Elsevier

Current Opinion in Virology

Volume 1, Issue 6, December 2011, Pages 455-462
Current Opinion in Virology

Cytosolic surveillance and antiviral immunity

https://doi.org/10.1016/j.coviro.2011.11.004Get rights and content

Innate immune surveillance mechanisms lie at the heart of the antiviral response. A growing number of germ-line encoded pattern recognition receptors have been identified which protect the host from infection by sensing the presence of viral molecules and inducing antiviral defenses. Most compartments that viruses gain access to are under active surveillance by one or more pattern recognition receptors. Members of the Toll-like receptor family guard the extracellular milieu and endosomal compartment where they are activated by viral glycoproteins or nucleic acids, respectively. More recently, the cytosolic compartment has emerged as the frontline in the arsenal of the host's antiviral defenses. Families of receptors in the cytosol recognize viral RNA or DNA or perturbations of cellular homeostasis and orchestrate effector responses to eliminate the invader. Here, we review this expanding area of innate immunity by focusing on the molecular mechanisms of cytosolic host-defenses.

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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