Key Points
-
The innate immune system can detect bacteria by sensing their cell-wall-associated molecules, including lipopolysaccharide, lipoproteins, peptidoglycan and flagellin. Each of these types of molecules is defined as a pathogen-associated molecular pattern (PAMP) and has the capacity to induce inflammatory responses to ensure host defence.
-
Three common themes govern innate immune responses to bacteria. These themes include the use of multiple host receptors to detect individual PAMPs, the use of cytosolic supramolecular organizing centres (SMOCs) to promote inflammation and the use of complementary SMOC-dependent activities to ensure host defence.
-
The best-defined SMOCs are the myddosome, which is assembled on bacterial detection by Toll-like receptors, and the inflammasome, which is assembled on bacterial detection by various cytosolic receptors.
-
Pathogenic and commensal bacteria have evolved mechanisms to avoid recognition by pattern-recognition receptors, particularly by altering the structure of their PAMPs. Multiple evasion strategies are shared by commensals and pathogens alike.
Abstract
The receptors of the innate immune system detect specific microbial ligands to promote effective inflammatory and adaptive immune responses. Although this idea is well appreciated, studies in recent years have highlighted the complexity of innate immune detection, with multiple host receptors recognizing the same microbial ligand. Understanding the collective actions of diverse receptors that recognize common microbial signatures represents a new frontier in the study of innate immunity, and is the focus of this Review. Here, we discuss examples of individual bacterial cell wall components that are recognized by at least two and as many as four different receptors of the innate immune system. These receptors survey the extracellular or cytosolic spaces for their cognate ligands and operate in a complementary manner to induce distinct cellular responses. We further highlight that, despite this genetic diversity in receptors and pathways, common features exist to explain the operation of these receptors. These common features may help to provide unifying organizing principles associated with host defence.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Change history
15 May 2017
In the version of this article initially published online, several instances of 'acetylated' have been corrected to 'acylated'. In addition, the definition of 'AIM (absent in melanoma)' has been corrected to 'absent in melanoma 2 (AIM2)'. These errors have been corrected in the HTML and PDF versions of the article.
References
Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004).
Slack, E. et al. Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science 325, 617–620 (2009).
Janeway, C. A. Pillars article: approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989).
Medzhitov, R. Approaching the asymptote: 20 years later. Immunity 30, 766–775 (2009).
Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J. M. & Hoffmann, J. A. The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973–983 (1996).
Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997).
Hayashi, F. et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099–1103 (2001).
Smith, K. D. et al. Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Nat. Immunol. 4, 1247–1253 (2003).
Gioannini, T. L. et al. Isolation of an endotoxin-MD-2 complex that produces Toll-like receptor 4-dependent cell activation at picomolar concentrations. Proc. Natl Acad. Sci. USA 101, 4186–4191 (2004).
Zanoni, I. et al. CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Cell 147, 868–880 (2011). This work was the first to demonstrate a broadly utilized TLR4-independent response to LPS, mediated by CD14.
Tan, Y., Zanoni, I., Cullen, T. W., Goodman, A. L. & Kagan, J. C. Mechanisms of Toll-like receptor 4 endocytosis reveal a common immune-evasion strategy used by pathogenic and commensal bacteria. Immunity 43, 909–922 (2015).
Takeuchi, O. et al. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol. 169, 10–14 (2002).
Takeuchi, O. et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol. 13, 933–940 (2001).
Brubaker, S. W., Bonham, K. S., Zanoni, I. & Kagan, J. C. Innate immune pattern recognition: a cell biological perspective. Annu. Rev. Immunol. 33, 257–290 (2015).
Wright, S. D., Ramos, R. A., Tobias, P. S., Ulevitch, R. J. & Mathison, J. C. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249, 1431–1433 (1990).
Park, B. S. et al. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature 458, 1191–1195 (2009).
