Key Points
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Recognizing the presence of invading pathogens is key to mounting an effective innate immune defence. Mammalian cells express different classes of germline-encoded pattern recognition receptors (PRRs) that monitor the extracellular and the intracellular compartments of host cells for signs of infection and that initiate several conserved signalling pathways.
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Recent advances have identified several new extracellular and intracellular PRRs and have shed light on the complex interplay of innate immune signalling pathways during pathogen infection.
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Although the function of most Toll-like receptors (TLRs) has been determined in the past, the functions of orphan mouse TLR11, TLR12 and TLR13, which are not found in humans, have so far eluded researchers. The ligands for these receptors have recently been characterized, which has revealed key differences between the human and mouse innate immune system.
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Cytoplasmic DNA is a strong activator of immune responses and induces type I interferon (IFN) production through the signalling adaptor stimulator of IFN genes protein (STING). Several candidate proteins have been proposed to bind to double-stranded DNA and to induce type I IFN production. More recently, a previously unrecognized role for cyclic dinucleotides in this signalling pathway has been described.
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NOD-like receptors are the largest group of intracellular receptors and are known for their ability to induce the assembly of inflammasome complexes. Recent reports have identified new inflammasome complexes and have characterized their function in the recognition of various bacterial pathogens.
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Canonical inflammasomes have been defined as macromolecular complexes that activate the cysteine protease caspase 1. However, recent findings have highlighted the role of caspase 8 and caspase 11 in inducing pro-inflammatory cytokine maturation and host cell death.
Abstract
Recognizing the presence of invading pathogens is key to mounting an effective innate immune response. Mammalian cells express different classes of germline-encoded pattern recognition receptors that monitor the extracellular and intracellular compartments of host cells for signs of infection and that activate several conserved signalling pathways. An efficient immune response often requires the sequential detection of a pathogen by different receptors in different subcellular compartments, which results in a complex interplay of downstream signalling pathways. In this Review, we discuss the recent identification of previously unknown pattern recognition receptors and how they complement the repertoire of established receptors.
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Acknowledgements
This work was supported by the following grants: PP00P3_139120/1 from the Swiss National Science Foundation to P.B., and AI095396 and AI08972 to D.M.M. from the US National Institute of Allergy and Infectious Diseases. We apologize to investigators whose contributions were not cited more extensively because of space limitations.
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Glossary
- Cyclic dinucleotides
-
Small bacterial or host-derived nucleic acids — such as cyclic diguanylate monophosphate (c-di-GMP), cyclic diadenylate monophosphate (c-di-AMP) or cyclic GMP–AMP — that function as secondary messengers and that can induce an innate immune response when present in the cytosol.
- Leaderless cytokines
-
Cytokines that lack a classical amino-terminal secretion signal sequence (also referred to as leader peptide or leader sequence) and that are thought to be secreted by an endoplasmic reticulum- and Golgi-independent mechanism.
- Pyroptosis
-
A lytic pro-inflammatory form of programmed cell death that is initiated by the activation of inflammatory caspases.
- Plasmacytoid dendritic cells
-
(pDCs). A dendritic cell subset that morphologically resembles a plasmablast. pDCs produce large amounts of type I interferons in response to viral infection.
- Necroptosis
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A form of programmed necrosis that is initiated by the kinases receptor-interacting protein 1 (RIP1) and RIP3 in response to external signals, in conditions in which caspase 8 activity is compromised.
- Ribonuclease A
-
(RNase A). An endoribonuclease that specifically cleaves single-stranded RNA and that is often used to remove RNA from samples.
- Macrolide, lincosamide and streptogramin B
-
(MLS). A group of antibiotics that function as translational inhibitors by targeting the 50S ribosomal subunit, which contains 23S ribosomal RNA.
- DExD/H box helicase
-
An enzyme that can unwind double-stranded RNA using energy derived from ATP hydrolysis. The DExD/H box is a characteristic amino acid signature motif of many RNA-binding proteins.
- Small interfering RNA
-
(siRNA). Short double-stranded RNAs of 19 to 23 nucleotides that induce RNA interference, which is a post-transcriptional process that leads to gene silencing in a sequence-specific manner.
- Short hairpin RNA
-
(shRNA). A sequence of RNA that makes a tight hairpin turn, which can be used to silence target gene expression via RNA interference.
- Leucine-rich repeat
-
(LRR). A protein structural motif composed of repeating stretches of 20 to 30 amino acids that are unusually rich in the hydrophobic amino acid leucine and that form an α/β-horseshoe fold. LRRs are found in many pattern recognition receptors, such as Toll-like receptors and NOD-like receptors, but also in many functionally unrelated proteins.
- β-catenin
-
This protein functions both as a transcriptional activator and as a membrane–cytoskeleton linker protein by binding to E-cadherin. Following detachment from E-cadherin, β-catenin can relocate to the nucleus.
- Type III secretion system
-
(T3SS). A virulence-associated specialized molecular machine present in some bacteria that facilitates the translocation of bacterial proteins into host cells.
- Colitis
-
An inflammatory disease of the colon. In humans, colitis is most commonly classified as ulcerative colitis or as Crohn's disease, which are two inflammatory bowel diseases that have unknown aetiologies. Various hereditary and induced mouse models of human colitis have been developed.
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Broz, P., Monack, D. Newly described pattern recognition receptors team up against intracellular pathogens. Nat Rev Immunol 13, 551–565 (2013). https://doi.org/10.1038/nri3479
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DOI: https://doi.org/10.1038/nri3479
