Evasion of Host Antiviral Innate Immunity by Paramyxovirus Accessory Proteins

Abstract

For efficient replication, viruses have developed multiple strategies to evade host antiviral innate immunity. Paramyxoviruses are a large family of enveloped RNA viruses that comprises diverse human and animal pathogens which jeopardize global public health and the economy. The accessory proteins expressed from the P gene by RNA editing or overlapping open reading frames (ORFs) are major viral immune evasion factors antagonizing type I interferon (IFN-I) production and other antiviral innate immune responses. However, the antagonistic mechanisms against antiviral innate immunity by accessory proteins differ among viruses. Here, we summarize the current understandings of immune evasion mechanisms by paramyxovirus accessory proteins, specifically how accessory proteins directly or indirectly target the adaptors in the antiviral innate immune signaling pathway to facilitate virus replication. Additionally, some cellular responses, which are also involved in viral replication, will be briefly summarized.

Keywords: IFN; accessory proteins; antiviral innate immunity; immune evasion; paramyxoviruses.

FIGURE 1

Common Structure and accessory proteins of paramyxoviruses. The common structure of paramyxoviruses (Left). The potential accessory proteins are encoded by paramyxoviruses (Right).

FIGURE 2

Paramyxoviruses accessory proteins-mediated evasion of the PRR-mediated antiviral innate immunity. PRRs, such as TLRs, and RLRs, could recognize pathogen-associated molecular patterns. TLR3/7/9 locate at endosomes. They sense viral RNA and signal through TRIF or MyD88 to activate IRFs and NF-κB. RIG-I and MDA5 recognize viral RNA and signal through MAVS to activate IRF3 and NF-κB. The NLRP3-mediated inflammasome pathway operates as a platform for the maturation of IL-1β and IL-18. Paramyxoviruses accessory proteins can hijack multiple steps in the PRR-mediated antiviral innate immunity. The V proteins of MeV, NiV, PIV5, PPRV, RPV, and SeV could inhibit RIG-I, and the V proteins of BeiPV, BPIV3, CDV, HPIV2, JPV, MeV, MuV, NiV, PIV5, PPRV, RPV, and SeV could inhibit MDA5. The V proteins of MeV and PIV5 could inhibit LGP2, and the V proteins of HeV, MeV, MuV, NDV, NiV, PIV5, and SeV could inhibit MAVS. The V proteins of HPIV2, MuV, and PIV5 could inhibit TBK1, the V and W proteins of NiV could inhibit IKKε. The PPRV P protein could inhibit TBK1-IRF3 interaction and the V proteins of MeV, NDV, and SeV could inhibit IRF3. The HPIV1 C protein could prevent the phosphorylation of IRF3. The P, V, and C proteins of MeV could inhibit p65. The NiV W protein could inhibit TLR3 and the HPIV2 V protein could inhibit TRAF6 and caspase1, respectively. The C proteins of BPIV3, MeV, NiV, and SeV could inhibit IKKα, the V proteins of MeV, NiV, and SeV could inhibit IRF7. The V proteins of MeV and SeV could inhibit NLRP3. Red solid lines indicate confirmed interactions between adaptors and accessory proteins, and red dashed lines indicate uncertain interactions or unknown underlying mechanisms; P, phosphate.

FIGURE 3

Paramyxoviruses accessory proteins-mediated evasion of the IFNAR-JAK-STAT signaling pathway. Following the binding of cytokines to the specific receptors, STATs are activated by members of the JAK family. Then they dimerize and translocate to the nucleus and regulate the expression of target genes, including ISGs. Accessory proteins from paramyxoviruses interact with adaptors to block the signal transduction, and some accessory proteins directly target ISGs to evade the innate immune responses. The V proteins of CDV, HeV, HPIV2, MeV, MuV, NiV, PIV5, PPRV, RPV, and SeV could inhibit STAT1/STAT2 mediated signaling pathways. The SeV C protein could inhibit IFNAR2, and the V proteins of MeV, NiV, PIV5, and SeV could inhibit TRIM25. The HPIV2 V protein could inhibit tetherin, the C proteins of MeV or SeV, and the MeV V protein could inhibit PKR. The PIV5 P and V proteins could inhibit the activation of PKR. Red solid lines indicate confirmed interactions between adaptors and accessory proteins, and red dashed lines indicate uncertain interactions or unknown underlying mechanisms; P, phosphate.

FIGURE 4

Paramyxoviruses accessory proteins-mediated evasion of apoptosis, autophagy, and SGs. Paramyxoviruses infection could induce other immune responses, including apoptosis, autophagy, and SGs to restrict viral replication. However, these immune responses can be manipulated by paramyxoviruses accessory proteins. The V proteins of NDV could inhibit apoptosis by interacting with CacyBP/SIP, TXNL1, or MSI1. The P protein of MeV could inhibit apoptosis with unknown mechanisms, and the MeV V protein could inhibit p73. The MuV V and PIV5 V protein could inhibit caspase 9 and caspase 12, respectively. The HPIV2 V protein could inhibit FTH1. The P protein of HPIV3 could inhibit autophagy through interacting with SNAP29. The P protein of HPIV3 and MeV C protein could inhibit stress granules (SG). Red solid lines indicate confirmed interactions between adaptors and accessory proteins, and red dashed lines indicate uncertain interactions or unknown underlying mechanisms; P, phosphate.