Miyake, K. Innate recognition of lipopolysaccharide by CD14 and toll-like receptor 4-MD-2: unique roles for MD-2. Int. Immunopharmacol. 3, 119–128 (2003).
Song, D. H. & Lee, J.-O. Sensing of microbial molecular patterns by Toll-like receptors. Immunol. Rev. 250, 216–229 (2012).
Mellman, I. Dendritic cells: master regulators of the immune response. Cancer Immunol. Res. 1, 145–149 (2013).
Medzhitov, R. et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol. Cell 2, 253–258 (1998).
Yamamoto, M. et al. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN- promoter in the Toll-like receptor signaling. J. Immunol. 169, 6668–6672 (2002).
Oshiumi, H., Matsumoto, M., Funami, K., Akazawa, T. & Seya, T. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3–mediated interferon-β induction. Nat. Immunol. 4, 161–167 (2003).
Horng, T., Barton, G. M. & Medzhitov, R. TIRAP: an adapter molecule in the Toll signaling pathway. Nat. Immunol. 2, 835–841 (2001).
Fitzgerald, K. A., Palsson-McDermott, E. M. & Bowie, A. G. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413, 78–83 (2001). References 23 and 24 report the discovery of TIRAP, a major factor that regulates TLR signalling. These papers demonstrated that additional factors regulate TLR signalling, leading to successive discoveries of other TLR adaptor proteins.
Fitzgerald, K. A. et al. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J. Exp. Med. 198, 1043–1055 (2003).
Gay, N. J., Symmons, M. F., Gangloff, M. & Bryant, C. E. Assembly and localization of Toll-like receptor signalling complexes. Nat. Rev. Immunol. 14, 546–558 (2014).
Bonham, K. S. et al. A promiscuous lipid-binding protein diversifies the subcellular sites of Toll-like receptor signal transduction. Cell 156, 705–716 (2014).
Motshwene, P. G. et al. An oligomeric signaling platform formed by the Toll-like receptor signal transducers MyD88 and IRAK-4. J. Biol. Chem. 284, 25404–25411 (2009).
Lin, S.-C., Lo, Y.-C. & Wu, H. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465, 885–890 (2010).
Kagan, J. C., Magupalli, V. G. & Wu, H. SMOCs: supramolecular organizing centres that control innate immunity. Nat. Rev. Immunol. 14, 821–826 (2014).
Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640–643 (2003).
Kagan, J. C. et al. TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-β. Nat. Immunol. 9, 361–368 (2008).
Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell 10, 417–426 (2002). This report identified the first inflammasome complex and initiated the field of inflammasome biology.
Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016).
Moltke, von, J., Ayres, J. S., Kofoed, E. M., Chavarría-Smith, J. & Vance, R. E. Recognition of bacteria by inflammasomes. Annu. Rev. Immunol. 31, 73–106 (2013).
Das, S. et al. Brain angiogenesis inhibitor 1 (BAI1) is a pattern recognition receptor that mediates macrophage binding and engulfment of Gram-negative bacteria. Proc. Natl Acad. Sci. USA 108, 2136–2141 (2011).
Billings, E. A. et al. The adhesion GPCR BAI1 mediates macrophage ROS production and microbicidal activity against Gram-negative bacteria. Sci. Signal. 9, ra14 (2016).
Nakamura, N. et al. Endosomes are specialized platforms for bacterial sensing and NOD2 signalling. Nature 509, 240–244 (2014).
Park, J. H. et al. RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs. J. Immunol. 178, 2380–2386 (2007).
Sorbara, M. T. et al. The protein ATG16L1 suppresses inflammatory cytokines induced by the intracellular sensors Nod1 and Nod2 in an autophagy-independent manner. Immunity 39, 858–873 (2013).
Tan, Y. & Kagan, J. C. A. Cross-disciplinary perspective on the innate immune responses to bacterial lipopolysaccharide. Mol. Cell 54, 212–223 (2014).
Hagar, J. A., Powell, D. A., Aachoui, Y., Ernst, R. K. & Miao, E. A. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341, 1250–1253 (2013).
