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Review
. 2013 May 12;2(2):57-70.
doi: 10.5501/wjv.v2.i2.57.

Paramyxovirus evasion of innate immunity: Diverse strategies for common targets

Michelle D Audsley  1 , Gregory W Moseley
Affiliations
Review

Paramyxovirus evasion of innate immunity: Diverse strategies for common targets

Michelle D Audsley et al. World J Virol. .

Abstract

The paramyxoviruses are a family of > 30 viruses that variously infect humans, other mammals and fish to cause diverse outcomes, ranging from asymptomatic to lethal disease, with the zoonotic paramyxoviruses Nipah and Hendra showing up to 70% case-fatality rate in humans. The capacity to evade host immunity is central to viral infection, and paramyxoviruses have evolved multiple strategies to overcome the host interferon (IFN)-mediated innate immune response through the activity of their IFN-antagonist proteins. Although paramyxovirus IFN antagonists generally target common factors of the IFN system, including melanoma differentiation associated factor 5, retinoic acid-inducible gene-I, signal transducers and activators of transcription (STAT)1 and STAT2, and IFN regulatory factor 3, the mechanisms of antagonism show remarkable diversity between different genera and even individual members of the same genus; the reasons for this diversity, however, are not currently understood. Here, we review the IFN antagonism strategies of paramyxoviruses, highlighting mechanistic differences observed between individual species and genera. We also discuss potential sources of this diversity, including biological differences in the host and/or tissue specificity of different paramyxoviruses, and potential effects of experimental approaches that have largely relied on in vitro systems. Importantly, recent studies using recombinant virus systems and animal infection models are beginning to clarify the importance of certain mechanisms of IFN antagonism to in vivo infections, providing important indications not only of their critical importance to virulence, but also of their potential targeting for new therapeutic/vaccine approaches.

Keywords: Innate immunity; Melanoma differentiation associated factor 5; Paramyxoviridae; Retinoic acid-inducible gene-I; Signal transducers and activators of transcription 1; Signal transducers and activators of transcription 2.

