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Pattern recognition receptors (PRRs) and inflammasomes are a key part of the anti-viral innate immune system as they detect conserved viral pathogen-associated molecular patterns ...(PAMPs). A successful host response to viral infections critically depend on the initial activation of PRRs by viruses, mainly by viral DNA and RNA. The signalling pathways activated by PRRs leads to the expression of pro-inflammatory cytokines, to recruit immune cells, and type I and type III interferons which leads to the induction of interferon stimulated genes (ISG), powerful virus restriction factors that establish the “antiviral state”. Inflammasomes contribute to anti-viral responses through the maturation of interleukin (IL)-1 and IL-18 and through triggering pyroptotic cell death. The activity of the innate immune system along with the adaptive immune response normally leads to successful virus elimination, although disproportionate innate responses contribute to viral pathology. In this review we will discuss recent insights into the influence of PRR activation and inflammasomes on viral infections and what this means for the mammalian host. We will also comment on how specific PRRs and inflammasomes may be relevant to how SARS-CoV-2, the virus responsible for the current COVID-19 pandemic, interacts with host innate immunity.
Immune Sensing of DNA Paludan, Søren R.; Bowie, Andrew G.
Immunity,
05/2013, Letnik:
38, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Although it has been appreciated for some years that cytosolic DNA is immune stimulatory, it is only in the past five years that the molecular basis of DNA sensing by the innate immune system has ...begun to be revealed. In particular it has been described how DNA induces type I interferon, central in antiviral responses and a mediator of autoimmunity. To date more than ten cytosolic receptors of DNA have been proposed, but STING is a key adaptor protein for most DNA-sensing pathways, and we are now beginning to understand the signaling mechanisms for STING. In this review we describe the recent progress in understanding signaling mechanisms activated by DNA and the relevance of DNA sensing to pathogen responses and autoimmunity. We highlight new insights gained into how and why the immune system responds to both pathogen and self DNA and define important questions that now need to be addressed in the field of innate immune activation by DNA.
Abstract Innate immune DNA sensing underpins many physiological and pathological responses to DNA, including anti-viral immunity to DNA viruses. Although it has been appreciated for many years that ...cytosolic DNA can evoke a type I interferon response, it is only within the past decade that the cellular mechanisms responsible for such a response have been defined. Here we review the discoveries that led to an appreciation of the existence of cytosolic DNA sensor proteins, and discuss two key such sensors, cGAS and IFI16, in detail. DNA sensors operate via STING, a protein shown to have a central role in controlling altered gene induction in response to DNA in vivo, and as such to be central to a rapidly expanding list of both protective and harmful responses to DNA. We also discuss recent insights into how and when DNA stimulates innate immunity, and highlight current outstanding questions in the DNA sensing field.
Recognition of DNA by the innate immune system is central to antiviral and antibacterial defenses, as well as an important contributor to autoimmune diseases involving self DNA. AIM2 (absent in ...melanoma 2) and IFI16 (interferon-inducible protein 16) have been identified as DNA receptors that induce inflammasome formation and interferon production, respectively. Here we present the crystal structures of their HIN domains in complex with double-stranded (ds) DNA. Non-sequence-specific DNA recognition is accomplished through electrostatic attraction between the positively charged HIN domain residues and the dsDNA sugar-phosphate backbone. An intramolecular complex of the AIM2 Pyrin and HIN domains in an autoinhibited state is liberated by DNA binding, which may facilitate the assembly of inflammasomes along the DNA staircase. These findings provide mechanistic insights into dsDNA as the activation trigger and oligomerization platform for the assembly of large innate signaling complexes such as the inflammasomes.
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► Electrostatic attraction underlies innate dsDNA recognition by the HIN domains ► Both OB folds and the linker between them engage the dsDNA backbone ► An autoinhibited state of AIM2 is activated by DNA that liberates the PYD domain ► DNA serves as an oligomerization platform for the inflammasome assembly
Highlights • Endosomal TLRs have new functions in sensing RNA. • Mechanisms are known for how RIG-I and MDA5 discriminate between host and viral RNA. • Multiple DExD/H-box helicases have been ...proposed as nucleic acid sensors. • New signaling pathways have been found controlling cytosolic DNA responses.