Kayagaki, N. et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341, 1246–1249 (2013).
Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998). References 6 and 44 identified TLR4 as the first human TLR and defined TLR4 as the receptor for LPS, respectively, laying the groundwork for the hypothesis that dedicated receptors for PAMP recognition exist.
Kagan, J. C. & Medzhitov, R. Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell 125, 943–955 (2006).
Yamamoto, M. et al. TRAM is specifically involved in the Toll-like receptor 4–mediated MyD88-independent signaling pathway. Nat. Immunol. 4, 1144–1150 (2003).
Dunzendorfer, S., Lee, H.-K., Soldau, K. & Tobias, P. S. TLR4 is the signaling but not the lipopolysaccharide uptake receptor. J. Immunol. 173, 1166–1170 (2004).
Chiang, C. Y., Veckman, V., Limmer, K. & David, M. Phospholipase C -2 and intracellular calcium are required for lipopolysaccharide-induced Toll-like receptor 4 (TLR4) endocytosis and interferon regulatory factor 3 (IRF3) activation. J. Biol. Chem. 287, 3704–3709 (2012).
Shi, J. et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514, 187–192 (2014).
Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015).
Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015). References 50 and 51 identified GSDMD as the effector of pyroptosis, one of the main pathways of cell death.
Aglietti, R. A. et al. GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. Proc. Natl Acad. Sci. USA 113, 7858–7863 (2016).
Liu, X. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153–158 (2016).
Ding, J. et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535, 111–116 (2016).
Rühl, S. & Broz, P. Caspase-11 activates a canonical NLRP3 inflammasome by promoting K +efflux. Eur. J. Immunol. 45, 2927–2936 (2015).
Aachoui, Y. et al. Caspase-11 protects against bacteria that escape the vacuole. Science 339, 975–978 (2013).
Kofoed, E. M. & Vance, R. E. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 477, 592–595 (2011).
Zhao, Y. et al. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477, 596–600 (2011).
Choi, Y. J., Jung, J., Chung, H. K., Im, E. & Rhee, S. H. PTEN regulates TLR5-induced intestinal inflammation by controlling Mal/TIRAP recruitment. FASEB J. 27, 243–254 (2013).
Choi, Y. J., Im, E., Chung, H. K., Pothoulakis, C. & Rhee, S. H. TRIF mediates Toll-like receptor 5-induced signaling in intestinal epithelial cells. J. Biol. Chem. 285, 37570–37578 (2010).
Parker, D. & Prince, A. Epithelial uptake of flagella initiates proinflammatory signaling. PLoS ONE 8, e59932 (2013).
Eaves-Pyles, T. et al. Luminal-applied flagellin is internalized by polarized intestinal epithelial cells and elicits immune responses via the TLR5 dependent mechanism. PLoS ONE 6, e24869 (2011).
Kim, Y.-M., Brinkmann, M. M., Paquet, M.-E. & Ploegh, H. L. UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature 452, 234–238 (2008).
Huh, J. W. et al. UNC93B1 is essential for the plasma membrane localization and signaling of Toll-like receptor 5. Proc. Natl Acad. Sci. USA 111, 7072–7077 (2014).
Franchi, L. et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in salmonella-infected macrophages. Nat. Immunol. 7, 576–582 (2006).
Miao, E. A. et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf. Nat. Immunol. 7, 569–575 (2006).
Matusiak, M. et al. Flagellin-induced NLRC4 phosphorylation primes the inflammasome for activation by NAIP5. Proc. Natl Acad. Sci. USA 112, 1541–1546 (2015).
Case, C. L., Shin, S. & Roy, C. R. Asc and Ipaf inflammasomes direct distinct pathways for caspase-1 activation in response to Legionella pneumophila. Infect. Immun. 77, 1981–1991 (2009).
Yoon, S.-I. et al. Structural basis of TLR5-flagellin recognition and signaling. Science 335, 859–864 (2012).
