Recognition of herpesviruses by the innate immune system

Abstract

Advances in innate immunity over the past decade have revealed distinct classes of pattern recognition receptors (PRRs) that detect pathogens at the cell surface and in intracellular compartments. This has shed light on how herpesviruses, which are large disease-causing DNA viruses that replicate in the nucleus, are initially recognized during cellular infection. Surprisingly, this involves multiple PRRs both on the cell surface and within endosomes and the cytosol. In this article we describe recent advances in our understanding of innate detection of herpesviruses, how this innate detection translates into anti-herpesvirus host defence, and how the viruses seek to evade this innate detection to establish persistent infections.

Figure 1. Innate immune recognition and activation by herpesviruses

a The virion is sensed by TLR2, which most likely detects herpesvirus glycoproteins and induces expression of pro-inflammatory cytokines and in specific cell types also type I IFNs. Viral genomic DNA is detected by TLR9 in endosomes, and by DAI, DHX9/36, AIM2, and IFI16 in the cytoplasm. DNA sensing by the Pol III/RIG-I system may take place in either the nucleus or the cytoplasm. b The intracellular DNA sensing pathways together lead to expression of both cytokines, type I IFNs, and activation of the inflammasome. Productive replication of herpesviruses leads to the accumulation of RNA species, including higher order RNA structures. These RNAs are sensed either in the cytoplasm by MDA5 or in endosomes by TLR3 and TLR7. The cellular response to RNA sensing involves the production of IFNs and cytokines. 1°, 2°, 3°, proposed relative importance of the downstream events activated by PRRs. AIM, absent in melanoma; DAI, DNA-dependent activator of interferon regulatory factors; DHX, DExD/H-box helicase; IFI; interferon-inducible; IFN, interferon; MDA, melanoma differentiation-associated gene; RIG, retinoic acid inducible gene; TLR, Toll-like receptor.

Figure 2. Intracellular detection of herpesvirus DNA and activation of signal transduction

Productive replication of herpesviruses requires transport of the capsid to the nuclear pore, where the genomic DNA is released into the nucleus. Alternatively, herpesvirus DNA may be released from the capsid into the cytosol and be subject to immune recognition. Cytosolic sensors of viral capsids may exist, which target the capsid for degradation either through autophagy or the proteasome. Autophagy-mediated degradation of the capsid will expose the viral DNA to TLR9 in endosomes. Alternatively, TLR9 could receive the viral DNA from an endocytic or phagocytic route. Degradation of the capsid in the cytosol will expose the DNA for the cytosolic DNA sensors, including IFI16, and DAI, which in turn associates with STING and re-localizes from the ER to perinuclear vesicles from where signaling takes place. DHX9 and 36 detect cytosolic DNA and signal through MyD88 like TLR9. DAI, DNA-dependent activator of interferon regulatory factors; DDX3, DEAD box protein 3; DHX, aspartate-glutamate-any amino acid-aspartate/histidine (DExD/H)-box helicase; ER, endoplasmic reticulum; IFI, interferon γ-inducible; MyD88, myeloid differentiation primary-response protein 88; NF-κB, nuclear factor κB; STING, stimulator of interferon genes; TBK, TANK-binding kinase 1;TLR, Toll-like receptor

Figure 3. Evasion of PRR-mediated recognition, signalling and gene expression by herpesviruses

The HSV proteins ICP34.5 and Vhs prevent the recognition of viral nucleic acids by inhibiting autophagy and degrading viral RNA, respectively. Herpesviruses inhibit signaling through both PRR-specific mechanisms (HSV-1 ICP0 inhibits TLR2 signalling by stimulating degradation of TLR adaptor molecules, and MCMV M45 inhibits recruitment or RIP1 to DAI) and more general mechanisms targeting all PRRs (for example, HHV8 ORF45 interacts with IRF7 and inhibits phosphorylation and nuclear translocation). Finally, several herpesvirus-encoded proteins (such as HHV8 vIRF3) inhibit transcription by interacting with NF-κB and IRF3 and/or IRF7 in the nucleus, hence preventing interaction with DNA and assembly of functional transcriptional complexes. CMV, cytomegalovirus; DAI, DNA-dependent activator of interferon regulatory factors; HHV, human herpesvirus; ICP, infected cell protein; IRF, interferon regulatory factor; NF, nuclear factor; ORF, open reading frame; PRR, pattern recognition receptor; RIP, receptor-interacting protein kinase; TLR, Toll-like receptor; Vhs, virion host shut-off.