Multi-step regulation of innate immune signaling by Kaposi's sarcoma-associated herpesvirus

Abstract

The innate immune system provides an immediate and relatively non-specific response to infection with the aim of eliminating the pathogen before an infection can be fully established. Activation of innate immune response is achieved by production of pro-inflammatory cytokines and type I interferon (IFN). The IFN response in particular is one of the primary defenses utilized by the host innate immune system to control pathogen infection, like virus infection. Hence, viruses have learned to manipulate host immune control mechanisms to facilitate their propagation. Due to this, much work has been dedicated to the elucidation of the Kaposi's sarcoma-associated herpesvirus (KSHV)-mediated immune evasion tactics that antagonize a host's immune system. This review presents our current knowledge of the immune evasion strategies employed by KSHV at distinct stages of its life cycle to control a host's immune system with a focus on interferon signaling.

Keywords: Immune evasion; Innate immune response; Interferon; Kaposi's sarcoma.

Figure 1

An outline of the inhibition of type I IFN signaling pathways by viral proteins of KSHV. Following KSHV infection of cells, specific TLRs are activated, initiating the recruitment of adaptor proteins, MyD88 and TRIF. Subsequently, it leads to the activation of TBK1 and IKKε, which phosphorylate IRF3. IRF3 then dimerizes and translocates to the nucleus and participates in the transcriptional activation of the IFN-β promoter. Binding of newly secreted IFN-β to the type I IFN receptor (IFNAR1) leads to the activation of the JAK-STAT, resulting in forming thee ISGF3 complex. ISGF3 binds to ISRE found in numerous IFN-induced gene promoters, like IRF7. Newly synthesized IRF7 is phosphorylated by TBK1 and IKKε, which can then homodimerize or heterodimerize with IRF3 before binding to the promoters of the genes that encode IFN-α/β. Moreover, dsDNA accumulates in the cytoplasm after infection by KSHV. The intracellular DNA recognized by cytoplasmic receptor, IFI16 and cGAS. Alternatively, dsDNA is transcribed into dsRNA by polymerase III in cell-type specific manner. Generated dsRNA is recognized by RIG-1 and production of type I IFNs are induced. Following DNA stimulation, an ER protein STING translocates from the ER to the cytoplasmic punctate structure and subsequently it recruits TBK1 and IKKε. Among the KSHV-encoded proteins, numerous proteins target this pathway. Black squares indicate KSHV proteins.