Andersen-Nissen, E. et al. Evasion of Toll-like receptor 5 by flagellated bacteria. Proc. Natl Acad. Sci. USA 102, 9247–9252 (2005).
Tenthorey, J. L., Kofoed, E. M., Daugherty, M. D., Malik, H. S. & Vance, R. E. Molecular basis for specific recognition of bacterial ligands by NAIP/NLRC4 inflammasomes. Mol. Cell 54, 17–29 (2014).
Qu, Y. et al. Phosphorylation of NLRC4 is critical for inflammasome activation. Nature 490, 539–542 (2012).
Suzuki, S. et al. Shigella type III secretion protein MxiI is recognized by Naip2 to induce Nlrc4 inflammasome activation independently of Pkcδ. PLoS Pathog. 10, e1003926 (2014).
Miao, E. A. et al. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc. Natl Acad. Sci. USA 107, 3076–3080 (2010).
Yang, J., Zhao, Y., Shi, J. & Shao, F. Human NAIP and mouse NAIP1 recognize bacterial type III secretion needle protein for inflammasome activation. Proc. Natl Acad. Sci. USA 110, 14408–14403 (2013).
Blocker, A., Komoriya, K. & Aizawa, S.-I. Type III secretion systems and bacterial flagella: insights into their function from structural similarities. Proc. Natl Acad. Sci. USA 100, 3027–3030 (2003).
Cole, L. E. et al. Toll-like receptor 2-mediated signaling requirements for francisella tularensis live vaccine strain infection of murine macrophages. Infect. Immun. 75, 4127–4137 (2007).
Brightbill, H. D. et al. Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285, 732–736 (1999).
Aliprantis, A. O. et al. Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science 285, 736–739 (1999).
Khare, S. et al. An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages. Immunity 36, 464–476 (2012).
Nakata, T. et al. CD14 directly binds to triacylated lipopeptides and facilitates recognition of the lipopeptides by the receptor complex of Toll-like receptors 2 and 1 without binding to the complex. Cell. Microbiol. 8, 1899–1909 (2006).
Raby, A.-C. et al. Targeting the TLR co-receptor CD14 with TLR2-derived peptides modulates immune responses to pathogens. Sci. Transl Med. 5, 185ra64 (2013).
Stuart, L. M. et al. Response to Staphylococcus aureus requires CD36-mediated phagocytosis triggered by the COOH-terminal cytoplasmic domain. J. Cell Biol. 170, 477–485 (2005).
Hoebe, K. et al. CD36 is a sensor of diacylglycerides. Nature 433, 523–527 (2005).
Jiang, Z. et al. CD14 is required for MyD88-independent LPS signaling. Nat. Immunol. 6, 565–570 (2005).
Takeuchi, O. et al. Cutting edge: preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a toll-like receptor 2- and MyD88-dependent signaling pathway. J. Immunol. 164, 554–557 (2000).
Horng, T., Barton, G. M., Flavell, R. A. & Medzhitov, R. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 420, 329–333 (2002).
Yamamoto, M. et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420, 324–329 (2002).
Hirschfeld, M. et al. Signaling by toll-like receptor 2 and 4 agonists results in differential gene expression in murine macrophages. Infect. Immun. 69, 1477–1482 (2001).
Toshchakov, V. et al. TLR4, but not TLR2, mediates IFN-β–induced STAT1α/β-dependent gene expression in macrophages. Nat. Immunol. 3, 392–398 (2002).
Barbalat, R., Lau, L., Locksley, R. M. & Barton, G. M. Toll-like receptor 2 on inflammatory monocytes induces type I interferon in response to viral but not bacterial ligands. Nat. Immunol. 10, 1200–1207 (2009).
Cervantes, J. L. & Dunham-Ems, S. M. Phagosomal signaling by Borrelia burgdorferi in human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-β. Proc. Natl Acad. Sci. USA 108, 3683–3688 (2011).
