Mechanisms of innate immune evasion in re-emerging RNA viruses

Abstract

Recent outbreaks of Ebola, West Nile, Chikungunya, Middle Eastern Respiratory and other emerging/re-emerging RNA viruses continue to highlight the need to further understand the virus-host interactions that govern disease severity and infection outcome. As part of the early host antiviral defense, the innate immune system mediates pathogen recognition and initiation of potent antiviral programs that serve to limit virus replication, limit virus spread and activate adaptive immune responses. Concordantly, viral pathogens have evolved several strategies to counteract pathogen recognition and cell-intrinsic antiviral responses. In this review, we highlight the major mechanisms of innate immune evasion by emerging and re-emerging RNA viruses, focusing on pathogens that pose significant risk to public health.

Figure 1

Summary of RNA virus inhibition of cytosolic innate immune signaling pathways. Viral protein antagonists of three cytosolic signaling pathways are represented here: (1) TLR3 activation leads to signaling through TRIF, TRAF6/Rip, and IKKα/β to turn on NFκB. (2) RIG-I activation requires binding to dsRNA and subsequent ubiquitination by E3 ubiquitin ligases, TRIM25 and Riplet. RIG-I is also independently activated by interactions with PACT. This signals through mitochondrial-bound MAVS, leading to TBK1/IKKɛ activation to initiate transcription factors NFκB, IRF3/IRF7. Additionally, PKR is activated by PACT or dsRNA binding, which also turns on TBK1/IKKɛ independently of RIG-I activation. (3) The RNAi pathway involves Dicer conversion of dsRNA to siRNA. The siRNA recognizes its complementary sequence in the target mRNA molecule, which recruits the RISC comprised of Argonaute 2, PACT and TRBP. The resulting mRNA is proteolytically degraded. Viral proteins that inhibit host signaling molecules are indicated. TRIF, TIR-domain-containing adapter-inducing interferon-β; TRAF6, TNF receptor associated factor; RIP, receptor-interacting protein.

Figure 2

RNA virus inhibition of type I IFN signaling. Binding of IFNAR by type I IFN (IFNα/β) initiates downstream kinases, JAK1 and TYK2. JAK1 and TYK2 phosphorylates STAT1 and STAT2, which leads to the formation of the STAT1:IRF9:STAT2 complex. This complex translocates to the nucleus and initiates transcription of IFN-stimulated response element (ISRE). SOCS1 and/or SOCS3 negatively regulate JAK-STAT signaling by interacting with JAK1/TYK2. Nuclear accumulation of phosphorylated STAT1 also depends on Karyopherins. Karyopherin α1 (or α2) complexes with phosphorylated STAT1, which then recruits Karyopherin β1. The complex of phospho-STAT1:Karyopherin α:Karyopherin β1 is able to cross the nuclear membrane and regulate gene expression. Viral proteins that either inhibit or degrade host signaling factors are indicated. ‘+’ denotes upregulation of expression.