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. 2012 Jun 20:3:201.
doi: 10.3389/fmicb.2012.00201. eCollection 2012.

Viral CNS infections: role of glial pattern recognition receptors in neuroinflammation

Samantha R Furr  1 , Ian Marriott
Affiliations

Viral CNS infections: role of glial pattern recognition receptors in neuroinflammation

Samantha R Furr et al. Front Microbiol. .

Abstract

Viruses are the major causative agents of central nervous system (CNS) infection worldwide. RNA and DNA viruses trigger broad activation of glial cells including microglia and astrocytes, eliciting the release of an array of mediators that can promote innate and adaptive immune responses. Such responses can limit viral replication and dissemination leading to infection resolution. However, a defining feature of viral CNS infection is the rapid onset of severe neuroinflammation and overzealous glial responses are associated with significant neurological damage or even death. The mechanisms by which microglia and astrocytes perceive neurotropic RNA and DNA viruses are only now becoming apparent with the discovery of a variety of cell surface and cytosolic molecules that serve as sensors for viral components. In this review we discuss the role played by members of the Toll-like family of pattern recognition receptors (PRRs) in the inflammatory responses of glial cells to the principle causative agents of viral encephalitis. Importantly, we also describe the evidence for the involvement of a number of newly described intracellular PRRs, including retinoic acid-inducible gene I and DNA-dependent activator of IFN regulatory factors, that are thought to function as intracellular sensors of RNA and DNA viruses, respectively. Finally, we explore the possibility that cross-talk exists between these disparate viral sensors and their signaling pathways, and describe how glial cytosolic and cell surface/endosomal PRRs could act in a cooperative manner to promote the fulminant inflammation associated with acute neurotropic viral infection.

Keywords: RLR; TLR; astrocytes; microglia; neuroinflammation; pattern recognition receptors; viral encephalitis.

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Figures

FIGURE 1
FIGURE 1
Retinoic acid inducible gene (RIG)-I-like receptors serve as cytosolic sensors for viral RNA motifs and can initiate anti-viral and inflammatory cell responses. Melanoma differentiation-associated gene 5 (MDA5) recognizes double-stranded RNA moieties (dsRNA), while RIG-I perceives short single or double-stranded RNAs with 5’ triphosphate ends (ppp-ssRNA). Helicase interaction with these viral RNAs induces the recruitment of downstream effector molecules including mitochondrial- or peroxisomal-associated interferon promoter stimulator (IPS)-1, TNF receptor associated factor (TRAF) 3, and/or stimulator of interferon genes (STING), leading to the activation of IκB kinase (IKK)-related kinases, TRAF family member-associated NF-κB activator binding kinase 1 (TBK1), and IKK-I. These kinases activate the transcription factors NF-κB and interferon-regulatory factors (IRF) 3, which translocate into the nucleus and activate transcription of anti-viral and inflammatory cytokines.
FIGURE 2
FIGURE 2
DNA-dependent activator of IFN regulatory factors (DAI) can serve as a cytosolic sensor for viral or microbial double-stranded DNA (dsDNA) motifs and initiate anti-viral and inflammatory cell responses. DAI elicits such immune functions via possible interactions with mitochondrial- or peroxisomal-associated interferon promoter stimulator (IPS)-1, and/or stimulator of interferon genes (STING), facilitating the activation of the interferon-regulatory factors (IRF) and NF-κB transcription factors. DAI-induced IRF activation is dependent on TANK-binding kinase 1 (TBK1). In contrast, DAI-induced NF-κB activation is mediated through interactions involving receptor-interacting protein (RIP) 1 and RIP3 kinases.
FIGURE 3
FIGURE 3
Possible interactions between Toll-like receptors (TLRs; e.g., TLR3 and TLR7/8), nucleotide oligomerization domain (NOD)-like receptors (NLRs; e.g., NOD2), retinoic acid inducible gene (RIG)-I-like receptors (RLRs; e.g., RIG-I and MDA5) and DNA-dependent activator of IFN regulatory factors (DAI) in the detection of viruses and the initiation of glial immune responses. These disparate cell surface, endosomal, and cytosolic sensors share common signaling components including interferon promoter stimulator (IPS)-1 and stimulator of interferon genes (STING), leading to the activation of the transcription factors NF-κB and interferon-regulatory factor (IRF) 3, which translocate into the nucleus and initiate anti-viral and inflammatory cytokine production. In addition, the activity of RNA polymerase III (Pol III) could provide an additional mechanism for the perception of DNA viruses via RLRs.
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