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Cell Host Microbe. Author manuscript; available in PMC 2010 July 23.
Published in final edited form as: Cell Host Microbe. 2009 July 23; 6(1): 10–21. doi:10.1016/j.chom.2009.06.007.

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Patterns of pathogenesis: discrimination of pathogenic and nonpathogenic microbes by the innate immune system
Russell E. Vance1, Ralph R. Isberg2, and Daniel A. Portnoy1,3 1 Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720

Howard Hughes Medical Institute and Department of Molecular Biology and Microbiology, Tufts University School of Medicine, 150 Harrison Avenue, Boston, MA 02111

School of Public Health, University of California, Berkeley, CA 94720

The dominant conceptual framework for understanding innate immunity has been that host cells respond to evolutionarily conserved molecular features of pathogens called ‘pathogen-associated molecular patterns’ (PAMPs). PAMPs should be understood in the context of how they are naturally presented by pathogens. This can be experimentally challenging since pathogens, almost by definition, bypass host defense. Nevertheless, in this review, we explore the idea that the immune system responds to PAMPs in the context of additional signals that derive from common ‘patterns of pathogenesis’ employed by pathogens to infect, multiply within, and spread among their hosts.

The mammalian innate immune system provides an early and important response to microbial attack. Over the past decade, compelling evidence has accumulated that the response to invading microorganisms is stimulated by recognition of several distinct microbial structures by germline-encoded host receptors of the innate immune system (Beutler et al., 2006; Kawai and Akira, 2008; Medzhitov, 2007). In this review, we consider evidence that the response to pathogens is not limited to recognition of these structures. We suggest that, in addition, hosts may recognize distinct pathogen-induced processes that contribute to the progression of disease. The reason for thinking along these lines is that recognition of pathogen-induced events would provide the host with strategies for distinguishing a virulent organism from one that has lower disease-causing potential. The host could then escalate immune responses to a level commensurate with the attack being mounted. As proposed by Janeway (Janeway, 1989), we will refer to the distinct microbial structures recognized by the host as “Pathogen-Associated Molecular Patterns” (PAMPs) and the host receptors that recognize them as “Pattern Recognition Receptors” (PRRs), despite some widely recognized problems with this nomenclature (see below). The details of the PRRs and their cognate PAMPs have been extensively reviewed elsewhere (Beutler et al., 2006; Kawai and Akira, 2008; Medzhitov, 2007). Examples of PAMPs of particular relevance to bacterial pathogens include lipid A, an essential constituent of the lipopolysaccharide in the Gramnegative outer membrane, which is sensed by Toll-like receptor 4 (TLR4); bacterial flagellin,

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a protein subunit that polymerizes to form the flagellum, which is a ligand for TLR5; bacterial lipoproteins, from Gram positive and Gram negative bacteria, which are recognized by TLR2; bacterial DNA containing particular CpG motifs that stimulate TLR9; and fragments of bacterial peptidoglycan that are sensed in the host cell cytosol by the NOD1 and NOD2 receptors. In addition to recognition of PAMPs, it has been suggested that the immune system responds to other signals commonly associated with infection. In particular, it has been proposed that cells dying of a ‘messy’ necrotic death, as opposed to a programmed apoptotic death, may release molecules such as DNA, ATP, uric acid, and DNA binding proteins (HMGB1) into the extracellular milieu (Kono and Rock, 2008; Matzinger, 1994). These molecules have been variously termed DAMPs (Damage Associated Molecular Patterns), alarmins, or ‘endogenous adjuvants’, and there is evidence that these host-derived molecules can stimulate immune responses, perhaps explaining the “sterile” inflammation in models such as ischemiareperfusion injury (Kono and Rock, 2008). There is also evidence that DNA damage stimulates innate immune responses mediated by the NKG2D receptor (Gasser et al., 2005). What remains unclear, however, is whether damage-induced responses play a significant role in the host response to pathogens. One major issue is that much of the damage that occurs in an infection may be due to the host response rather than to the pathogen. This self-inflicted damage may amplify immune responses, but cannot be used to explain the initiation of immune responses to pathogens, which is our primary concern here. In fact, many pathogens appear to go to considerable lengths to avoid host damage. Another unresolved question with damage-based models is whether or how hosts can distinguish sterile damage from pathogen-induced damage in order to initiate appropriate healing or inflammatory responses to each (Barton, 2008). The plant immunity literature has long discussed a model conceptually related to the damage model, termed the “Guard Hypothesis” (Chisholm et al., 2006; Jones and Dangl, 2006), which proposes that specific kinds of cellular disruption, for example of certain host signaling pathways, may trigger host defense responses. In contrast to the damage-based models, in which generic cellular injury initiates immune responses, the Guard Hypothesis focuses immune responsiveness on the specific disruptions caused by pathogens. It remains unclear whether mammalian cells utilize a similar “guard” strategy. In this review, we attempt to extend these ideas and ask whether there are signals specifically associated with living, pathogenic microbes that could play a role in the initiation of innate immune responses. We focus exclusively on bacterial pathogens, and consider two main questions: (1) Do living and dying bacteria produce distinct PAMPs, i.e., PAMPS-post mortem (PAMPS-PM) and PAMPS-pro vita (PAMPS-PV)? and if so, are they differentially recognized by the immune system? (2) Does the immune system initiate responses based not only on whether PAMPs are present, but on where and under what cellular context the PAMPs are presented? Our overall hypothesis is that PAMPs are delivered along with additional information that can be used by the host to distinguish pathogenic from non-pathogenic microbes and thereby guide the ensuing innate immune response.

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Pathogen-associated molecular patterns
Dual recognition of PAMPs A relatively select group of bacterial molecules are able to function as PAMPs, and importantly, several PAMPs are recognized by at least two different sensors, often in different contexts (Figure 1). For example, flagellin is a ligand for TLR5 at the cell surface, but is also recognized cytosolically by an entirely distinct sensor, the Naip5/Ipaf inflammasome. The two flagellin sensors appear to have evolved independently as they recognize distinct domains of the flagellin molecule (Lightfield et al., 2008). Likewise, DNA is recognized in a specialized intracellular compartment by TLR9 (Ahmad-Nejad et al., 2002;Hacker et al., 1998;Honda et
Cell Host Microbe. Author manuscript; available in PMC 2010 July 23.

2006).. Sirard et al.. Thus. Several cytosolic PRRs. Page 3 al. Petrilli et al.. 2006). notably MyD88 and Trif. 2008). numerous observations support that idea that single PAMPs can trigger dual responses... but are instead produced by all microbes. 2009.. but is also sensed in the cytosol by several distinct sensors. 2005. 2008. 2008. Mackey and McFall. the immune system can initiate responses based not only on whether PAMPs are present. Miao et al.. leading to a transcriptional response primarily dependent on the NF-κB and IRF-3/7 families of transcription factors (Kawai and Akira. TLR signaling is required for the transcription of pro-IL-1β and pro-IL-18.. For example. and the post-translational inflammasome response is then required for subsequent cleavage and secretion of the active cytokine (Franchi et al.. For example. primarily via cytosolic sensing pathways.. there may be important differences in the kinetics. the PAMP model cannot by itself explain how pathogens and non-pathogens might be distinguished by the innate Cell Host Microbe. Thus. nucleic acid ligands can induce expression of type I interferons from a phagosome or the cytosol. a multiprotein complex that triggers a posttranslational response. and cell-surface TLRs and the cytosolic Nod1/2 sensors both activate NF-κB (Ishii et al. 2005). on the other hand. but the rapid and potent release of type I IFNs into the serum by plasmacytoid dendritic cells occurs uniquely downstream of TLR signaling.. He et al. Examples of PAMPs that activate the inflammasome include flagellin and DNA. 2006. 2009. It is important to acknowledge that there is not always a clear-cut distinction between signals originating from extracellular.. Muruve et al. 2008). but instead often lead to unique signaling outcomes.Ishii et al. Krug et al. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript . even if the fundamental signaling pathways are similar. 2007a). some of which remain to be identified (Burckstummer et al. Two major categories of responses elicited by PAMPs are transcriptional and posttranslational. intensity. 2004). 2006. most cell types can produce type I IFNs. Caspase-1 in turn cleaves and activates the secretion of a variety of substrates. Kato et al. 2008.. The cytosolic nucleic acid sensors recognize features of their ligands distinct from the features recognized by TLRs (Yoneyama and Fujita. and not from the cell surface (Franchi et al.Hornung et al. 2009). host cells appear to assess the context in which PAMPs are sensed.. Caspase-1 is also required for a rapid. Both cytosolic and TLRmediated production of type I IFNs appear to play essential roles in distinct contexts (Delale et al... The dual transcriptional and post-transcriptional responses downstream of PAMP recognition can be collaborative in important ways. or cytosolically detected PAMPs..Muruve et al. including pro-interleukin-1β and pro-interleukin-18. but on where those PAMPs are presented. appear to stimulate the inflammasome.. Nevertheless. Such dual control may be an important regulatory mechanism to limit inappropriate or unnecessary production of cytokines that trigger potent responses that are potentially damaging to the host. available in PMC 2010 July 23. 2006). 2006. the multiple receptors involved in recognizing a single PAMP do not appear to be redundant. and that this contextual information is used to generate distinct responses. 2006.Fernandes-Alnemri et al. 2008). 2009... but these PAMPs only activate the inflammasome upon delivery to the cytosol. the cleavage and activation of the cysteine protease caspase-1 (Franchi et al.Stetson and Medzhitov. non-apoptotic death termed “pyroptosis” (Bergsbaken et al. 2006.. 2009. 2009. or cell types involved in cytosolic versus TLR signaling. RNA is recognized by TLR3 within a vacuole and by RIG-I and Mda5 in the cytosol. Molofsky et al. Author manuscript. 2007a). Petrilli et al. Issues that complicate the PAMP hypothesis One oft-heard criticism of the PAMP hypothesis is that PAMPs are not restricted to pathogens. 2008. Taken together. For example.. vacuolar. Lightfield et al. Importantly. Toll-like receptors signal through several signaling adaptors. one suggestion has been that PAMPs should really be renamed MAMPs or “microbe-associated microbial pathogens” (Benko et al. 2005. Indeed. 2006... Ren et al. Moreover.Vance et al.