Dietrich, N., Lienenklaus, S., Weiss, S. & Gekara, N. O. Murine Toll-like receptor 2 activation induces type I interferon responses from endolysosomal compartments. PLoS ONE 5, e10250 (2010).
Nilsen, N. J. et al. A role for the adaptor proteins TRAM and TRIF in toll-like receptor 2 signaling. J. Biol. Chem. 290, 3209–3222 (2015).
Stack, J. et al. TRAM is required for TLR2 endosomal signaling to type I IFN induction. J. Immunol. 193, 6090–6102 (2014).
Triantafilou, M. et al. Lipoteichoic acid and Toll-like receptor 2 internalization and targeting to the Golgi are lipid raft-dependent. J. Biol. Chem. 279, 40882–40889 (2004).
Motoi, Y. et al. Lipopeptides are signaled by Toll-like receptor 1, 2 and 6 in endolysosomes. Int. Immunol. 26, 563–573 (2014).
Heit, B. et al. Multimolecular signaling complexes enable Syk-mediated signaling of CD36 internalization. Dev. Cell 24, 372–383 (2013).
Underhill, D. M. et al. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401, 811–815 (1999).
O'Connell, C. M., Ionova, I. A., Quayle, A. J., Visintin, A. & Ingalls, R. R. Localization of TLR2 and MyD88 to Chlamydia trachomatis inclusions. Evidence for signaling by intracellular TLR2 during infection with an obligate intracellular pathogen. J. Biol. Chem. 281, 1652–1659 (2006).
Radian, A. D., Khare, S., Chu, L. H., Dorfleutner, A. & Stehlik, C. ATP binding by NLRP7 is required for inflammasome activation in response to bacterial lipopeptides. Mol. Immunol. 67, 294–302 (2015).
Ozören, N. et al. Distinct roles of TLR2 and the adaptor ASC in IL-1beta/IL-18 secretion in response to Listeria monocytogenes. J. Immunol. 176, 4337–4342 (2006).
Zhou, Y. et al. Virulent Mycobacterium bovis Beijing strain activates the NLRP7 inflammasome in THP-1 macrophages. PLoS ONE 11, e0152853 (2016).
Mariathasan, S. et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430, 213–218 (2004).
Wang, L. et al. Enterococcus faecalis lipoteichoic acid-induced NLRP3 inflammasome via the activation of the nuclear factor kappa B pathway. J. Endod. 42, 1093–1100 (2016).
Kieser, K. J. & Rubin, E. J. How sisters grow apart: mycobacterial growth and division. Nat. Rev. Microbiol. 12, 550–562 (2014).
Chen, G., Shaw, M. H., Kim, Y.-G. & Núñez, G. NOD-like receptors: role in innate immunity and inflammatory disease. Annu. Rev. Pathol. 4, 365–398 (2009).
Wolf, A. J. et al. Hexokinase is an innate immune receptor for the detection of bacterial peptidoglycan. Cell 166, 624–636 (2016).
Irving, A. T. et al. The immune receptor NOD1 and kinase RIP2 interact with bacterial peptidoglycan on early endosomes to promote autophagy and inflammatory signaling. Cell Host Microbe 15, 623–635 (2014).
Tanabe, T. et al. Regulatory regions and critical residues of NOD2 involved in muramyl dipeptide recognition. EMBO J. 23, 1587–1597 (2004).
Philpott, D. J., Sorbara, M. T., Robertson, S. J., Croitoru, K. & Girardin, S. E. NOD proteins: regulators of inflammation in health and disease. Nat. Rev. Immunol. 14, 9–23 (2013).
Martinon, F., Agostini, L., Meylan, E. & Tschopp, J. Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Curr. Biol. 14, 1929–1934 (2004).
Shimada, T. et al. Staphylococcus aureus evades lysozyme-based peptidoglycan digestion that links phagocytosis, inflammasome activation, and IL-1beta secretion. Cell Host Microbe 7, 38–49 (2010).
