Viral pathogen-induced mechanisms to antagonize mammalian interferon (IFN) signaling pathway

Abstract

Antiviral responses of interferons (IFNs) are crucial in the host immune response, playing a relevant role in controlling viralw infections. Three types of IFNs, type I (IFN-α, IFN-β), II (IFN-γ) and III (IFN-λ), are classified according to their receptor usage, mode of induction, biological activity and amino acid sequence. Here, we provide a comprehensive review of type I IFN responses and different mechanisms that viruses employ to circumvent this response. In the first part, we will give an overview of the different induction and signaling cascades induced in the cell by IFN-I after virus encounter. Next, highlights of some of the mechanisms used by viruses to counteract the IFN induction will be described. And finally, we will address different mechanism used by viruses to interference with the IFN signaling cascade and the blockade of IFN induced antiviral activities.

Keywords: Antiviral responses; IFN-I pathway; Viral evasion mechanisms.

Fig. 1

IFN-I induction and viral counteracting actions. Viral motifs (e.g. dsRNA), are recognized by PPRs. This leads to the activation of adaptor proteins such as NFκB, TBK-1, IKKε and AP-1. TBK-1 and IKKε phosphorylate IRF3, which translocate to the nucleus and induce IFN-I expression. In a second IFN signaling wave, IRF7 is phosphorylated and translocated to the nucleus, creating an amplification loop of IFN-I induction. Several viruses have developed mechanisms to block several steps of this IFN induction cascade, indicated in red blades in the figure

Fig. 2

Type I IFN signaling and viral countermeasures. IFN binds to the receptor IFNAR and triggers a signaling cascade that is summarized in this figure. Viruses has developed strategies to counteract different steps on this signaling cascade. It is marked in red blades the main signaling targets of viruses

Fig. 3

Viral interference with accessory cellular components involved in PRR activation. MeV can interfere with RLR activation by targeting the phosphatase PP1 using 2 distinct mechanisms. MeV V protein can interact with PP1 to prevent the dephosphorylation of MDA-5 required for activation. MeV can interact on the cell surface with the C-lectin receptor DC-SIGN which results in the association of PP1-inhibitor 1 with PP1 thus preventing RLR dephosphorylation. Ebola virus VP35 protein, MERS-CoV 4a protein and arenavirus NP can interfere with PACT binding to dsRNA, a mechanism that potentiates RLR activation. RLR ubiquitination is also essential for adequate activation and transport to MAVS for subsequent IFN signaling events to take place. Riplet and TRIM25 are critical to RIG-I ubiquitination. IAV-NS1 and Denv sfRNA can interfere with TRIM25 activity, whereas Hepatitis C NS3-4A protease can cleave Riplet to impair RIG-I ubiquitination. The mitochondrial-targeting chaperone 14-3-3ε is responsible for RIG-I translocation to the mitochondrial membrane. DenV NS3 protein targets 14-3-3ε using a phosphomimetic domain that displaces activated RIG-I from this chaperone. WNV NS3 possesses a similar domain