Interferons and viruses: an evolutionary arms race of molecular interactions

Abstract

Over half a century has passed since interferons (IFNs) were discovered and shown to inhibit virus infection in cultured cells. Since then, researchers have steadily brought to light the molecular details of IFN signaling, catalogued their pleiotropic effects on cells, and harnessed their therapeutic potential for a variety of maladies. While advances have been plentiful, several fundamental questions have yet to be answered and much complexity remains to be unraveled. We explore the current knowledge surrounding four main questions: are type I IFN subtypes differentially produced in response to distinct pathogens? How are IFN subtypes distinguished by cells? What are the mechanisms and consequences of viral antagonism? Lastly, how can the IFN response be harnessed to improve vaccine efficacy?

Keywords: innate immunity; interferon subtype; interferons; vaccine adjuvants.; viral antagonism; viruses.

Figure 1

Human interferon (IFN) proteins. Unrooted phylogenetic tree of human IFN proteins: types I, II, and III. Type I IFN, green; type II IFN, red; type III IFN, blue. The scale bar indicates amino acid substitutions per site. The tree was generated using Geneious software [157].

Figure 2

Interferon (IFN) signaling via the JAK–STAT pathway. Once type I or III IFNs engage their cognate receptors at the cell surface, individual receptor chains are brought into close proximity. As a result, intracellular receptor-associated tyrosine kinases of the Janus kinase (JAK) family of proteins are juxtaposed and become activated. Activated JAK proteins subsequently phosphorylate (P) members of the signal transducer and activator of transcription (STAT) family of proteins, ultimately leading to the transcriptional activation of IFN-stimulated genes (ISGs). Inasmuch as is currently known, after receptor engagement, type I and III IFNs signal through the same pathway: activation of the two JAK proteins, JAK1 and TYK2, results in the phosphorylation of conserved tyrosine residues on STAT1 and STAT2, followed by formation of a heterotrimeric complex with IFN-regulatory factor 9 (IRF9). This complex, referred to as IFN-stimulated gene factor 3 (ISGF3), translocates to the nucleus and binds to a DNA sequence known as the IFN-stimulated response element (ISRE) in the promoters of ISGs. As a result, hundreds of ISGs are transcriptionally regulated. In addition to stimulating transcription of numerous genes, IFN signaling also leads to the transcriptional repression of a variety of genes; however, the underlying mechanisms and outcomes are comparatively underexplored (reviewed in [188]). Abbreviations: GAF, γ-interferon activation factor; GAS, γ-interferon activation site.

Figure 3

Genome organization and coding capacity of paramyxoviruses based on Respiroviruses. (A) General genome organization of paramyxoviruses. Abbreviations: F, fusion protein; H/HN/G, hemagglutinin/hemagglutinin-neuraminidase/glycoprotein (depending on virus); L, RNA-dependent RNA polymerase; M, matrix protein; N/NP, nucleocapsid protein; P/V/C, phosphoprotein and accessory proteins. (B) Coding capacity of the P/V/C gene of Respiroviruses. The P/V/C gene encodes multiple proteins by means of initiation of translation from an internal open reading frame (ORF), generating 4 C proteins (C1-4), and by means of co-transcriptional pseudo-templated G nucleotide insertion editing. Additional non-coded G nucleotides are inserted at the indicated RNA editing site causing a +1 or +2 frameshift, which results in the V and W/D proteins, respectively. The full-length P protein and the edited V and W/D proteins share the N-terminal region but have distinct C termini.