indicating that more factors may come into play. and might even lead to the view that pathogens and non-pathogens are indistinguishable. For example.. These additional mechanisms might. 2004. Almost by definition. is not efficiently recognized by TLR5 (Andersen-Nissen et al. moreover.. personal communication). Shen and Higgins.. Page 4 immune system. 2004. we suspect that to the extent required for their replication and transmission. for example. which can be stimulatory. Avoidance of PAMP recognition is not limited to LPS.. it seems likely that PAMP signals are interpreted in the context of other cues that occur in the course of infection. Although PAMPs are usually portrayed as invariant or highly constrained structures that are extremely difficult for microbes to alter. 2007). The flagellin of Helicobacter pylori. but the challenge is to understand how they are distinguished. 2006. permit specific recognition of microorganisms that have high pathogenic potential. However. Thus. or antagonistic to TLR4 (Coats et al. 2002. The selective pressure for certain pathogens to circumvent responses to PAMPs is evidence in favor of the model that PAMP recognition plays an important role in stimulating host innate immunity. 2007). for example. and is often neglected in discussions of the PAMP model. Author manuscript.. dominated by production of interferon-β that is downstream of TLR4. 2006). the oral pathogen Porphyromonas gingivalis can produce an astonishing variety of at least 12 different lipid A molecules (Reife et al. Hornef et al. 2006). many still potently induce interferon-β via a cytosolic immunosurveillance pathway that remains to be fully defined (Perry et al. Gewirtz et al. leading to the unique transcriptional response. many pathogens defy strict categorization in this way.. LPS provides several striking examples of variants that appear to confound the host. Although it is unlikely that any pathogen is able to render its PAMPs entirely invisible to the immune system. and while Gram-positive bacteria lack LPS... the idea that the innate immune system views pathogens as mere ‘bags of PAMPs’ ignores Cell Host Microbe. The PAMP model is also complicated by the extent to which pathogens can modify their PAMPs to avoid host recognition. available in PMC 2010 July 23. Rebeil et al. Darveau. several bacterial pathogens have efficient mechanisms for downregulating flagellin expression within hosts (Akerley et al. For example..Vance et al. and it is presumed that pathogens must be able to avoid innate immunity to some extent (Hedrick. As an additional example. Our view is that pathogenic and non-pathogenic microbes are distinguishable... Puel et al. Pathogens are also able to manipulate downstream signaling pathways to prevent responses downstream of PAMP recognition (Bhavsar et al. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Patterns of Pathogenesis Concept defined The PAMP framework has been useful because it provides a relatively straightforward system for categorizing responses to microbes based on the PAMPs that are expressed. while a PAMP barcode provides some useful information to the immune system. For example. 2008. Montminy et al. Yersinia pestis modifies its LPS via specific acylation. Wolfgang et al. Further supporting this idea is the evidence that mutations in PRRs often (but do not always) lead to increased host susceptibility (Ishii et al... . Lee et al. 2004). 2005). This is one important consideration that leads us to consider whether additional mechanisms of pathogen-sensing may complement PAMP-sensing. pathogens can avoid recognition of their PAMPs. 2005).. the extent of PAMP plasticity is appreciable. The barcode hypothesis is one model that has been proposed to explain how responses could be tailor-made to certain microbes (Aderem. many Gram-negative pathogens lack LPS that is stimulatory for TLR4 (Munford and Varley. 2003). 1995. 2006). This model suggests that the different combinations of PAMPs found on different microbial species could be interpreted in a way that would allow for unique responses to distinct classes of pathogens. However. 2006. a Gramnegative (but not a Gram-positive) pathogen would stimulate TLR4. a pathogen is a microorganism that causes disease by avoidance or manipulation of host innate immunity. invisible (R. rendering it a poor ligand for TLR4 (Kawahara et al. 2002). 2005. 2003)..

. available in PMC 2010 July 23. In fact. we will attempt to illustrate the concept of molecules generated during growth and death by examining the factors that control the production of peptidoglycan fragments recognized by PRRs. Below is a broad and non-exhaustive description of some of these patterns. Molecules potentially associated with bacterial death and lysis would include any large macromolecule that is only released during bacteriolysis. As each strategy is found in a broad swath of pathogens. Small molecules that could be associated with growth includes those that could be secreted by living bacteria. in which a B-subunit mediates binding and translocation of the enzymatic Asubunit into the host cytosol (Finlay and Falkow. Below. We propose that a PAMP signifying life be named PAMPs-PV (pro-vita) and one that signifies death as PAMPS-PM (postmortem). 1997). such as dedicated systems for secretion of bacterial proteins into the host cell cytosol. 2006). conversely. can utilize T3SS systems to deliver effectors that block uptake of bacteria into cells. called protective antigen (PA). each can be considered conceptually similar to a common molecular pattern recognized by PRRs. 2001). and sometimes encode unusual biochemical functions (Bhavsar et al. This is not the only means by which pathogens access the host cell cytosol. the most common pattern associated with pathogens is their ability to grow in their hosts upon invasion. This proposal is based on decades of research that has led to the recognition that pathogens use a few common strategies to cause disease (Finlay and Falkow. Indeed. such as peptidoglycan fragments. For example. Here we propose a complementary framework for understanding innate responses to pathogens that we call “patterns of pathogenesis” (Figure 2).. are even more closely linked with the presence of viable bacteria. mediates the delivery of the A subunits (lethal factor and edema factor) from an acidified endosome into the host cell cytosol (Young and Collier.Vance et al. 2007). such as Salmonella. the B-subunit of Anthrax toxin. It should be beneficial for the immune system to distinguish growing and dying bacteria. the effectors and their activities are distinct. into the host cell cytosol. in order to organize the appropriate response. These secretion systems are often described as molecular syringes that deliver bacterial proteins. intracellular pathogens. 2007). Bacterial pathogens lacking NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Cell Host Microbe. or perhaps bacterial nucleotide-based second messengers such as c-di-GMP (Karaolis et al. we will explore whether immune recognition of the events that result from these patterns potentiates innate immune signaling. Pattern I: Growth With the exception of a very small subset of toxin-producing organisms. Later. usually enzymes. Page 5 important contextual information that accompanies PAMPs when they are delivered by virulent microorganisms. Once in host cells. bacterial pyrophosphates such as HMB-PP (Hintz et al. quorum-regulating autoinducers (Zimmermann et al. One of the best characterized versions of this strategy is the deployment of AB toxins.. 2007). Pattern II: Cytosolic Access A primary characteristic of many pathogens is the ability to deliver microbial molecules into the host cell cytosol. such as Yersinia. 1997). Here we ask if there are bacterial molecules that signify growing versus dead and dying bacteria. Author manuscript. 2006).. such as DNA or RNA. especially in the context of an acute infection. Extracellular pathogens. The secreted proteins are referred to as ‘effectors’ and are analogous to the A subunit of AB toxins. 2006). other mechanisms. one can consider auxiliary secretion systems as elaborate B-subunits that deliver toxins directly into target cells. . in the section on innate immune recognition. A T3SS is thus a flexible scaffold that is compatible with a highly diverse set of pathogenic lifestyles. can utilize T3SS to enter cells and establish intracellular compartments that support replication (Galan and Wolf-Watz. the effectors perform a variety of functions that contribute to pathogenesis. The best characterized of these auxiliary secretion systems are the type III secretion systems (T3SSs) encoded by numerous Gram-negative bacterial pathogens (Galan and Wolf-Watz. It is worth noting that while the apparatus of the T3SS itself is conserved across species.