Vance, R. E., Isberg, R. R. & Portnoy, D. A. Patterns of pathogenesis: discrimination of pathogenic and nonpathogenic microbes by the innate immune system. Cell Host Microbe 6, 10–21 (2009).
Blander, J. M. & Sander, L. E. Beyond pattern recognition: five immune checkpoints for scaling the microbial threat. Nat. Rev. Immunol. 12, 215–225 (2012).
Kawahara, K., Tsukano, H., Watanabe, H., Lindner, B. & Matsuura, M. Modification of the structure and activity of lipid A in Yersinia pestis lipopolysaccharide by growth temperature. Infect. Immun. 70, 4092–4098 (2002).
Paciello, I. et al. Intracellular Shigella remodels its LPS to dampen the innate immune recognition and evade inflammasome activation. Proc. Natl Acad. Sci. USA 110, E4345–E4354 (2013).
Gewirtz, A. T. et al. Helicobacter pylori flagellin evades toll-like receptor 5-mediated innate immunity. J. Infect. Dis. 189, 1914–1920 (2004).
Kao, C.-Y., Sheu, B.-S. & Wu, J.-J. Helicobacter pylori infection: an overview of bacterial virulence factors and pathogenesis. Biomed. J. 39, 14–23 (2016).
Yang, J. et al. Flagellins of Salmonella Typhi and nonpathogenic Escherichia coli are differentially recognized through the NLRC4 pathway in macrophages. J. Innate Immun. 6, 47–57 (2014).
Bera, A., Biswas, R., Herbert, S. & Götz, F. The presence of peptidoglycan O-acetyltransferase in various staphylococcal species correlates with lysozyme resistance and pathogenicity. Infect. Immun. 74, 4598–4604 (2006).
Cullen, T. W. et al. Gut microbiota. Antimicrobial peptide resistance mediates resilience of prominent gut commensals during inflammation. Science 347, 170–175 (2015).
Maeshima, N. & Fernandez, R. C. Recognition of lipid A variants by the TLR4-MD-2 receptor complex. Front. Cell. Infect. Microbiol. 3, 3 (2013).
Rosadini, C. V. & Kagan, J. C. Microbial strategies for antagonizing Toll-like-receptor signal transduction. Curr. Opin. Immunol. 32, 61–70 (2015).
Baxt, L. A., Garza-Mayers, A. C. & Goldberg, M. B. Bacterial subversion of host innate immune pathways. Science 340, 697–701 (2013).
Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).
Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011).
Komai-Koma, M., Jones, L., Ogg, G. S., Xu, D. & Liew, F. Y. TLR2 is expressed on activated T cells as a costimulatory receptor. Proc. Natl Acad. Sci. USA 101, 3029–3034 (2004).
Reynolds, J. M. et al. Toll-like receptor 2 signaling in CD4+ T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity 32, 692–702 (2010).
Saraiva, M. & O'Garra, A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 10, 170–181 (2010).
Lage, S. L., Buzzo, C. L. & Amaral, E. P. Cytosolic flagellin-induced lysosomal pathway regulates inflammasome-dependent and-independent macrophage responses. Proc. Natl Acad. Sci. USA 110, E3321–E3330 (2013).
Case, C. L. & Roy, C. R. Asc modulates the function of NLRC4 in response to infection of macrophages by Legionella pneumophila. mBio 2, e00117-11 (2011).
Belkaid, Y. & Hand, T. W. Role of the microbiota in immunity and inflammation. Cell 157, 121–141 (2014).
Geijtenbeek, T. B. H. & Gringhuis, S. I. Signalling through C-type lectin receptors: shaping immune responses. Nat. Rev. Immunol. 9, 465–479 (2009).
Rogers, N. C. et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22, 507–517 (2005).