Figure 4

Induction of interferon (IFN) and its antagonism by viral proteins. The nucleotidyltransferase cyclic GMP-AMP (cGAMP) synthase (cGAS) detects viral DNAs while the RNA helicases retinoic acid-inducible gene 1 (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) detect viral RNAs. These recognized pathogen-associated molecular patterns (PAMP) initiate a signaling cascade that results in the activation of transcription factors to promote the induction of IFN-α/β. Binding of viral double-stranded (ds) DNA to cGAS stimulates the synthesis of cGAMP, which binds directly to the endoplasmic reticulum (ER)-located stimulator of IFN genes (STING). Upon activation, STING stimulates TANK-binding kinase 1 (TBK1) activity to phosphorylate IFN regulatory factor (IRF)3. Binding of viral single-stranded (ss)- and dsRNA stimulates ATPase activity in RIG-I-like receptors (RLRs – RIG-I, MDA5) and triggers major conformational changes, allowing their homodimerization. Upon homodimerization, RIG-I and MDA5 interact with the downstream adaptor protein mitochondrial antiviral-signaling protein (MAVS), which leads eventually to the activation of IRF3 via IκB kinase ε (IKKε) and TBK1. The activation of IRF3 due to viral DNAs and RNAs, together with IRF7 and nuclear factor κB (NF-κB), is required for transcriptional induction of the IFN-β promoter. Viral antagonist proteins disturb the signaling pathway at multiple sites with diverse mechanisms as indicated. Abbreviations: AdV, adenovirus; EBV, Epstein–Barr virus; HAV, hepatitis A virus; HBV, hepatitis B virus; HCMV, human cytomegalovirus; HCV, hepatitis C virus; hPIV2, human parainfluenza virus 2; HPV-16, human papilloma virus 16; IAV, influenza A virus; ICP0, infected-cell polypeptide 0; IκB, inhibitor of κB; KSHV, Kaposi’s sarcoma-associated herpesvirus; LANA-1, latency-associated nuclear antigen; LGP2, Laboratory of Genetics and Physiology 2; MeV, measles virus; MuV, mumps virus; NiV, Nipah virus; NS1, non-structural protein 1; NS3-4A, non-structural protein 3-4A; P, phosphorylation; PIV5, parainfluenza virus 5; pp65, phosphoprotein 65; Riplet, RING finger protein 135; SeV, Sendai virus; TRIM25, tripartite motif-containing protein 25, Ub, ubiquitination.

Figure 5

Type I and III interferon (IFN) signaling and its antagonism by viral proteins. Binding of type I IFN to the IFN receptor subunits IFNα/β receptor (IFNAR)1 and IFNAR2 leads to their dimerization and activates its receptor-associated kinases tyrosine kinase 2 (TYK2) and Janus kinase 1 (JAK1). TYK2 phosphorylates IFNAR1 and enables binding of signal transducer and activator of transcription (STAT)2. STAT2 is subsequently phosphorylated (P) by TYK2 whereas STAT1 is phosphorylated by JAK1. Binding of type III IFN to the IFN-λ receptor subunits (IFNLR)1 and interleukin (IL)10 receptor (IL10R)2 leads to their dimerization, activation of the receptor kinases TYK2 and JAK1, and subsequent phosphorylation of STAT1 and STAT2. Phosphorylated STAT1 and STAT2 form a stable heterodimer, which binds to the DNA-binding subunit IFN regulatory factor (IRF) 9. This newly formed trimeric complex IFN-stimulated gene factor 3 (ISGF3) translocates into the nucleus, binds to IFN-stimulatory response elements (ISREs), and acts as an enhancer at the 5′-regulatory regions of many IFN-responsive gene promoters. STAT3 is involved in type II IFN and IL-6 cytokine signaling (pathways not shown). Viral antagonist proteins interfere with the signal transduction at multiple sites and diverse mechanisms as indicated. Abbreviations: AdV: adenovirus; DENV: dengue virus; EBOV: Ebola virus; EBV: Epstein–Barr virus; HCMV: human cytomegalovirus; hPIV2: human parainfluenza virus 2; HPV-16/18: human papilloma virus 16/18; LMP-1: latent membrane protein 1; MARV: Marburg virus; MeV: measles virus; MuV: mumps virus; NS5: non-structural protein 5; PIV5: parainfluenza virus 5; VP24: minor viral matrix protein; VP40: viral matrix protein.