Cytosolic surveillance and antiviral immunity
Highlights
► Central role of cytosol as a site of immune surveillance. ► Several distinct families of sensors mediate viral recognition. ► Sensors include receptors that drive IFN and cytokines.
Introduction
The innate immune system is composed of receptors that collectively serve as a pathogen sensor to monitor the extracellular, vacuolar, and cytosolic compartments for signs of infection. Viruses interact with all of these compartments. The cytosol in particular represents a critical subcellular niche in the life cycle of the majority of RNA viruses and a limited number of DNA viruses such as poxviruses. Furthermore, herpes viruses traverse the cytosol en route to the nucleus, the site of their replication. During these processes, virions and/or their components accumulate in the cytosol. Intensive investigation over the last five years or so has unveiled new receptors that patrol the cytosolic compartment [1]. These cytosolic receptors include the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), the nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), the more recently identified absent in melanoma 2(AIM2)-like receptors (ALRs) and an expanding family of DEXDc helicases (DLRs). During viral infection the cytosol accumulates viral RNAs or DNAs that originate from the incoming viral genome, viral transcripts, or transcription and replication intermediates. Consequently, the cytosolic sensing of viruses relies largely on viral nucleic acids as major viral pathogen-associated molecular pattern (PAMPs) [2]. The recognition of viral PAMPs by cytosolic sensors leads to the elaboration of a robust program of gene expression that involves the production of antiviral inflammatory cytokines, chemokines, and interferons (IFNs). Most extensively studied in this context are the type I IFNs and the IL-1 family of cytokines [3].
Section snippets
Cytosolic sensors that induce type I IFN responses
The production of the type I IFNs (IFNα/β) represents one of the pivotal responses mediating the antiviral immune response. Type I IFNs exert antiviral effects by acting on immune cells (both innate and adaptive immune cells) as well as non-immune cells such as epithelial cells. The production of IFNα/β at the initial stages of viral infection not only establishes an early antiviral state in non-immune cells but also primes for the subsequent development of optimal antigen-specific T cell and
Core signaling pathway mediates type I IFN production
Although a multitude of receptors exist in the cytosol that induce IFNα/β gene transcription, the majority converge on the inhibitor of kappa B (IkB) kinase related kinases TRAF, family member-associated NF-κB activator (TANK), (TNF receptor-associated factor (TRAF) family member-associated nuclear factor (NF)-κB activator)-binding kinase 1 (TBK1) and IkB kinase epsilon [4, 5]. In contrast to the classical IkB kinases, IKKα and β, these kinases phosphorylate and activate the transcription
The RLRs
RIG-I and melanoma differentiation-associated gene 5 (MDA5) were the first set of receptors identified to sense viral products in the cytosol [9]. RIG-I senses the nascent 5′ triphosphate moiety of viral genomes or virus derived transcripts of negative-sense ssRNA viruses [10]. In addition to the uncapped 5′ triphosphorylated RNA, base pairing at the 5′-end allows RIG-I to discriminate between viral and host mRNAs, which are capped with a 7-methyl-guanosine group [11, 12, 13]. In contrast, MDA5
IFN-inducing DNA sensors
As outlined above, in addition to RNA sensing mechanisms a growing number of DNA sensing pathways have been identified which signal in response to DNA that gains access to the cytosolic compartment. The first evidence for the existence of a TLR9-independent pathway for detecting DNA was provided by Stetson and Medzhitov [32] and Ishii et al. [33] who reported the ability of dsDNA to induce type I IFNs in cells lacking TLR signaling. Subsequent research efforts have unveiled a plethora of
Cytosolic sensors that induce IL-1 family of cytokines
Although the type I IFN response is the predominant antiviral signature associated with immunity to viruses, the cytokines belonging to the IL-1 family such as IL-1β and IL-18 also play an important role in the antiviral response [44]. These cytokines have potent proinflammatory functions and act in a number of ways to enhance antiviral immunity. IL-1β and IL-18 exert antiviral effects through distinct mechanisms. While IL-18 is mainly involved in coordinating IFN-γ production from NK cells and
Conclusions
The discovery of new classes of innate immune sensors, which patrol the cytosol for nucleic acids, or other components of viruses has provided enormous insights into the host–pathogen interface. However, despite these tremendous advances, key questions remain to be resolved before a comprehensive understanding of immunity to viruses can be obtained. With the exception of RIG-I and AIM2, the ligand specificity and molecular basis of ligand recognition are still unclear for most cytosolic
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
V.A.R is supported by a postdoctoral fellowship from the New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (NERCE; NIH/NIAID AI057159). This work is also supported by NIH grant AI083713 to K.A.F.
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