Gut Microbes 3:2, 62–70; March/April 2012; G 2012 Landes Bioscience Innate immune response to Salmonella typhimurium, a model enteric pathogen Petr Broz,† Maikke B. Ohlson† and Denise M. Monack* Department of Microbiology and Immunology; School of Medicine; Stanford University; Stanford, CA, USA †These authors contributed equally to this work. Keywords: enteric pathogens, innate immunity, inflammation, Salmonella enterica, pattern recognition receptors The innate immune system provides the first line of defense be tightly regulated and quickly terminated to prevent unneces- against invading microorganisms by inducing a variety of sary damage to tissues and to the organism. inflammatory and antimicrobial responses. These responses Over the past decade, compelling evidence has demonstrated are particularly important in the gastrointestinal tract, where that detection of invading microbes is based on germline-encoded the needs for efficient nutrient uptake and host defense pattern-recognition receptors (PRRs), which recognize conserved collide. Many pathogens have evolved to specifically colonize microbial molecules, called pathogen- associated molecular the intestine, causing millions of cases of enteric infections a patterns (PAMPs).2 In addition to PAMPs, PRRs also respond year. A paradigm of an enteric pathogen is Salmonella enterica, to endogenous, host-derived danger signals, termed DAMPs a gram-negative bacterium that causes a wide range of gastro- (Danger-associated molecular patterns) or alarmins, which are ienntteesrticinaaslearonvda©rsTyysptehmimicu2rdiuisme0a(sSe. st.y1pInhfime2cutiroiunms ) Lwleiathd atSoaalmnnoanceudltlaeeresleased Bin reispoonse sto ctissuieeinjurny,strcess eorn.ecrotic cell death. intestinal inflammation in human and animal hosts, as a result Several families of pattern-recognition receptors have been of the bacterium invading the mucosa. A distinctive feature of discovered thus far and are known to engage in the surveillance Salmonella is that it has not only adapted to survive in a strong of both the extracellular and intracellular space. These families inflammatory a strategy to environment, gain a growth but adDvantaoge it also uses ovnerthoeinttestindali this adaptation as sC-tytpe include rlecitinbsthuatrectogenize.PAMPs/DAMPs the membrane-bound Toll-like receptors in the (TLRs) extracellular and microbiota. We will use the model organism S. typhimurium to compartment and in endosomes, and recognize the cytosolic discuss the innate immune mechanisms employed by the NOD-like receptors (NLRs), PYHIN-proteins and RIG-I-like mammalian gastrointestinal system and how the pathogen receptors (RLRs) that monitor the intracellular space. These responds and subverts these mechanisms. In particular, we receptors allow the discrimination of various types of tissue insults focus on the recognition of extra- and intra-cellular and launch appropriate inflammatory responses. Salmonellae by germline-encoded pattern recognition rmecigehpttoprrsofoitf ftrhoemTtLhRe aancdtivNatLioRnfaomftilhieess,earnedcehpotowrsS.almonella The Gastrointestinal Immune System Innate Immunity The innate immune system comprises many different mechanisms and components that act in a coordinated fashion to restrict an infection and eliminate the invading pathogen. A diverse array of immune cells cooperate in the rapid recognition and elimination of invading microbes through phagocytosis-mediated killing and the induction of inflammation.1 Acute inflammation is character- ized by an increased blood flow, rapid influx and activation of immune cells, and the release of pro-inflammatory cytokines. This results in heat, swelling and redness of the affected area and serves to prevent the spread of the infection and to promote pathogen clearance and tissue repair. The inflammatory response needs to *Correspondence to: Denise M. Monack; Email: dmonack@stanford.edu Submitted: 11/15/11; Revised: 12/16/11; Accepted: 12/21/11 http://dx.doi.org/10.4161/gmic.19141 The immune system is particularly important in the gastro- intestinal (GI) tract, since it is the location where the divergent needs of nutrient absorption and host defense collide. The former requires a large surface area and a thin epithelium, which in turn has the potential to compromise host defenses. It is therefore not surprising that many pathogens have evolved to take advantage of this apparent impairment. The importance of protecting the gut from these pathogens is evident in the abundance of lym- phoid tissue and immune cells it harbors. Yet, the most difficult challenge that the gastrointestinal immune system has to face is to respond to pathogens while remaining relatively unresponsive to food antigens and the commensal microflora. The need for tight control of the inflammatory response and the maintenance of gut homeostasis is highlighted by the severity of chronic auto- inflammatory bowel diseases, such as Crohn disease and ulcerative colitis (UC).3 The primary cellular barrier of the gut is a single layer of intestinal epithelial cells, which are critical for nutrient uptake yet provide a physical and chemical barrier (Fig. 1). This gastro- intestinal barrier not only blocks the entry of commensals and 62 Gut Microbes Volume 3 Issue 2