. Galan research groups have recently published intra-cellular pathogens by germline-encoded, pattern-recognition studies that support such a mechanism.73,74 Bruno et al. report receptors. These receptors play a crucial role in the GI tract in that infections of human epithelial cells induced a transcriptional recognizing the presence of invading pathogens and inducing response through the activation of mitogen-activated protein mucosal inflammation. Investigating Salmonella pathogenesis has (MAP) kinase and NFkB signaling.73 This activation was significantly contributed to our understanding of how pathogens dependent on the SPI-1 bacterial effector proteins SopE, SopE2 are detected in the gut and also how they respond to innate and SopB, and partially on the activation of Rho-family GTPase immune defense mechanisms. A particularly interesting field of Cdc42, but independent of intracellular sensors such as NOD1, study is how Salmonella has adapted to thrive in the gut despite NOD2 and RIP2 kinase. In addition, S. typhimurium induced massive inflammation, illustrating how a pathogen has evolved intestinal inflammation in mice deficient for TLR4 and MyD88, to trigger intestinal inflammation in order to outcompete the consistent with an active role of SPI-1 effectors in the activation of intestinal microbiota. Recent reports have revealed fascinating innate immune responses.73 In addition to a role in the activation insights into how Salmonella takes advantage of the immune of NFkB signaling, SopE seems to also have a role in the responses in the mucosa and turns them in its favor. For example, activation of Caspase-1.74 Mueller et al. report that infection of inflammation helps Salmonella to outcompete the microbiota HeLa cells or RAW264 macrophages with wild-type S. by ROS generating a novel respiratory electron acceptor, which typhimurium or with a strain that expresses SopE and not can be used by Salmonella but not the microbiota. In addition, the other SPI-1 effectors induced the activation of Caspase-1, as the detection of Salmonella by TLRs has been shown to be crucial measured with the fluorescent Caspase-1 activity probe FLICA, for Salmonella virulence, since it induces the acidification of and IL-1β secretion.74 This activation was independent of the phagosome, which in turn provides a cue for Salmonella flagellin, a known activator of the NLRC4/Caspase-1 axis.75 that it has reached its intracellular niche protected from extra- Consistent with the in vitro findings, the effector-less mutant cellular immune responses.32 Finally, recent reports indicate that expressing SopE induced intestinal inflammation in wild-type, Salmonella might have evolved the ability to actively trigger but not in Caspase-1-deficient mice. Similarly this strain failed NFkB and inflammasome signaling pathways through injected to induce inflammation in il-1R2/2 and il-182/2 mice, again effector proteins.74 supporting an important role of IL-18 in mucosal inflammation. Despite these recent advances, we are only beginning to Finally, bone-marrow chimeras demonstrated that inflammation decipher the role of different bacterial ligands, host pattern induced by this effector-less mutant strain expressing SopE was recognition receptors and different cell types in directing the 68 Gut Microbes Volume 3 Issue 2