The expression of pattern-recognition receptors (PRRs) by immune and tissue cells provides the host with the ability to detect and respond to infection by viruses and other microorganisms. ...Significant progress has been made from studying this area, including the identification of PRRs, such as Toll-like receptors and RIG-I-like receptors, and the description of the molecular basis of their signalling pathways, which lead to the production of interferons and other cytokines. In parallel, common mechanisms used by viruses to evade PRR-mediated responses or to actively subvert these pathways for their own benefit are emerging. Accumulating evidence on how viral infection and PRR signalling pathways intersect is providing further insights into the function of the pathways involved, their constituent proteins and ways in which they could be manipulated therapeutically.
The discovery of Toll-like receptors (TLRs) was an important event for immunology research and was recognized as such with the awarding of the 2011 Nobel Prize in Physiology or Medicine to Jules ...Hoffmann and Bruce Beutler, who, together with Ralph Steinman, the third winner of the 2011 Nobel Prize and the person who discovered the dendritic cell, were pioneers in the field of innate immunity. TLRs have a central role in immunity - in this Timeline article, we describe the landmark findings that gave rise to this important field of research.
The micronutrient iron is now recognized to be important in regulating the magnitude and dynamics of ocean primary productivity, making it an integral component of the ocean's biogeochemical cycles. ...In this Review, we discuss how a recent increase in observational data for this trace metal has challenged the prevailing view of the ocean iron cycle. Instead of focusing on dust as the major iron source and emphasizing iron's tight biogeochemical coupling to major nutrients, a more complex and diverse picture of the sources of iron, its cycling processes and intricate linkages with the ocean carbon and nitrogen cycles has emerged.
The interleukin receptor-associated kinase (IRAK) family are involved in regulating Toll-like receptor (TLR) and interleukin-1 (IL-1) signalling pathways. TLRs are pattern recognition receptors of ...the innate immune response that are responsible for sensing pathogens and initiating immunity, while IL-1 is one of the key cytokines that mediates inflammation. As such, IL-1/TLR signalling pathways and the IRAK family are critical in anti-pathogen responses, inflammation and autoimmunity. The family comprises of four members, IRAK-1, IRAK-2, IRAK-M (IRAK-3) and IRAK-4, and has a role in both positive and negative regulation of signal transduction. While it was once thought that the family displayed some redundancy, each member of the family is emerging as a distinct and vital contributor to IL-1/TLR signalling mechanisms. Knockout mouse studies have explored the relative contribution of each of the IRAKs in IL-1/TLR signalling, while the recent generation of kinase-inactive knock-in IRAK-4 mice have revealed which of IRAK-4 functions require its kinase activity. IRAK-2, previously thought of as a pseudokinase, has recently been proposed to have kinase activity that is essential for TLR signalling. Not surprisingly given their critical role in IL-1/TLR signalling, the IRAK family members have been implicated in certain disease models including human immunodeficiencies. Thus the potential targeting of these essential protein kinases therapeutically is also discussed.
Recent advances in our understanding of nucleic acid pattern-recognition receptor (PRR) sensing of viruses have revealed a previously unappreciated level of complexity of the host antiviral response. ...As well as direct recognition of viral nucleic acid by PRRs, viruses also induce the release of host nucleic acid from the nucleus and mitochondria into the cytosol, which boosts nucleic acid activation of antiviral PRRs. Crosstalk and cooperation between DNA- and RNA-recognition signaling pathways has also been revealed, as has direct restriction of viral genomes in an interferon-independent manner by PRRs, and new roles for inflammasomes in sensing viral nucleic acid. Further, newly identified viral-evasion strategies targeting PRR pathways emphasize the importance of nucleic acid detection during viral infection at the host–pathogen innate immune interface.
•DNA sensor interferon-inducible protein 16 also senses viral RNA.•RNA viral infection releases mitochondrial DNA that is sensed by DNA receptors.•Retinoic acid-inducible gene I both senses and restricts RNA viruses..•NLRP1 senses double-stranded RNA, leading to inflammasome activation.•Severe acute respiratory syndrome coronavirus-2antagonizes nucleic acid sensing .
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