Key Points
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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.
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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.
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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.
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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.
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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.
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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).
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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.
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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
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DOI: https://doi.org/10.1038/nri.2017.25
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