Zhu, L.-L. et al. C-Type lectin receptors Dectin-3 and Dectin-2 form a heterodimeric pattern-recognition receptor for host defense against fungal infection. Immunity 39, 324–334 (2013).
Gringhuis, S. I. et al. Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome. Nat. Immunol. 13, 246–254 (2012).
Barbalat, R., Ewald, S. E., Mouchess, M. L. & Barton, G. M. Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol. 29, 185–214 (2011).
Lund, J., Sato, A., Akira, S., Medzhitov, R. & Iwasaki, A. Toll-like receptor 9–mediated recognition of herpes simplex virus-2 by plasmacytoid dendritic cells. J. Exp. Med. 198, 513–520 (2003).
Ewald, S. E. et al. The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature 456, 658–662 (2008).
Ewald, S. E. et al. Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase. J. Exp. Med. 208, 643–651 (2011).
Oldenburg, M. et al. TLR13 recognizes bacterial 23S rRNA devoid of erythromycin resistance-forming modification. Science 337, 1111–1115 (2012).
Liu, S. et al. MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades. eLife 2, e00785 (2013).
Liu, S. et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347, aaa2630 (2015).
Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5, 730–737 (2004).
Satoh, T. et al. LGP2 is a positive regulator of RIG-I− and MDA5-mediated antiviral responses. Proc. Natl Acad. Sci. USA 107, 1512–1517 (2010).
Bruns, A. M., Leser, G. P., Lamb, R. A. & Horvath, C. M. The innate immune sensor LGP2 activates antiviral signaling by regulating MDA5- RNA interaction and filament assembly. Mol. Cell 55, 771–781 (2014).
Chiu, Y.-H., MacMillan, J. B. & Chen, Z. J. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138, 576–591 (2009).
Burdette, D. L. et al. STING is a direct innate immune sensor of cyclic di-GMP. Nature 478, 515–518 (2011).
Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z. J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).
Chen, Q., Sun, L. & Chen, Z. J. Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing. Nat. Immunol. 17, 1142–1149 (2016).
Schaefer, L. Complexity of danger: the diverse nature of damage-associated molecular patterns. J. Biol. Chem. 289, 35237–35245 (2014).
Zanoni, I. et al. An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science 352, 1232–1236 (2016).
Bochkov, V. N. et al. Protective role of phospholipid oxidation products in endotoxin-induced tissue damage. Nature 419, 77–81 (2002).
Yeon, S. H., Yang, G., Lee, H. E. & Lee, J. Y. Oxidized phosphatidylcholine induces the activation of NLRP3 inflammasome in macrophages. J. Leukoc. Biol. 101, 205–215 (2017).
Rathinam, V. A. K. et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat. Immunol. 11, 395–402 (2010).
Vladimer, G. I. et al. The NLRP12 inflammasome recognizes Yersinia pestis. Immunity 37, 96–107 (2012).
Acknowledgements
The authors thank members of the Kagan laboratory for helpful discussions and the anonymous referees for insightful critiques. The US National Institutes of Health (grants AI116550, AI093589 and P30 DK34854), the Burroughs Wellcome Fund (Investigator of the Pathogenesis of Infectious Disease Award) and an unrestricted gift from Mead Johnson & Company support research in the laboratory of J.C.K. K.J.K. is supported by a Life Sciences Research Foundation postdoctoral fellowship (Good Ventures Fellow).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Glossary
- Pyroptosis
-
A form of cell death that is inflammatory and is executed by the inflammatory caspase 1 and caspase 11, as opposed to the apoptotic caspases (for example, caspase 8). During pyroptosis, the plasma membrane blebs, the cell lyses and pro-inflammatory cytokines are released.
- Myddosome
-
A supramolecular organizing centre that forms to initiate Toll-like receptor (TLR)-dependent inflammatory responses. It is comprised of Toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) bound to the TIR domain of the TLR, to which myeloid differentiation primary response protein 88 (MYD88) binds. The interleukin-1 receptor-associated kinase (IRAK) kinases IRAK4 and IRAK2 or IRAK1 then associate to initiate a pro-inflammatory signalling cascade. The myddosome can form at the plasma or endosomal membrane.
