Innate Immune Responses to Herpesvirus Infection

Abstract

Infection of a host cell by an invading viral pathogen triggers a multifaceted antiviral response. One of the most potent defense mechanisms host cells possess is the interferon (IFN) system, which initiates a targeted, coordinated attack against various stages of viral infection. This immediate innate immune response provides the most proximal defense and includes the accumulation of antiviral proteins, such as IFN-stimulated genes (ISGs), as well as a variety of protective cytokines. However, viruses have co-evolved with their hosts, and as such, have devised distinct mechanisms to undermine host innate responses. As large, double-stranded DNA viruses, herpesviruses rely on a multitude of means by which to counter the antiviral attack. Herein, we review the various approaches the human herpesviruses employ as countermeasures to the host innate immune response.

Keywords: HCMV; HSV; KSHV; antiviral host response; herpesvirus; innate immune response; innate immunity; intrinsic immunity.

Figure 1

Herpesvirus infection triggers PRR signaling. TLR signaling is induced from the cell membrane (left) or endosomal membrane (middle). TLR2-mediated signaling (left) via MyD88 interaction via TLR2′s cytoplasmic domain, activates transcription factors that in turn initiate inflammatory cytokine and ISG transcription. TLR3, TLR7/8, and TLR9 signaling from endosomes (middle) is activated by dsRNA, ssRNA, or CpG DNA, respectively. Downstream activation of NFĸB, IRF7, or IRF3 leads to the upregulation of inflammatory cytokine and ISG production. The cytoplasmic RLR family of PRRs (right), such as RIG-I, use MAVS as an adaptor for innate signaling, resulting in the activation of inflammatory cytokines and ISGs. The data summarized in this figure is reviewed in ref. [4]. Created with BioRender.com (accessed on 13 August 2021).

Figure 2

cGAS-STING signaling induces a potent innate immune response. DNA in the cytosol activates cGAS, inducing the formation of a cGAS-DNA dimer. This dimeric complex uses ATP and GTP to then synthesize 2′,3′-cGAMP, which then binds and activates STING via conformational changes in the endoplasmic reticulum. Coat protein complex II (COP II) transports STING as its cargo to ERGIC Activated STING is then translocated to the Golgi or targeted for autophagy via LC3. From the Golgi, activated STING can shuttle to endosomes, where it either undergoes lysosomal degradation via multivesicular bodies (MVB) or recruits TBK1, resulting in IRF3 phosphorylation. Active IRF3 then dimerizes, translocates to the nucleus, and drives the type I interferon response. Alternatively, activated STING phosphorylates IKK, ultimately leading to NFĸB activation. Nuclear translocation of NFĸB induces cytokine production. Created with BioRender.com (accessed on 13 August 2021).