whereas other pathogens disrupt host actin in order to block phagocytosis (Viboud and Bliska. Zhou et al. replicate in the cytosol. Again. Coxiella. 2000. the key point of emphasis here is that disruption of the host cytoskeleton is a common “pattern” employed by many NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Cell Host Microbe. Author manuscript. and thus. Just et al. 1997. Goehring et al. Chardin et al. 1989. Von Pawel-Rammingen et al. and cause disease in hosts (Schnupf and Portnoy.. 2005). Mycobacterium marinum. but also replicate in the host cytosol.... A large number of additional pathogens disrupt the host cytoskeleton for completely distinct purposes. 1989. Schmidt et al. 1999. The events associated with cytosolic replication emphasize that a third major pattern may mark a pathogen for recognition by the host: many microorganisms can either hijack or disrupt host cytoskeletal function. thereby spreading the infection without exiting the cells (Gouin et al. in its natural setting.. There also exist AB toxins or translocated substrates of specialized secretion systems that change the activation state of Rho family members by chemical alteration. In Grampositive microorganisms.. 2000). Hayward and Koronakis. 1995.. manipulate host actin in order to invade cells (Galan and Wolf-Watz.. and Brucella) and the more recently discovered type VI secretion system (T6SS.. but it fulfills the same basic function of delivering bacterial products to the cytosol of host cells. 2000. Many bacterial pathogens disrupt function of these proteins either by mimicking key regulators of the cycle or chemically modifying Rho family members. What all these systems have in common is that they promote cytosolic access of microbial molecules. Shigella.g. some pore-forming toxins such as streptolysin O may serve as portals for the injection of bacterial molecules into the host cell cytosol (Madden et al. of Legionella. 2009). Some pore-forming toxins deliver not just a few effectors to the cytosol. such as Salmonella. . including Mycobacteria. 2006). Examples include type IV secretion systems (T4SS. 1999. functionally similar mechanisms appear to exist. a pore-forming toxin required for Listeria monocytogenes to escape the phagosome. some bacterial proteins act more directly after they access the host cytoplasm and target either actin itself or an actin-associated protein.g. exploit the host cell system of actin-based motility. 1999. allowing their movement within cells and from cell-to-cell. allowing an entire pathogen to access the cytosol. the pore-forming toxin appears to function as an elaborate B-subunit. Fu and Galan. The use of dedicated secretion systems is not limited to Gram-negative bacteria. The molecular mechanisms by which pathogens modulate host actin are also diverse. Despite the remarkably diverse ways that pathogens affect the host cytoskeleton.. For instance. 2009) is evolutionarily distinct from those described above. but are also involved in phagosome disruption. Some pathogens. 2006).. 2001). These four bacterial species. including Listeria.. In each case. Yarbrough et al.. 2007). In the case of Gram positive organisms. 1999). 2005). This is the case for listeriolysin O. proteins associated with the surface of the pathogen recruit key regulators of the cytoskeleton to initiate novel rounds of actin polymerization within the host cell. multiple bacterial pathogens translocate proteins that cause GTP hydrolysis and inactivation of the Rho family member (Black and Bliska.. e. 2005). Page 6 type III secretion systems often encode evolutionarily unrelated systems that nevertheless fulfill the same basic function. usually disrupting protein function (Aktories et al. 2008).Vance et al. resulting in alterations of cytoskeletal dynamics (Fullner and Mekalanos. and Rickettsial species (Gouin et al. Pattern III: Hijacking and disrupting normal host cytoskeleton function Several highly divergent species of bacteria not only access. as well as poxvirus. mutants lacking auxiliary or pore forming systems are typically avirulent. available in PMC 2010 July 23. in Pseudomonas and Vibrio) (Pukatzki et al. e. Finally. A key point is that pathogens that access the cytosol require cytosolic access as a critical component of their virulence strategy. The ESX-1 secretion system of Mycobacterium tuberculosis (Simeone et al. A common way to target the cytoskeleton is to directly manipulate the function of Rho family small GTPases that control cellular cytoskeletal processes (Heasman and Ridley.

it is released (Cloud-Hansen et al. Just as relatively few bacterial structures are targeted as PAMPs. Not surprisingly.. For example. Here we extend this idea to consider how PAMP-sensing and other forms of immunosurveillance might be coordinated. 2008). 2006). To accommodate growth and PGN remodeling. whereas in Gram-positive bacteria. bacteria utilize a collection of PGN-specific degrading enzymes called autolysins (Vollmer et al. 2008). such as during treatment with β-lactam antibiotics. Page 7 pathogens (but not non-pathogenic microbes). Here we focus on just one possible pathway in some detail by examining host responses to the most ubiquitous of bacterial PAMPs. For example. TCT consists of a single monomeric unit of PGN (GlcNAc. Pathogen growth or death could be sensed by the host in a variety of ways. Clearly. peptidoglycan (PGN).. 2008). It is reasonable to suspect that PGN released by growing bacteria may be structurally distinct from non-growing bacteria or those undergoing bacteriolysis. Bacteria also remodel their PGN during assembly of macromolecular structures such as flagella and auxiliary secretion systems (Vollmer et al. diaminopimelic acid and two alanines). Jones and Dangl. 2008). 2005). In Gramnegative bacteria. Bacteria often express more than a dozen autolysins with many distinct activities. Although TCT generation requires cleavage at a glycosidic bond that is also targeted by lysozyme. perhaps it is also the case that relatively few host pathways are suitable points of vulnerability that can be exploited by pathogens. Animals also express enzymes that degrade PGN. or hubs. available in PMC 2010 July 23. pathogen replication could alter local levels of host amino acids. Sensing Pathogen Replication and Death It remains an open question whether there are molecules whose structure signifies either growing or dying microbes. active TCT is not generated by lysozyme.Vance et al. an essential. other nutrients.. including lysozyme (N-acetyl muramidase) and PGRPs (amidase activity). PGN from many pathogens is resistant to lysozyme (Boneca et al. One example may be tracheal cytotoxin (TCT) (Luker et al.. Autolysins of this class are used by Cell Host Microbe. for example signifying the presence of live pathogenic bacteria. . and some Drosophila PGRPs (Aggarwal and Silverman. 2007). The term autolysin is misleading because these enzymes are essential for PGN remodeling and their regulated activity prevents autolysis.. conserved and abundant structure that is shed during bacterial growth. perhaps in conjunction with additional signals (Harty and Badovinac. but rather requires the activity of a bacterial-specific lytic transglycosylase that leaves a 1. 2007). the presence of dead bacteria might indicate that the immune response has been successful and therefore be a signal to begin contracting and resolving the response. there appears to be a relatively select group of cellular targets. Chang et al. Author manuscript. and could therefore be an important cue to the host immune system. PGN is a wellcharacterized PAMP. it may provide more specific signals..6anhydro-bond upon cleavage (Cloud-Hansen et al. 2008. but when produced in the context of a natural infection. 2008). The receptors for TCT include murine Nod1 (Magalhaes et al. that many pathogens exploit as points of vulnerability. Royet and Dziarski.. MurNAc. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Recognition of Pathogenic Strategies by the Innate Immune System The above discussion presents the idea that although there are numerous mechanisms of pathogenesis. approximately 60% of shed PGN is recycled (Park and Uehara.. Lysozyme and PGRPs can be bacteriocidal and act to limit the inflammatory properties of PGN (Ganz et al. 2006). it would make sense for the host to monitor these host structures for signs of distress that could indicate the presence of a pathogen. 1995).. although with limited substrate specificity.. 2006). 2006. or oxygen (Rius et al. A similar model has been termed the guard hypothesis in the plant innate immunity literature (Chisholm et al. it might be helpful to the immune system if such discrimination were possible. which causes autolysis (bacteriolysis). glutamic acid.. 2008). Autolysins can be divided into families based on their site of cleavage and precise enzymatic mechanisms. 2003. It is their deregulation. If so.

originally isolated from killed M. For example. For example. depending on the infectious context in which the fragments are generated. 2008).. Maeda et al. A central premise of this hypothesis is that the bacterial molecules that are sensed cannot diffuse across the plasma or phagosomal membrane and therefore only reach the cytosol by active or inadvertent translocation by the secretion system.. TCT production signifies bacterial growth and stimulates inflammation. TCT or MDP lead to RIP2 and NF-κB activation downstream of Nod1 or Nod2. MDP may activate the inflammasome (Hsu et al. the PGN cleavage that generates MDP also destroys TCT. Pan et al. Additional contextual clues are likely to be critical for the immune system to interpret Nod1/2 signals. Unlike TCT. 2006).. but its specific release is associated with the induction of inflammation and pathogenesis of Bordetella pertussis and Neisseria gonorrhoeae. 2005. either may have additional receptors and/or target other responses.. and are hence necessary for pathogenesis. another bioactive PGN fragment may fulfill the criteria of a PAMP-PM. 2008. 1974). The first is that secretion systems are detected via cytosolic recognition of specific translocated bacterial molecules (PAMPs). 2006) to promotion of Th2-like polarization in the gut (Magalhaes et al. in fact. Muramyl dipeptide (MDP). Pan et al. Thus. Watanabe et al. 2008).. 2004. is recognized by Nod2 (Benko et al. generation of ligands for Nod2 (presumably MDP) occurs in the phagolysosomes of activated macrophages.. so it is not clear that host signaling distinguishes one as a PAMP-PV and the other as a PAMP-PM (Benko et al. its presence is not specific for growing bacteria and. Another complication is that designating any PGN fragment a PAMP-PM is difficult. There are two mutually nonexclusive models that describe how host cells sense cytosolic access by secretion systems. 2009).. (Ferwerda et al. Although TCT and MDP target Nod1 and Nod2 respectively. The presence of such molecules in the cytosol is therefore a strong indication that a secretion system (or B subunit) is present. A second hypothesis is that secretion or pore-forming systems are sensed by host cells via detection of the physical damage associated with bacterial structures penetrating the plasma or phagosomal membranes. leading to differential readouts for these two molecules. The immunological consequences of Nod2 stimulation are still controversial and range from NF-κB stimulation. 2007)... it is conceivable that the presence of MDP represents either harmless flora or killed and degraded bacteria: exactly as expected for a PAMP-PM. 2008. 2008.. Author manuscript. but only upon bacteriolysis (Herskovits et al... Further emphasizing the connection between MDP and lack of viability. Martinon et al. . as there is no easy way for material from a dead organism to access the cytosol. 2004. However. 2004).Vance et al. a role for peptide transporters has been suggested (Swaan et al.. Vavricka et al. 2008. MarinaGarcia et al. 2008.. fulfilling the requirements of a PAMPS-PV. In contrast. tuberculosis and an active component of Freund’s complete adjuvant (Ellouz et al.. Sensing Cytosolic Access Although secretion systems and AB/pore-forming toxins provide pathogens with the ability to access the cytosol and thereby control the inner workings of host cells.. 2003).. 2007). Generation of MDP requires the activity of a bacterial-specific endopeptidase (Humann and Lenz. 2008) and down regulation of PGN-induced colitis (Yang et al. available in PMC 2010 July 23. or their activities. specific peptidoglycan fragments can differentially signify growing or dying bacteria. there has been the suggestion that pore-forming toxins or the needles of type III and type IV secretion systems cause damage NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Cell Host Microbe. Hsu et al. 2007).. Page 8 bacteria to remodel PGN during biosynthesis and assembly of macromolecular structures such as auxiliary secretion systems (Koraimann. 2007) to suppression of TLR signaling (Watanabe et al. 2008). As we have suggested here. it is possible that in different scenarios. Hence.. much recent evidence supports the idea that “violation of the sanctity of the cytosol” also triggers significant host responses (Lamkanfi and Dixit. and PGN fragments may enter intestinal epithelial cells by normal cellular damage (Miyake et al. TCT is normally recycled by Gram-negative bacteria.

