Innate Immune Evasion of Alphaherpesvirus Tegument Proteins

Abstract

Alphaherpesviruses are a large family of highly successful human and animal DNA viruses that can establish lifelong latent infection in neurons. All alphaherpesviruses have a protein-rich layer called the tegument that, connects the DNA-containing capsid to the envelope. Tegument proteins have a variety of functions, playing roles in viral entry, secondary envelopment, viral capsid nuclear transportation during infection, and immune evasion. Recently, many studies have made substantial breakthroughs in characterizing the innate immune evasion of tegument proteins. A wide range of antiviral tegument protein factors that control incoming infectious pathogens are induced by the type I interferon (IFN) signaling pathway and other innate immune responses. In this review, we discuss the immune evasion of tegument proteins with a focus on herpes simplex virus type I.

Keywords: IFN; alphaherpesvirus; immune evasion; signaling pathway; tegument protein.

Figure 1

Structure and replication process of herpes virus. (A) Structure of alphaherpesviruses. The viral particle structure of alphaherpesviruses includes the genome, tegument, envelope, and capsid. (B) The viral replication process of alphaherpesviruses. The viral replication process of alphaherpesviruses includes adsorption, replication, and assembly, secondary envelopment and exocytosis. Some inspiration for this figure was obtained from previous articles (3).

Figure 2

MyD88, Mal, TIRAP,TIRAP-induced IFN-β and TRAM. The formation of protein complexes of unique TBK1 and IKK inhibitors leads to activation of the transcription factors IRF3 and IRF7 and induction of IFN-β expression. Viral proteins can degrade TLRs and interfere with TLR recognition. The ubiquitination activity of viral proteins can inhibit MyD88, Mal, and TRAF6. A series of strategies is used for virus immune evasion. Some inspiration for this figure was obtained from previous articles (4).

Figure 3

A schematic diagram of the pathogen-derived molecules used to escape intracellular RNA sensing pathways. The sensors in the pathway include RIG-I and MDA-5, which can detect different RNA species, primarily those containing 5′ diphosphate or triphosphate or long dsRNA, respectively. Pathogen-derived degradative or inhibitory helper proteins inhibit RIG-I activation through direct binding to block the interaction between RIG-I and MAVS and prevent RIG-I from entering mitochondria.

Figure 4

A schematic diagram of pathogen-derived molecules used to escape intracellular DNA sensing pathways. The primary sensor of cytoplasmic DNA is cGAS, which is responsible for activating the binding protein STING. Pathogen-mediated degradation targets cGAS to prevent it from binding to DNA or to inhibit its catalytic activity. At the same time, pathogen invaders also degrade cGAMP and bacterial circulating dinucleotides. IFI16 positively affects the activation of the cGAS-STING pathway. Other DNA sensors, such as DAI and AIM2, are also viral factors that block DNA binding and downstream pathway activation. Viral proteolytic enzymes can decompose and degrade these factors; blocking their translocation and preventing their interaction from the downstream signaling protein TBK1, thus hindering STING function.

Figure 5

A schematic diagram of the pathogen-derived molecules used to escape cytokine-sensing pathways in cells. In the basic transmission process of the JAK/STAT signaling pathway, the binding of cytokines to their receptors causes dimerization of the receptor molecules. The close proximity, of JAKs to the receptors enables their activation through interactive tyrosine phosphorylation. The immune evasion effect of the virus can be achieved through the degradation of IFNAR1 and ISG mRNA.