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Figures

Figure 1
Figure 1
Coding strategies of paramyxovirus P genes. A: Genome organisation of the Paramyxovirinae subfamily; B: Paramyxoviruses express multiple proteins from the P gene through RNA editing to insert additional non-coded G nucleotides into P gene transcripts at the editing site (indicated), causing a frameshift in the downstream open reading frame (ORF) to generate distinct C-termini. Editing strategies of the 5 best-studied genera are shown, with proteins produced from unedited (+0), or edited (+1 or +2 frameshift) mRNA indicated below the P gene. Several members of the henipavirus, respirovirus and morbillivirus genera, but not the rubulaviruses or avulaviruses, produce one or more C proteins by translation from internal start codon(s) in alternate ORF(s) (indicated as a white bar above the P gene).
Figure 2
Figure 2
Conserved residues in the paramyxovirus V C-terminal domain. Paramyxovirus V protein C-terminal sequences are aligned with identical and similar residues highlighted. Asterisks indicate absolutely conserved histidine and cysteine residues involved in zinc-binding (see text for details). Residue numbers are indicated in the sequence titles. MuV: Mumps virus; PIV5: Parainfluenza virus 5; hPIV: Human PIV; MPRV: Mapuera virus; PoRV: Porcine rubulavirus; SeV: Sendai virus; MeV: Measles virus; CDV: Canine distemper virus; RPV: Rinderpest virus; PDV: Phocine distemper virus; NDV: Newcastle disease virus; APMV2: Avian paramyxovirus 2; HeV: Hendra virus; NiV: Nipah virus; ASPV: Atlantic Salmon Paramyxovirus; FDLV: Fer-de-Lance virus; SalV: Salem virus; MoV: Mossman virus; MenV: Menangle virus; PPV-1: Pigeon paramyxovirus 1; BeV: Beilong virus; J-V: J-virus; TioV: Tioman virus; NarPV: Nariva virus.
Figure 3
Figure 3
Type I interferon induction is inhibited by paramyxovirus interferon-antagonist proteins at multiple stages. Pathogen-associated molecular patterns (PAMPs) generated during virus infection, such as dsRNA, are recognised by PRRs including endosomal/surface expressed Toll-like receptor 3 (TLR3) and cytoplasmic retinoic acid-inducible gene-I (RIG-I)/melanoma differentiation associated protein 5 (MDA5). TLR3 signals through the adaptor molecule Toll/interleukin-1 receptor domain-containing adaptor inducing interferon (IFN)β (TRIF), which recruits tumor necrosis factor receptor-associated factor (TRAF)2 to activate the inhibitor of nuclear factor κB (NF-κB) kinase (IKK)α/β kinases to phosphorylate inhibitory inhibitor of NF-κB (IκB), triggering its degradation and activation/nuclear translocation of NF-κB. TLR3 signalling via TRAF3 results in phosphorylation/activation of IFN regulatory factor (IRF)-3, causing its homodimerisation, or heterodimerisation with IRF-7 in professional IFN producing/IFN-primed cells, and translocation into the nucleus where, with NF-κB and activating transcription factor 2 (ATF2)/c-jun (not shown), it activates early type I IFN transcription. RIG-I and MDA5 also induce phosphorylation of IRF-3 following recognition of cytoplasmic PAMPs in infected cells via interaction with the mitochondrial membrane protein IFNβ promoter stimulator 1 (IPS-1), which recruits and activates TANK and the TANK-binding kinases (TBKs). TBK-1 and IKKε via the E3 ubiquitin ligase TRAF3. Many paramyxoviruses target this pathway; steps commonly targeted are indicated (black bars) with specific examples of the paramyxovirus proteins responsible (see text for details). DC: Dendritic cell; PIV5: Parainfluenza virus 5; MeV: Measles virus; MuV: Mumps virus; SeV: Sendai virus; hPIV: Human PIV; HeV: Hendra virus; NiV: Nipah virus; SalV: Salem virus; TioV: Tioman virus; NDV: Newcastle disease virus; MPRV: Mapuera virus; MenV: Menangle virus; PoRV: Porcine rubulavirus; LGP2: Laboratory of genetics and physiology 2.
Figure 4
Figure 4
Interferon signalling pathways are targeted by paramyxovirus interferon-antagonist proteins through diverse mechanisms. Interferon (IFN)β binds to type I IFN receptor subunits IFNα/β receptor (IFNAR)1 and IFNAR2, causing dimerization, activation and phosphorylation of the receptor-associated kinases Janus kinase 1 (JAK1) and tyrosine kinase 2 (Tyk2), to create docking sites for the SH2 domains of signal transducers and activators of transcription (STAT)1 and 2. STAT1 and 2 are phosphorylated by Tyk2 and JAK1 respectively, and form a heterodimer that translocates into the nucleus, forming the heterotrimeric transcription factor complex IFN-stimulated gene factor 3 (ISGF3) with IFN regulatory factor (IRF)-9. ISGF3 binding to IFN stimulatory response element (ISRE) sequences in the promoters of hundreds of IFN-stimulated genes (ISGs) activates the transcription of antiviral and immune-modulatory proteins to establish an antiviral state in infected and neighbouring cells, and contribute to shaping the adaptive immune response. STAT1 and/or STAT2 are targeted by almost all paramyxoviruses through the activity of several IFN antagonists by mechanisms that are reported to differ significantly; mechanisms and specific viral proteins responsible are indicated (see text for details). HeV: Hendra virus; NiV: Nipah virus; MuV: Mumps virus; RPV: Rinderpest virus; MeV: Measles virus; PIV5: Parainfluenza virus 5; NDV: Newcastle disease virus; hPIV: Human PIV; CDV: Canine distemper virus; MPRV: Mapuera virus.
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