. but the variety of secretion systems is impressive... but it remains unclear how LF is sensed. Stetson and Medzhitov. The host sensor protein that responds to LF was recently identified as Nalp1b (Boyden and Dietrich. Aderem. 2007) and other secretion systems (Stanley et al. Once in the cytosol. 2008). Roux et al. 2006). flagellin monomers are normally secreted by the flagellar secretion system.. The protease activity of LF appears to be essential in order to trigger a host response. 2008... and the addition of exogenous poly I:C can stimulate type I IFN induction dependent on the Cell Host Microbe.. 2006). Viboud and Bliska. and that secretion-system-induced pores or membrane damage do not appear to play an essential role (Lightfield et al. 1998. Since delivery of flagellin to the host cell cytosol is strictly dependent on type III or IV secretion systems. Ren et al.Vance et al. Although transfected DNA can recapitulate the response (Ishii et al. 2006. 2005). 2006. Another cytosolic pathway triggered in response to pathogen access of the cytosol is a TLRindependent pathway leading to the induction of interferon-β and other coregulated genes. 2008) to type III (Auerbuch and Isberg. 2006). Shin and Cornelis.. 2007. 2008). Henry et al. Author manuscript.. In order to assemble a flagellum. recent work has established that the Ipaf inflammasome is also capable of responding to the conserved inner rod component of the type III secretion system itself (E.. In each case it has been demonstrated that induction of interferon-β requires pathogen expression of an auxiliary secretion system.. unpublished). it is clear that the cytosolic presence of flagellin is sufficient to activate the Naip5/Ipaf inflammasome. Interestingly. Page 9 or lead to ion efflux when they insert into host membranes (Kirby and Isberg. Stetson and Medzhitov. Stetson and Medzhitov. Anthrax Lethal Factor (LF) is another example of a translocated molecule that activates a host response in the cytosol... though the mechanism of translocation remains unclear (Molofsky et al.. Interestingly. Miao et al. so it is likely that the activity of LF is sensed as opposed to the molecule itself or the pore formed by the Lethal Toxin B subunit (PA). 2008. 2007. recent data have demonstrated that flagellin can be translocated into the host cell cytosol via type III secretion systems (Sun et al. Stanley et al. IV (Roux et al. In this case. Both hypotheses have some merit and are discussed in turn below.. VI (Henry et al.. Another well-characterized example of a translocated PAMP that is sensed in the cytosol is flagellin. leading to IL-1β/IL-18 release and pyroptotic cell death (Franchi et al.. 2007) has also been shown to allow fragments of bacterial peptidoglycan to access the host cell cytosol and trigger Nod1. 2004). Leber et al. ranging from multidrugresistance transporters (Crimmins et al. 2007). NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript . 2007. This conserved component is apparently translocated into host cells where it functions as a PAMP that directly indicates the presence of a pathogen with a secretion system. Molofsky et al. 2006). 2006. Sensing of Translocated PAMPs as a signal for cytosolic access One of the first pathogens shown to translocate a PAMP into the cytosol was the extracellular pathogen. the cytosolic presence of flagellin is a strong signal to the immune system that a pathogen (as opposed to a commensal) is present. 2007). 2007. The pore-forming toxin pneumolysin from Streptococcus pneumoniae (Ratner et al. 2006. 2002.. 2007. and perhaps because of this homology. personal communication). O’Riordan et al. flagellin triggers the Naip5/Ipaf inflammasome. an apparatus that shares considerable homology with type III secretion systems (Chevance and Hughes. 2006).. 2006). 2008. 2006. This pathway is apparently activated by an extremely diverse group of Gram-positive and Gramnegative pathogens (Charrel-Dennis et al. Ren et al... It remains unclear whether the induction of type I IFN in all these cases proceeds via the same basic mechanism. Miao and A. since presumably only pathogens will encode such secretion systems. Flagellin also appears to be reach the host cell cytosol via the type IV secretion system of L. Lightfield et al. available in PMC 2010 July 23. Helicobacter pylori. pneumophila. which delivers PGN-derived ligands for Nod1 via its type IV secretion system (Viala et al..

Listeria itself delivers LLO in a highly regulated manner and appears to go to considerable lengths to avoid damaging the host cell in which it must replicate (Schnupf and Portnoy. Shin and Cornelis. or whether it results from a host-response.. Vogel et al. 2004. 2006. growing bacteria that access the host cell cytosol. membrane pore formation does seem to trigger specific host immune responses (Aroian and van der Goot. Petrilli et al. it is often difficult to know whether the apparent damage is directly inflicted by the toxin or secretion system.. Segal et al. 1998. although excessive extracellular application of the pore-forming toxin listeriolysin O can lead to activation of host caspase-1 and IL-1β secretion. 1994) is supported by some data (Kono and Rock. treatment of cells with pore-forming toxins such as aerolysin. 2007). 2006). 2006. In cases where pore-forming toxins or secretion systems apparently trigger host cell damage. one suggestion is that K+ efflux is a common mechanism by which cells can sense membrane pores and activate the Nlrp3 inflammasome (Mariathasan et al. available in PMC 2010 July 23. 2008).Vance et al. in other cases. Gurcel et al... Viboud and Bliska. 2007.. Mariathasan et al. unpublished]. 2006). For example. such as stimulation of cationselective P2X7 channels by millimolar concentrations of extracellular ATP. 2001) and Auerbuch and Isberg. but this has not been established for the other secretion systems. but there is surprisingly little evidence that secretion systems themselves cause damage when expressed by wildtype bacteria at physiologically relevant multiplicities of infection. . However. 2006. Ren et al. Miao et al. induce K+ ion efflux from cells.. previously suspected to be due to the damage induced by the “pore-forming” activity of secretion systems. For example. For example. 2006. However. consistent with responses made to the translocon itself or pores. under certain scenarios. Strains of Yersinia lacking expression of all known translocated effectors still trigger host responses dependent on the type III secretion system translocon [(Bergsbaken and Cookson.. Nigericin and other activators of the Nlrp3 inflammasome. Thus. Nevertheless. that is triggered in response to an unknown translocated PAMP. 2007. Molofsky et al. 1998). The apparent response to the Yersinia translocon does not require very high multiplicities of infection. it is very difficult to rule out the existence of an unknown translocated effector or PAMP... 2007). Page 10 type III system (Auerbuch and Isberg. What is clear is that in all cases the responses are associated with auxiliary secretion systems of live. 2006) and have identified a hemichannel pore protein Pannexin-1 as an essential and more proximal activator of Nlrp3. However.. Fink and Cookson. has turned out to be due primarily to a host response triggered by a molecule (flagellin) translocated by the secretion system (Franchi et al. 2009.. 2007. other studies have demonstrated that potassium efflux is not sufficient to activate Nlpr3 (Pelegrin and Surprenant. the broader idea that the immune system can respond to cellular damage (Matzinger. Type IV secretion systems are able to translocate DNA (Hamilton and Dillard. 2006. 2007). the macrophage cell death provoked by secretion-competent pathogens such as Legionella and Salmonella. and may thus represent examples of host recognition of a PAMP-PV. so its physiological significance and the mechanism by which it activates Nlrp3 remains uncertain. such as pyroptosis (Bergsbaken et al. very high and possibly nonphysiological multiplicities of infection seem to be required for bacterial secretion systems to trigger pore formation. Author manuscript. 2007b). As mentioned above.. nigericin or maitotoxin lead to activation of caspase-1 via an inflammasome that contains the Nlrp3 protein (Freche et al. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Cell Host Microbe. the identity of the actual ligand(s) sensed and its receptor(s) is still not known. Sensing of pores or membrane damage as a signal for cytosolic access The idea that pores formed by bacterial secretion systems or toxins can be sensed by the innate immune system is attractive because it could provide a unified mechanism by which diverse bacterial pathogens could be sensed (Freche et al. Nigericin comes from the non-pathogenic soil organism Streptomyces and has therefore presumably not evolved to target mammalian cells. 2005)... unpublished).