- Inflammasome
-
A supramolecular organizing centre that forms to initiate inflammatory responses to cytosolic bacterial products. It is formed by a pattern- recognition receptor, the adaptor protein ASC and caspase 1. It results in the production of interleukin-1β and cleavage of gasdermin D.
- Supramolecular organizing centres
-
(SMOCs). Multi-protein complexes that are assembled on detection of microorganisms, either at the plasma membrane or on intracellular organelles. These large complexes activate enzymes that initiate inflammatory responses to promote host defence.
- Triffosome
-
A putative supramolecular organizing centre that assembles on the endosomal membrane in response to activated Toll-like receptor 4 (TLR4) and TLR3. Its main constituent is TIR domain-containing adaptor protein inducing IFNβ (TRIF), which through TNF receptor-associated factor 3 (TRAF3) or TRAF6 can activate interferon regulatory factor 3 (IRF3) or IRF7, respectively, for interferon production. Apart from TRIF-related adaptor molecule (TRAM), which bridges TRIF to TLR4, the adaptor molecules used to assemble the triffosome remain unknown.
- Inflammatory caspases
-
This group of caspases is composed of caspase 1, caspase 11 and caspase 12. These proteases are involved in the inflammasome pathway and promote an inflammatory form of cell death (pyroptosis). Caspase 1 cleaves immature pro-interleukin-1β (pro-IL-1β) and pro-IL-18 to their mature forms. Caspase 1 and caspase 11 cleave gasdermin D, which is required for pyroptosis. Caspase 4 and caspase 5 are the human homologues of caspase 11. Inflammatory caspases are distinct from apoptotic caspases, which promote the programmed cell death pathway called apoptosis and include caspase 2, caspase 3 and caspase 6 to caspase 10.
- Flagellum
-
A helical filament that extends from the bacterial cell surface. It promotes bacterial movement and is often essential for flagellated pathogens to be able to colonize their respective hosts.
- Lipoteichoic acid
-
(LTA). A polymer found in the cell wall of Gram-positive bacteria that is embedded in the bacterial plasma membrane by a glycerol head group. Attached to the head group are long chains of either ribitol or glycerol phosphate. It is a Toll-like receptor 2 ligand.
- Pam3CSK4
-
A synthetic lipoprotein containing three palmitoyl (Pam) chains that are glycerol-linked to the short peptide CSKKKK (CSK4). It is a classic ligand for Toll-like receptor 2 (TLR2)–TLR1 activity. Pam2CSK4 stimulates TLR2–TLR6.
Rights and permissions
About this article
Cite this article
Kieser, K., Kagan, J. Multi-receptor detection of individual bacterial products by the innate immune system. Nat Rev Immunol 17, 376–390 (2017). https://doi.org/10.1038/nri.2017.25
Published:
Issue Date:
DOI: https://doi.org/10.1038/nri.2017.25
This article is cited by
-
NLRP3 inflammasome activation and NETosis positively regulate each other and exacerbate proinflammatory responses: implications of NETosis inhibition for acne skin inflammation treatment
Cellular & Molecular Immunology (2024)
-
Therapeutic and immunomodulatory role of probiotics in breast cancer: A mechanistic review
Archives of Microbiology (2023)
-
Macrophage subsets and their role: co-relation with colony-stimulating factor-1 receptor and clinical relevance
Immunologic Research (2023)
-
Moniezia benedeni infection enhances neuromedin U (NMU) expression in sheep (Ovis aries) small intestine
BMC Veterinary Research (2022)
-
Bacillus licheniformis PF9 improves barrier function and alleviates inflammatory responses against enterotoxigenic Escherichia coli F4 infection in the porcine intestinal epithelial cells
Journal of Animal Science and Biotechnology (2022)
