Innate immune evasion strategies of influenza viruses

Abstract

Influenza viruses are globally important human respiratory pathogens. These viruses cause seasonal epidemics and occasional worldwide pandemics, both of which can vary significantly in disease severity. The virulence of a particular influenza virus strain is partly determined by its success in circumventing the host immune response. This article briefly reviews the innate mechanisms that host cells have evolved to resist virus infection, and outlines the plethora of strategies that influenza viruses have developed in order to counteract such powerful defences. The molecular details of this virus-host interplay are summarized, and the ways in which research in this area is being applied to the rational design of protective vaccines and novel antivirals are discussed.

Figure 1. Retinoic acid-inducible gene-I-mediated type I interferon pathway and its regulation during influenza A virus infection

(A–E) Critical checkpoints. (A) Virus replication produces triphosphorylated vRNA and potentially dsRNA byproducts that are pathogen-associated molecular patterns recognized by cytoplasmic RIG-I. (B) NS1 regulates the activation of RIG-I by binding to and sequestering dsRNA and/or by interaction with RIG-I. Formation of viral RNP complexes may also contribute to ‘hiding’ pathogen-associated molecular patterns from RIG-I. (C) Binding of NS1 to TRIM25 prevents essential ubiquitination of RIG-I. (D) Cap-snatching activity of the viral polymerase complex may reduce the pool of host antiviral mRNAs available for nuclear export and translation. The NS1 protein also directly inhibits global cellular pre-mRNA processing by binding to host CPSF30. (E) NS1 binds to components of the nuclear pore complex and inhibits nuclear export of cellular mRNA. CPSF30: 30-kDa cleavage and polyadenylation specificity factor; IRF: Interferon regulatory factor; MAVS: Mitochondrial antiviral signaling adaptor; NEMO: NF-κB essential modulator; NS1: Nonstructural protein 1; PPP: Triphosphate; RIG: Retinoic acid-inducible gene; RIP: Receptor-interacting protein; RNP: Ribonucleoprotein; TANK: TRAF family member-associated NF-κB activator; TRAF: TNF-receptor-associated factor; TRIM: Tripartite motif; Ub: Ubiquitin.

Figure 2. Type I interferon receptor signaling pathway and expression of interferon-stimulated genes

Binding of IFN-α/β to the IFN receptor stimulates the phosphorylation of STAT1 and STAT2. Phosphorylated STAT1 and 2 associate with IRF-9 to form the transcription factor ISGF3, which relocalizes to the nucleus and stimulates the transcription of ISGs whose promoters contain IFN-stimulated response elements. Although IFN stimulates the transcription of more than 300 ISGs, only the antiviral functions of a small percentage have been well characterized. Notable examples of IFN-induced antiviral effectors and their regulation by influenza viruses are indicated. See text for further details. A/NS1: Influenza A virus NS1 protein; B/NS1: Influenza B virus NS1 protein; IFN: Interferon; IRF: IFN regulatory factor; ISG: IFN-stimulated gene; MxA: Myxovirus resistance gene A; NP: Nucleocapsid protein; NS1: Nonstructural protein 1; OAS: 2′-5′ oligoadenylate synthetase; SOCS: Suppressor of cytokine signaling.

Figure 3. Potential multifunctional antiviral target on the influenza A virus NS1 protein

(A) Surface representation of an NS1 ED monomer (dark gray) in complex with a fragment of CPSF30 (light gray, cartoon ribbon representation). Aromatic residues of CPSF30 that dock into the NS1 hydrophobic pocket [109] are highlighted as sticks. (B) Surface representation of NS1 ED in complex with a fragment of NS1, as seen in helix–helix dimeric conformations of NS1 [181,183]. Tryptophan-187 of the neighboring NS1 monomer docks into the same hydrophobic pocket as that required for CPSF30-binding. Images were prepared using MacPyMol (Protein Data Bank files: 2RHK & 3EE9). CPSF30: 30-kDa cleavage and polyadenylation specificity factor; ED: Effector domain; NS1: Nonstructural protein 1.