Furthermore. or produce cellular damage that triggers host responses. 2008. Li et al. adherence of pathogens to host cells is a common “pattern of pathogenesis” that may well trigger specific host responses. in addition to sensing of PAMPs. the host innate immune system is able to respond to “patterns of pathogenesis” – signals that derive from the strategies that live pathogens use to invade. Alternatively.Vance et al.g.. 2004). Extracellular enzymes may be especially central to the sensing of certain eukaryotic pathogens that lack PAMP-like molecules (Sokol et al.. 2008). Dostert et al. Cytoskeletal structures may control NLR responses as both Nod1 and Nod2 localize to actin-rich regions near the plasma membrane (Kufer et al.. monocytogenes during intracellular actin based motility (Waite et al. but it does suggest that components of the inflammasome associate with regions of active actin polymerization.. manipulate. Though not the focus of this review. the large pores formed by Pannexin-1 do not seem to correlate with Nlrp3 activation (Pelegrin and Surprenant. it was suggested that NOD1 is activated by PGN released through the Helicobacter pylori Type IV secretion system (Viala et al. stimulation of the NOD1 pathway that leads to transcriptional responses is enhanced by cytochalasin D (Magalhaes et al. 2008) and/or the generation of reactive oxygen species (Cassel et al. NODs may act as “guards” of the actin cytoskeleton and may be released and activated upon perturbations such as those associated with bacterial toxins and effectors (Legrand-Poels et al. there are suggestions that cytosolic sensors of viruses. it seems clear that PAMPs are not sensed in a vacuum. 2008. Author manuscript. or spread among their hosts. 2006). Interestingly.. invasion and PGN release (Kufer et al. agents that block actin polymerization promote transcriptional activation mediated by NF-κB (Kustermans et al. 2008. Perhaps NODs are located at the plasma membrane. Page 11 Again. 2005). Thus. 2009). and that infection by live pathogens provides additional contextual cues that shape the immune response. 2008). Sensing actin cytoskeleton disruption As discussed above. Legrand-Poels et al. Even more intriguingly. It is not yet possible to make any conclusions from this single observation.. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Conclusions Here we have considered the hypothesis that. there is nevertheless considerable evidence that Nlrp3 can play an important role in stimulating a variety of immune responses in vivo (Eisenbarth et al. Kool et al. 2008). proteases.. Pyrin and ASC. phospholipases) is another “pattern of pathogenesis” that may liberate host ligands that are sensed by the innate immune system. 2008). ASC and pyrin localized to the actin tails of L. there is little evidence that most naturally-delivered toxins activate the inflammasome via pore formation and the physiological mechanism by which the Nlrp3 inflammasome is activated in the context of infection remains very poorly understood. 2009). such as RIG-I. Whatever the mechanism of Nlrp3 activation. 2008. There are at least two models consistent with these observations. Our discussion has clearly not been exhaustive and we suspect that there may be additional patterns that we have not discussed in detail that might also be sensed by host cells. The production of extracellular enzymes (e..... We suggest that these cues may potentially allow the immune system to distinguish living pathogens from dead or Cell Host Microbe.. . localize at the plasma membrane at sites of actin polymerization (Waite et al.... and may involve lysosomal disruption (Hornung et al.... a common host target of many pathogens is the actin cytoskeleton. 2009). as this is the site of bacterial attachment. Although sensing of PAMPs is central to the generation of effective immune responses. 2008. are also associated with the actin cytoskeleton (Mukherjee et al. 2007). Indeed. 2007).. available in PMC 2010 July 23. 2007). though the significance of this observation remains to be fully elucidated. replicate within. There may also be a link between the actin cytoskeleton and inflammasome activation. For example. Sutterwala et al. Two proteins associated with inflammation.

[PubMed: 2492192] Andersen-Nissen E. Bauer S. The rho gene product expressed in E.V is supported by the Cancer Research Institute and NIAID awards AI075039 and AI080749. and no generalizeable procedure. other than trial and error. L. Portnoy. monocytogenes strains that fail to access the host cell cytosol due to mutations in listeriolysin O not only fail to immunize against subsequent challenge with virulent L. Biochem Biophys Res Commun 1989. Eur J Immunol 2002.R. [PubMed: 12792849] Aggarwal K.. Phagocytosis and the inflammatory response. BMB Rep 2008. but the general notion that PAMPs are interpreted by the immune system in the context of other infection-derived signals is likely an important concept for future consideration. and the availability of a variety of host and pathogen genetic systems has made an analysis of innate immunity to pathogens increasingly feasible (Persson and Vance. Thus. Braun U. tuberculosis.I is an Investigator of the Howard Hughes Medical Institute and supported by NIAID award R37-AI023538.P. References Aderem A. Smith KD. R. Just I. monocytogenes. An example of such a vaccine may be the relatively ineffective BCG vaccine for M. but there is no theoretical consensus as to why live pathogens are especially immunostimulatory. Moreover.32:1958–1968. is supported by NIAID awards AI27655 and P01 AI063302. Wagner H. There is at present little direct evidence to support this specific idea. Page 12 otherwise harmless microbes. Logan SM. monocytogenes provides potent protection against a subsequent challenge. Cotter PA. J Infect Dis 2003. and D. Positive and negative regulation of the Drosophila immune response. Author manuscript. Miller JF. [PubMed: 15956202] Cell Host Microbe. monocytogenes confers no protective immunity (von Koenig et al. they also appear to actively suppress host immunity via a pathway dependent on IL-10 (K. but also in response to contextual cues – e. Proc Natl Acad Sci U S A 2005. [PubMed: 7867068] Aktories K. One of the most striking observations that underscores the notion that living pathogens induce unique immune responses comes from the model of experimental listeriosis. D.A.E. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Acknowledgments R.41:267–277.A.Vance et al. Silverman N. 1982). but it is probably crucial to do so. it might be expected that a vaccine strain which has been attenuated through the deletion of an immunostimulatory secretion system may fail to elicit protective immunity. Bahjat. Ectopic expression of the flagellar regulon alters development of the Bordetella-host interaction.80:611–620. Cell 1995. Cookson BT. Vabulas RM. In this model. for how best to attenuate pathogens for their use as vaccines. Based on the considerations we present above. D. Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments.G Brockstedt.. Because of the complexity of many host-pathogen interactions. coli is a substrate of botulinum ADP-ribosyltransferase C3. Evasion of Toll-like receptor 5 by flagellated bacteria. . Rosener S. [PubMed: 12115616] Akerley BJ. N. unpublished). 2007). Live-attenuated pathogens have shown considerable utility as vaccines.102:9247–9252. it can be experimentally challenging to use living pathogens to dissect immune responses. those provided by growing bacteria or bacteria that access the host cell cytosol as part of their virulence strategy. in which the ESX secretion system (RD1 locus) was deleted during its generation. whereas immunization with killed L.187(Suppl 2):S340–345. Rutz M.158:209–213. A prediction following from our conceptual framework would therefore be that strains lacking secreted effectors (“A” subunits) but retaining the immunostimulatory translocation system (“B” subunits) would function as more effective live-attenuated vaccines. Strobe KL. Hall A. Aderem A. host immune responses are shaped not only in response to PAMPs. [PubMed: 18452646] Ahmad-Nejad P. available in PMC 2010 July 23. Barrett SL.g. Meyer-Morse. Hacker H.S. immunization with live L.

Peterson SB. Paquin A. Sutterwala FS. Madaule P. Hackett KT. [PubMed: 18246191] Benko S. Manipulation of host-cell pathways by bacterial pathogens. Chan S. A calculated response: control of inflammation by the innate immune system. Baumann C. Trieu-Cuot P. [PubMed: 19148178] Beutler B. Psylinakis E.38:240–244. Flavell RA. Science 2006. Guttman JA. [PubMed: 17983266] Bergsbaken T. Cytokine 2008. Akira S.449:827–834. Hughes KT. Latz E. Cookson BT. [PubMed: 18715799] Bergsbaken T. [PubMed: 10931345] Boneca IG. Dussurget O. [PubMed: 16894338] Crimmins GT. Planyavsky M. Colegio OR. Bliska JB. Rothman PB. Day B. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. A critical role for peptidoglycan N-deacetylation in Listeria evasion from the host innate immune system. Du X. Nature 2007. Giovannini M. Dillard JP. et al.43:368–373. Cookson BT. McFall-Ngai MJ. Bilban M. Mengin-Lecreulx D. TLRindependent type I interferon induction in response to an extracellular bacterial pathogen via intracellular recognition of its DNA. Curr Opin Microbiol 2007. Nahori MA. [PubMed: 16551253] Bhavsar AP. MyD88-dependent and -independent murine cytomegalovirus sensing for IFN-alpha release and initiation of immune responses in vivo. Coaker G.10:266–272. Lecuit M. Pore-forming toxins and cellular non-immune defenses (CNIDs). The microbial and danger signals that activate Nod-like receptors. Bates EE. Handelsman J. Borek D. Tephly LA.7:99–109. [PubMed: 2501082] Charrel-Dennis M. Herskovits AA. Sivick KE. Pyroptosis: host cell death and inflammation. Deisenhofer J. Proc Natl Acad Sci U S A 2008. Listeria monocytogenes multidrug resistance transporters activate a cytosolic surveillance pathway of innate immunity. Carter AB. Rehder K. Embo J 1989. Stabb EV. [PubMed: 17215377] Boyden ED. The Nalp3 inflammasome is essential for the development of silicosis. Sadler JJ. Dalod M. et al. Vicari A. Cell 2006.8:1087–1092. J Clin Invest 2008. Gill DM. Hoebe K.24:353– 389. Finlay BB. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. [PubMed: 17234446] Barton GM. Brizard G. Jahn H. [PubMed: 16272328] NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Cell Host Microbe. Chelliah Y. Nat Rev Microbiol 2009.190:5989–5994. Colinge J. Hugot JP. J Immunol 2005. Cabanes D.10:57–61. Breaching the great wall: peptidoglycan and microbial interactions. Croker B. Proc Natl Acad Sci U S A 2007.118:413–420. Nat Immunol 2009. Staskawicz BJ. [PubMed: 16556841] Chardin P. Golenbock DT. Rutschmann S. Boquet P. Proc Natl Acad Sci U S A 2008. Dubensky TW Jr. Eisenbarth SC. Halmen KA.175:6723–6732. Portnoy DA. [PubMed: 19158679] Cassel SL. Coordinating assembly of a bacterial macromolecular machine. available in PMC 2010 July 23.104:997–1002. Kastner P.4:543–554. Structure of tracheal cytotoxin in complex with a heterodimeric pattern-recognition receptor. Sousa S. Nat Genet 2006. Bennett KL. Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. The mammalian G protein rhoC is ADP-ribosylated by Clostridium botulinum exoenzyme C3 and affects actin microfilaments in Vero cells. Jiang Z. Crozat K. PLoS Pathog 2007. Annu Rev Immunol 2006. Lauer P. Nat Rev Microbiol 2006. Dixit E. Rubin EJ. Asselin-Paturel C. Author manuscript.4:710–716. Mol Microbiol 2000. [PubMed: 18577586] Chang CI.37:515–527. The RhoGAP activity of the Yersinia pseudotuberculosis cytotoxin YopE is required for antiphagocytic function and virulence.124:803–814.105:9035–9040. [PubMed: 18483484] Chisholm ST. Georgel P. Popoff MR. Garcia DL. Girardin SE. Neisseria gonorrhoeae uses two lytic transglycosylases to produce cytotoxic peptidoglycan monomers. Host-microbe interactions: shaping the evolution of the plant immune response. Goldman WE.Vance et al.3:e161. Cell Host Microbe 2008. Fink SL. Philpott DJ. [PubMed: 18567658] Cloud-Hansen KA. [PubMed: 16497589] Cloud-Hansen KA. van der Goot FG. [PubMed: 19064255] Chevance FF. Fitzgerald KA.311:1761–1764. [PubMed: 17943119] Black DS. [PubMed: 18632558] Delale T. J Bacteriol 2008. [PubMed: 16429160] Burckstummer T. Kasper DL. Bouriotis V. . Durnberger G. Nat Rev Microbiol 2008. Macrophage activation redirects yersinia-infected host cell death from apoptosis to caspase-1-dependent pyroptosis. Page 13 Aroian R. Dietrich WF. Iyer SS.105:10191–10196. Bluml S.6:455–465. et al.

7:576–582. Girardin SE. Cell 2006. Petrilli V. Adam A. [PubMed: 19221555] Freche B. Munoz-Planillo R.101:2388–2392. 2008 Ellouz F. Cole AM. Bertin J. [PubMed: 10499590] Fullner KJ. Piccini A. Lyons SL. Yu JW.59:376–385. Author manuscript. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Girardin S. Wolf-Watz H. Eigenbrod T. Graf T. Coyle A. Biochem Biophys Res Commun 1974. Wagner H. Ciorbaru R. et al. Devesaginer I. Schmid R. de Jong D. Adema GJ. Eur J Immunol 2008. Datta P. Ozoren N.436:1186–1190. Schmidt G.59:1317–1325. Kanneganti TD. [PubMed: 10593930] Gouin E. Wu J. [PubMed: 17805541] Fu Y. available in PMC 2010 July 23. Cossart P. Apoptosis. Protein delivery into eukaryotic cells by type III secretion machines.19:5315–5323. Liao HI. J Infect Dis 2004.274:36369–36372.Vance et al. Mossman BT. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 2008. [PubMed: 12411294] Gasser S. Nunez G. Lederer E. Dillard JP. [PubMed: 4606813] Fernandes-Alnemri T.38:184–191. Yu Y. Nature 2005. 2009 Ferwerda G. van der Meer JW. Kullberg BJ. Cookson BT. Sparwasser T. Microbiol Mol Biol Rev 1997. Common themes in microbial pathogenicity revisited. A salmonella protein antagonizes Rac-1 and Cdc42 to mediate host-cell recovery after bacterial invasion. Inohara N. Abrami L. Tschopp J. Krishna US. Jagirdar R. Colegio OR. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat Immunol 2006.8:35–45. Pederson KJ. Lipford GB. Heeg K. J Biol Chem 1999.401:293–297. Actin-based motility of intracellular pathogens. Helicobacter pylori flagellin evades toll-like receptor 5-mediated innate immunity. Welch MD. van der Goot FG. van der Goot FG. Mol Microbiol 2006.29:249–260. [PubMed: 15784530] Finlay BB. O’Connor W. Body-Malapel M. Miethke T. Reig N. Alnemri ES. Brown EJ.126:1135– 1145. Peek RM Jr. [PubMed: 16990137] Hacker H. Natural transformation of Neisseria gonorrhoeae: from DNA donation to homologous recombination. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. [PubMed: 15694855] Gurcel L. Page 14 Dostert C. Barbieri JT. [PubMed: 18403674] Eisenbarth SC. Van Bruggen R. [PubMed: 9799232] Hamilton HL. Gabayan V. et al. Nature.17:6230–6240. Kramer M. Minimal structural requirements for adjuvant activity of bacterial peptidoglycan derivatives. [PubMed: 9184008] Franchi L. Liu L. Galan JE. Embo J 1998. The N-terminal domain of Pseudomonas aeruginosa exoenzyme S is a GTPase-activating protein for Rho GTPases. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript .444:567–573. Blood 2003. Sutterwala FS. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. [PubMed: 16648852] Franchi L. [PubMed: 15995699] Gewirtz AT. Israel DA.10:241–247. Flavell RA.189:1914–1920. The role of the inflammasome in cellular responses to toxins and bacterial effectors. Nature 2006. [PubMed: 11032799] Galan JE. [PubMed: 15122529] Goehring UM.73:1907–1916. Mischak H. Mekalanos JJ. Joosten LA. In vivo covalent cross-linking of cellular actin by the Vibrio cholerae RTX toxin. Engagement of NOD2 has a dual effect on proIL-1beta mRNA transcription and secretion of bioactive IL-1beta. CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. Tschopp J. Vandenabeele P. Nature 1999. Nat Immunol 2009. Infect Immun 2005. Curr Opin Microbiol 2005. Steele C. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. [PubMed: 18157816] Fink SL.61:136–169. Increased inflammation in lysozyme Mdeficient mice in response to Micrococcus luteus and its peptidoglycan. Liptay S. Aktories K. Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival.320:674–677. Embo J 2000. Orsulic S. and necrosis: mechanistic description of dead and dying eukaryotic cells. Amer A. pyroptosis. [PubMed: 16390436] Cell Host Microbe. [PubMed: 17136086] Ganz T. Nature. Falkow S. Semin Immunopathol 2007. Raulet DH. Oren A.

Negishi H. Takahashi M. Monack DM. Page 15 Harty JT. Watanabe H.6:256–258.1143:1– 20. Nakagawa A. Taya C. [PubMed: 17452523] Herskovits AA. Fitzgerald KA. Legionnaires’ disease: the pore macrophage and the legion of terror within. Fitzgerald KA. Mann M.9:690–701. Hayakawa Y. Lenz LL. Nat Immunol. Philpott D. Nature.434:1035– 1040. Ohba Y. Wilm M. Ali SR.105:7803–7808. Rock KL. Bacterial ligands generated in a phagosome are targets of the cytosolic innate immune system. Coban C. Eberl M. Muraille E. Cold Spring Harb Symp Quant Biol 1989. Bauernfeind F. Ablasser A. Nature 2005.8:107– 119. [PubMed: 18219309] Hayward RD. Bacterial peptidoglycan-degrading enzymes and their impact on host muropeptide detection.23:19–28. Humke EW. Altincicek B. Taniguchi T. Means TK. et al. Takaoka A. Thompson LJ. Powell JJ. Infect Immun 2002. Ann N Y Acad Sci 2008.54(Pt 1):1–13. Caffrey DR. Type I interferon signaling is required for activation of the inflammasome during Francisella infection. Tseng PH. Charrel-Dennis M. Halle A. Bauernfeind F. Trends Microbiol 1998. 2008 Hsu LC. [PubMed: 17277122] Kato H. Kato H. Author manuscript. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. McGillivray S. [PubMed: 9717211] NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Cell Host Microbe. Shaping and reshaping CD8+ T-cell memory. Matsui K. Mammalian Rho GTPases: new insights into their functions from in vivo studies. [PubMed: 7777059] Karaolis DK. [PubMed: 17108957] Just I. Takeda K. Eckmann L.18:4926–4934. Uematsu S. Akira S. Matsuura M. FEBS Lett 2001. Auerbuch V. Brotcke A. Dixit VM.444:323–329. J Immunol 2007. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Kollas AK. [PubMed: 18541212] Janeway CA Jr. [PubMed: 17397264] Hintz M. Modification of the structure and activity of lipid A in Yersinia pestis lipopolysaccharide by growth temperature. available in PMC 2010 July 23. Jomaa H. Nat Rev Immunol 2008. Yoneyama M. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Bahr U. Identification of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate as a major activator for human gammadelta T cells in Escherichia coli. [PubMed: 18511561] Humann J. Takahashi K. [PubMed: 18719708] Henry T. Sato S. Yamamoto M. Nat Immunol 2006. Samstad EO. [PubMed: 19076341] Kirby JE. J Exp Med 2007. 2009 Hornung V. Portnoy DA. Beck E.Vance et al. Nature 1995. Latz E. J Innate Immun 2008. Cell Host Microbe 2008. et al. A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide. Reichenberg A. PLoS Pathog 2007.3:e51. Weiss DS. Host innate immune receptors and beyond: making sense of microbial infections. et al. [PubMed: 10487745] Heasman SJ. Approaching the asymptote? Evolution and revolution in immunology.70:4092– 4098. Schroeder JT. Hemmi H. Lindner B. Nat Rev Mol Cell Biol 2008. Proc Natl Acad Sci U S A 2008. Bacterial c-di-GMP is an immunostimulatory molecule. Immunity 2005. Yoshimura T. The plant immune system. Aktories K. Dangl JL.178:2171–2181.3:352–363. Isberg RR. [PubMed: 12117916] Kawai T. Koyama S. Embo J 1999. Tsujimura T.7:40–48.509:317–322. Toll-like receptor and RIG-I-like receptor signaling. et al. [PubMed: 11741609] Honda K. [PubMed: 2700931] Jones JD. [PubMed: 15815647] Hornung V. Koronakis V. Badovinac VP.375:500–503. [PubMed: 16286919] Ishii KJ. Horvath G. Glucosylation of Rho proteins by Clostridium difficile toxin B. Takeuchi O. Gschwind RM. Coban C. Ludwig H. Takeshita F. Yanai H. Latz E.204:987–994. Nizet V. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Kono H. von Eichel-Streiber C. Mariathasan S. Cell type-specific involvement of RIG-I in antiviral response. Wiesner J. Tsukano H. Ridley AJ. Akira S. Mizutani T. Suzuki K. Nature 2006. [PubMed: 16039576] Kawahara K. Direct nucleation and bundling of actin by the SipC protein of invasive Salmonella. . Sutter G. [PubMed: 19319201] Ishii KJ. Selzer J. Fujita T.1:88–97. Hyodo M. Yang D. Torii Y.

Kagnoff MF. Ting JP. Viala J. The pattern-recognition molecule Nod1 is localized at the plasma membrane at sites of bacterial interaction. Caparon M. Cado D. Eckmann L. Distinct TLR. Vucic D. Dixit VM. Marshall GR. Travassos LH. [PubMed: 16211083] Mariathasan S. Immunol Rev 2009. Nat Immunol 2008. Orihuela MM. Dzionek A. Selvanantham T. Hsu LC. Hammad H. [PubMed: 17970764] Kustermans G. Mol Microbiol 1995. Jehanno M. Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. Henry T. [PubMed: 18566365] Lightfield KL.430:213–218.181:17–21. Tyler AN. Liu H. Lee WP. Nat Rev Immunol 2008. Fritz JH. Sansonetti PJ. Bertin J. Raghavan S. O’Rourke K. van Nimwegen M. Rolaz A. J Cell Sci 2007. Lee WP. [PubMed: 11163247] Maeda S. Weiss DS. Legrand-Poels S. Gommerman JL.104:143–152. Colonna M. Monack DM. von Moltke J. Immunity 2004. Biochem Pharmacol 2008.Vance et al. [PubMed: 18768827] Koraimann G. Science 2005. Rock KL. [PubMed: 18789311] Lamkanfi M. [PubMed: 15692052] Magalhaes JG. Giovannini M. Girardin SE. Nahori MA. [PubMed: 17356065] Li H. Dietrich WF. et al. Cox JS. [PubMed: 14625683] Krug A.6:1201–1207.10:477– 486. Tracheal cytotoxin structural requirements for respiratory epithelial damage in pertussis.181:3755–3759. [PubMed: 18193943] Lee SK.9:1171–1178. Erickson S. Le Bourhis L.5:1345–1356. Helicobacter pylori flagellins have very low intrinsic activity to stimulate human gastric epithelial cells via TLR5. Brubaker SW. [PubMed: 15345224] Kufer TA. French AR. Meyer-Morse N. Piette J. Bergen IM. Bankston LA. Le Bourhis L. Dixit VM. Nature 2004. Microbes Infect 2003. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Philpott DJ. Re F. Portnoy DA. Katzowitsch E. French DM. [PubMed: 16407890] NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Cell Host Microbe. Sun YH. Murine Nod1 but not its human orthologue mediates innate immune detection of tracheal cytotoxin. Nod2 mutation in Crohn’s disease potentiates NF-kappaB activity and IL-1beta processing. Philpott DJ. Tschopp J. Karin M.307:734– 738. Lambrecht BN. Willingham SB. Newton K. Kufer TA. Critical function for Naip5 in inflammasome activation by a conserved carboxyterminal domain of flagellin.227:95– 105. Kremmer E. How dying cells alert the immune system to danger. Weinrauch Y. Modulation of Nod2-dependent NF-kappaB signaling by the actin cytoskeleton. Stack A. Philpott DJ. Dixit VM. Kustermans G. Ruiz N. Akira S. Kremmer E.and NLRmediated transcriptional responses to an intracellular pathogen. Monack DM. J Immunol 2008.181:7925–7935.76:1214–1228. Iimura M. TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Barchet W. Nature 2006. Pingel JT. [PubMed: 19120479] Leber JH. Jacobs N. Roose-Girma M. [PubMed: 18724372] Luker KE. Actin cytoskeleton differentially modulates NF-kappaB-mediated IL-8 expression in myelomonocytic cells. [PubMed: 15190255] Mariathasan S. Cell Mol Life Sci 2003. Author manuscript. Inflammasomes: guardians of cytosolic sanctity.120:1299–1310. Aizawa SI. Cell Microbiol 2008. Crimmins GT. . [PubMed: 18340345] Kool M. Dunipace EA. Yokoyama WM. Newton K.16:733–743. [PubMed: 7476167] Madden JC. McBride J. Lytic transglycosylases in macromolecular transport systems of Gram-negative bacteria. Nod2-dependent Th2 polarization of antigen-specific immunity. Goldman WE. Cryopyrin activates the inflammasome in response to toxins and ATP. Fischer JA.60:2371–2388. Roose-Girma M.4:e6.8:279– 289. Horion J. Page 16 Kono H. Persson J. De Smedt T. Bex F. Josenhans C. Adam AC. Sellge G. available in PMC 2010 July 23. [PubMed: 14670447] Legrand-Poels S. J Immunol 2008. Piette J. et al. Petrilli V. EMBO Rep 2005. Cutting edge: inflammasome activation by alum and alum’s adjuvant effect are mediated by NLRP3. J Immunol 2008. Castillo R. [PubMed: 19017983] Magalhaes JG. El Mjiyad N. PLoS Pathog 2008.21:107–119. Hugot JP. Cell 2001. Fritz J. Cytolysin-mediated translocation (CMT): a functional equivalent of type III secretion in gram-positive bacteria.440:228–232. Suerbaum S. Witte CE.

J Immunol 2008. How bacteria consume their own exoskeletons (turnover and recycling of cell wall peptidoglycan). Al-Mousa H. Bader MW.99:13861–13866. Uehara T. [PubMed: 16176658] NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Cell Host Microbe. PLoS Pathog 2006. Shen L. Pannexin-1-Mediated Intracellular Delivery of Muramyl Dipeptide Induces Caspase-1 Activation via Cryopyrin/NLRP3 Independently of Nod2. Clark SA. Tolerance. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. MDP-induced interleukin-1beta processing requires Nod2 and CIAS1/ NALP3. Shield as signal: lipopolysaccharides and the evolution of immunity to gramnegative bacteria. Papin S. Santos OF. [PubMed: 16648853] Miyake K.449:819–826. Lawrence T. Miller D. Fuse ET. [PubMed: 18322214] Martinon F. Bustamante J.180:4050–4057. Agostini L. [PubMed: 17121814] Perry AK.2:e67. Whitfield NN.7:569– 575. Varley AW. Tschopp J. et al. [PubMed: 17977705] Petrilli V. Curr Opin Immunol 2007a. Mathison J. [PubMed: 16980981] Mukherjee A. Turner JR. Author manuscript. Alpuche-Aranda CM. [PubMed: 17403772] Park JT. Ross PJ. Nature 2007. Curr Biol 2004. Proc Natl Acad Sci U S A 2002. Fearns C. Muruve DA. Kim KS. Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide response. J Biol Chem 2007. Kusumoto S. Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Parks RJ. von Bernuth H. Lee KD. [PubMed: 17874090] Petrilli V. Kobayashi KS. Fukase K. Tang H. Nunez G. [PubMed: 16933971] Molofsky AB. Meylan E. Cell Res 2005. Sweet C. [PubMed: 17599094] Puel A. Chen G. Sharp F. Immunogenetics 2007. Portnoy DA. Cheng G. Nat Immunol 2006.282:2386–2394. et al. Dors M. Weber CR. Swanson MS. Embo J 2006.7:1066–1073. Pannexin-1 couples to maitotoxin. [PubMed: 8011301] Medzhitov R. Tateda K. Tschopp J. Petrilli V.72:211–227. Surprenant A. Disruption-induced mucus secretion: repair and protection. Clark AE. [PubMed: 15987599] Persson J.15:407–422. Coyle AJ.452:103–107. Nat Immunol 2006.and nigericin-induced interleukin-1beta release through a dye uptake-independent pathway. Da Silva Correia J. White LR. Tschopp J.19:615–622. Mayor A. Nature 2008. Aderem A. Hoffman HM. The inflammasome: a danger sensing complex triggering innate immunity. [PubMed: 19122199] Munford RS.59:761–778.11:220–224. Grant EP. available in PMC 2010 July 23. Surprenant A. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf.203:1093–1104. PLoS Biol 2006.4:e276. Byrne BG.25:5071–5082. Yi CH. [PubMed: 16606669] Montminy SW. [PubMed: 18288107] O’Riordan M. J Exp Med 2006. McGrath S. Retinoic acidinduced gene-1 (RIG-I) associates with the actin cytoskeleton via caspase activation and recruitment domain-dependent interactions. J Biol Chem 2009. J Endotoxin Res 2005. Recognition of microorganisms and activation of the immune response.12:991–1045. Tanaka T. Vance RE. McNeil PL. danger. Walkowicz MJ. Franchi L. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Innate recognition of bacteria by a macrophage cytosolic surveillance pathway. et al. [PubMed: 15530394] Matzinger P. Picard C. J Leukoc Biol 2007.14:1929–1934. Zheng D. Cell Death Differ 2007b. McDonald C.14:1583–1589.Vance et al. Wang T. Kravchenko VV. [PubMed: 17943118] Miao EA. [PubMed: 16846256] Muruve DA. Martinon F. Khan N. and the extended family. Zaiss AK. Dostert C. Coyne CB. Heritable defects of the human TLR signalling pathways. Page 17 Marina-Garcia N. Microbiol Mol Biol Rev 2008. [PubMed: 12359878] Pan Q. Chang HH.82:177–183. Ku CL. Morosky SA. Kim YG. Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection.284:6486–6494. Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. Gonzales R. Boons GJ. Bertin J. Miller SI. Yang K. Tschopp J. Madigan CA. The host type I interferon response to viral and bacterial infections. Dostert C. Miyake K. [PubMed: 18535144]table of contents Pelegrin P. . Annu Rev Immunol 1994. Conlon JE. Genetics-squared: combining host and pathogen genetics in the analysis of innate immunity and bacterial virulence. [PubMed: 17036048] Pelegrin P.

Nelson WC. [PubMed: 16413926] Sun YH.178:3143–3152.95:1669–1674. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Farr AG.9:1851–1869. Bao S. Barton GM. [PubMed: 16432199] Ratner AJ. Cornelis GR. Higgins DE. [PubMed: 17441987] Royet J. [PubMed: 17312162] Stetson DB. Peptidoglycan recognition proteins: pleiotropic sensors and effectors of antimicrobial defences. Listeriolysin O: a phagosome-specific lysin. J Immunol 2007. Ma AT.188:1381–1388. Host cell killing and bacterial conjugation require overlapping sets of genes within a 22-kb region of the Legionella pneumophila genome. Adams KN. Tsolis RM. A mechanism for the initiation of allergen-induced T helper type 2 responses. Shchepetov M. Cell Microbiol 2006. Akassoglou K. Adams LG. Khantwal CM. Hinnebusch BJ. Cox JS. Sturtevant D. Brosch R. [PubMed: 18474668] NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Cell Host Microbe. Cell Microbiol 2007.5:264–277. Type III secretion translocation pores of Yersinia enterocolitica trigger maturation and release of pro-inflammatory IL-1beta. Jarrett CO. Sehr P. Ekins S.9:1343–1351. The Type I IFN response to infection with Mycobacterium tuberculosis requires ESX-1-mediated secretion and contributes to pathogenesis. J Biol Chem. Nizet V. Characterization of late acyltransferase genes of Yersinia pestis and their role in temperature-dependent lipid A variation. Haddad GG. Bahadduri PM.12:4–10. Grant EP. [PubMed: 16452420] Reife RA. Rolan HG. Medzhitov R. Nod1 mediates cytoplasmic sensing of combinations of extracellular bacteria. Purcell M. Al-Qutub M. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Identification of a conserved bacterial protein secretion system in Vibrio cholerae using the Dictyostelium host model system. Cell Microbiol 2007. Lichtenberger GS. Lara-Tejero M.387:725–729.and Naip5-mediated macrophage immunity. Lysenko ES. [PubMed: 16546100] Swaan PW.39:536–542. Selzer J. Galan JE. Mann M. Santos RL. Bensman T. Howald WN. [PubMed: 17720603] Segal G. [PubMed: 16611234] Ren T. et al. Heidelberg JF.8:857–868. Krastins B. [PubMed: 9192900] Schnupf P. Bacterial peptide recognition and immune activation facilitated by human peptide transporter PEPT2. [PubMed: 18432192] Roux CM. Brucella requires a functional Type IV secretion system to elicit innate immune responses in mice. Nature 1997. [PubMed: 17363965] Schmidt G. Guma M. [PubMed: 16552444] Rius J. [PubMed: 9465074] Shen A. Ogura Y.2:e18. Zinkernagel AS. PLoS Pathog 2006. Johndrow JE. Gln 63 of Rho is deamidated by Escherichia coli cytotoxic necrotizing factor-1. Johnson RS. Weiser JN. Shuman HA.2:e30. ESX/type VII secretion systems and their role in host-pathogen interaction. Am J Respir Cell Mol Biol 2008. available in PMC 2010 July 23. [PubMed: 19155186] Sokol CL. Dixon DM. Manzanillo P.24:93–103. Microbes Infect 2007.9:1176–1187. Askenase PW. Coats SR. Dietrich WF. [PubMed: 16617375] Shin H. Author manuscript. Sarkar A. Ernst RK. Billharz RJ. J Bacteriol 2006. Roy CR. Darveau RP. Aktories K. Coyle AJ. Wilm M. Tsolis RM. Proc Natl Acad Sci U S A 2006. . Zamboni DS. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 2006. Aguilar JL. Injection of flagellin into the host cell cytosol by Salmonella enterica serotype typhimurium. Nat Immunol 2008. Thomas TL. Schachtrup C. Nature 2008.453:807–811. Rolan HG. Nat Rev Microbiol 2007. Vance RE. Medzhitov R. Beremand PD. Immunity 2006. Dziarski R. Karin M. Portnoy DA.103:1528–1533. Knoell DL. Cell Microbiol 2007. Mekalanos JJ. Szczepanik M.24:317–327. Hall MW. [PubMed: 17474907] Rebeil R. 2007 Sutterwala FS.Vance et al. The MogR transcriptional repressor regulates nonhierarchal expression of flagellar motility genes and virulence in Listeria monocytogenes. Bertin J.9:2893–2902. Miller SI. Page 18 Pukatzki S. Flagellin-deficient Legionella mutants evade caspase-1. Bottai D. Curr Opin Microbiol 2009. Sarracino D. [PubMed: 17991047] Simeone R. PLoS Pathog 2006.9:310–318. [PubMed: 18300366] Stanley SA. Proc Natl Acad Sci U S A 1998. Braham PA. Porphyromonas gingivalis lipopolysaccharide lipid A heterogeneity: differential activities of tetraand penta-acylated lipid A structures on E-selectin expression and TLR4 recognition.

Immunity 2008. Induction of neutrophil chemotaxis by the quorum-sensing molecule N-(3-oxododecanoyl)-L-homoserine lactone. Hong A. et al. Waypa TS. Kinch LN. [PubMed: 10844661] Waite AL. [PubMed: 17915219] Yarbrough ML. Hof H. Andrews HL. Gastroenterology 2007. Bacterial peptidoglycan (murein) hydrolases. Annu Rev Microbiol 2005. [PubMed: 15084751] Yang Z. [PubMed: 17335404] Zhou D. Murray PJ. Grishin NV. NOD2 transgenic mice exhibit enhanced MDP-mediated down-regulation of TLR2 responses and resistance to colitis induction.279:873–876. Nat Immunol 2004. Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis. [PubMed: 15847602] Vogel JP. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nakagawa Y. [PubMed: 6176874] Von Pawel-Rammingen U. Page 19 Vavricka SR.127:1401–1409. Wolf-Watz H. Failure of killed Listeria monocytogenes vaccine to produce protective immunity. Bliska JB. Asano N. Merlin D. [PubMed: 18701081] Young JA.25:473–485. Strober W. Pseudomonas aeruginosa regulates flagellin expression as part of a global response to airway fluid from cystic fibrosis patients. Immunity 2006.133:1510–1521. [PubMed: 15489856] Viboud GI. Boneca IG. Li Y. Athman R. Infect Immun 2006. Watanabe T.32:259–286.323:269–272. Wakatsuki Y. Lory S. Davey MP. Brenner-Weiss G. Proc Natl Acad Sci U S A 2004.Vance et al. Annu Rev Biochem 2007. Prior B. Schmidt G. Huerre MR. Collier RJ. Coyle AJ. Nature 1982. Science 2009. Ball HL. Rosenbaum JT. FEMS Microbiol Rev 2008. Wagner C. Balci-Peynircioglu B. Conjugative transfer by the virulence system of Legionella pneumophila. Finger H. [PubMed: 15521010] Viala J. Murray PJ.29:178–181. Embo J 2001. Muller W. Isberg RR. Orth K. An invasion-associated Salmonella protein modulates the actinbundling activity of plastin. Hansch GM. and translocation. Bliska JB. [PubMed: 16949315] Wolfgang MC. Kitani A. Schneewind O. [PubMed: 19109554] Watanabe T. Aktories K. Jyot J. Exp Biol Med (Maywood) 2009. Richards N. NOD2 is a negative regulator of Toll-like receptor 2mediated T helper type 1 responses. Galan JE. A bacterial type III secretion system inhibits actin polymerization to prevent pore formation in host cell membranes. Phanvijhitsiri K. Proc Natl Acad Sci U S A 1999. hPepT1 transports muramyl dipeptide. Fox M. Rosqvist R. Yersinia outer proteins: role in modulation of host cell signaling responses and pathogenesis. Anthrax toxin: receptor binding. Chang EB. Structural mechanism of RNA recognition by the RIG-I-like receptors.59:69–89. Fujita T. Chaput C. Cardona A.76:243–265. Mol Microbiol 2000. Gastroenterology 2004. [PubMed: 9452389] Vollmer W. Telepnev MV. internalization. Strober W. Author manuscript. Schaner P. Girardin SE. pore formation. Charlier P. Chang JE. Science 1998. Obst U. Foster S. available in PMC 2010 July 23. [PubMed: 11574469] Viboud GI. Pyrin and ASC co-localize to cellular sites that are rich in polymerizing actin. Fuss IJ.36:737–748. GAP activity of the Yersinia YopE cytotoxin specifically targets the Rho pathway: a mechanism for disruption of actin microfilament structure. activating NF-kappaB and stimulating IL-8 secretion in human colonic Caco2/bbe cells. Ramphal R. Joris B. [PubMed: 19039103] Yoneyama M. Strober W. Memet S. [PubMed: 10468582] Zimmermann S. Goodman AL.297:233–234. Kitani A. Wong SK.20:5373–5382.5:1166–1174.5:800–808. AMPylation of Rho GTPases by Vibrio VopS disrupts effector binding and downstream signaling. [PubMed: 16988244] NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Cell Host Microbe. Hu C. [PubMed: 18266855] von Koenig CH. Fuss IJ. Kitani A.234:40–52. Hug F.101:6664–6668. Moran AP. Mooseker MS. [PubMed: 15220916] Watanabe T. Nat Immunol 2004.96:10176–10181. Gumucio DL.74:5687–5692. Musch MW. .

available in PMC 2010 July 23. Page 20 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 1. Author manuscript. PAMPs are often sensed in different subcellular compartments. or in different cell types. Dual Recognition of PAMPs A highly simplified schematic of the responses to three PAMPs is shown. host cells not only sense whether a PAMP is present but also sense when and where the PAMP is present. Thus.Vance et al. leading to distinct responses. Cell Host Microbe. .

. leading to specific immune responses that discriminate pathogenic and non-pathogenic microbes.Vance et al. These strategies appear to be detected as unique patterns by the host. Author manuscript. and spread among their hosts. Figure 2. available in PMC 2010 July 23. replicate within. Patterns of Pathogenesis Live pathogens commonly employ a small number of strategies to infect. Page 21 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Cell Host Microbe.