Innate Immunity Evasion Strategies of Highly Pathogenic Coronaviruses: SARS-CoV, MERS-CoV, and SARS-CoV-2

Abstract

In the past two decades, coronavirus (CoV) has emerged frequently in the population. Three CoVs (SARS-CoV, MERS-CoV, SARS-CoV-2) have been identified as highly pathogenic human coronaviruses (HP-hCoVs). Particularly, the ongoing COVID-19 pandemic caused by SARS-CoV-2 warns that HP-hCoVs present a high risk to human health. Like other viruses, HP-hCoVs interact with their host cells in sophisticated manners for infection and pathogenesis. Here, we reviewed the current knowledge about the interference of HP-hCoVs in multiple cellular processes and their impacts on viral infection. HP-hCoVs employed various strategies to suppress and evade from immune response, including shielding viral RNA from recognition by pattern recognition receptors (PRRs), impairing IFN-I production, blocking the downstream pathways of IFN-I, and other evasion strategies. This summary provides a comprehensive view of the interplay between HP-hCoVs and the host cells, which is helpful to understand the mechanism of viral pathogenesis and develop antiviral therapies.

Keywords: IFN signaling pathway; SARS-CoV-2; highly pathogenic coronaviruses; host–virus interaction; innate immunity.

FIGURE 1

Genome organization of SARS-CoV-2, SARS-CoV, and MERS-CoV. The common trait is that their genomes encode two replicase polypeptides pp1a and pp1b translated from ORF1a and ORF1b. The polypeptides undergo a series of proteolytic cleavages to form 16 non-structural proteins encoded by the first two-thirds of the genome. The remaining one-third 3′ region of the viral genome encodes viral structural proteins [spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins] and virus-specific accessory proteins. Accessory proteins are interspersed within these structural proteins. Some proteins can inhibit innate immune responses by employing a variety of tactics. Their locations are indicated with specific-colored spheres. The different colored spheres represent the different immune evasive strategies. Each virus-encoded multifunctional protein, employing multiple different activities to suppress innate immunity responses.

FIGURE 2

IFN-mediated antiviral responses. (A) SARS-CoV and SARS-CoV-2 use the same receptor ACE2 for host cellular entry, while MERS-CoV utilizes DPP4 for host cellular entry. They are most likely recognized by PRRs, including cytoplasmic RIG-I and MDA5 and by endosomal TLR3 and TLR7. RIG-I/MDA5 conveys signal through a mitochondrial adaptor MAVS, while TLR signals through TRIF/MyD88. Subsequently, activating the shared downstream kinases and transcription factors. Both pathways can activate the key transcription factors (IRF3 and NF-κB) phosphorylation and subsequent dimerization, which are translocated into the nucleus to promote IFN-I expression. (B) IFNs bind to the heterodimeric receptor complexes IFNAR1/IFNAR2, initiating JAK/STAT signaling. Receptor-associated tyrosine kinases Jak1 and Tyk2 are triggered for self-phosphorylation and activation, leading to the phosphorylation of STATs. Phosphorylated STAT1/2 with IRF9 forms a complex ternary ISGF3 (STAT1/STAT2/IRF9), which translocates into the nucleus and binds to IFN-stimulated response elements (ISREs), promoting the transcription of hundreds of IFN-stimulated genes (ISGs). ACE2, angiotensin-converting enzyme 2; DPP4, dipeptidyl peptidase 4; DMVs, double-membraned vesicles; RIG-1, retinoic acid-inducible gene I; MDA5, melanoma differentiation-associated protein 5; MyD88, myeloid differentiation primary response 88; TRIF, TIR-domain-containing adapter-inducing IFN-β; MAVS, mitochondria antiviral signaling protein; PACT, protein activator of protein kinase R; Iκβα, inhibitor of NF-κB; IRF3, interferon regulatory factor 3; TBK1, TANK-binding kinase 1; IKKε, I-kappa-B kinase ε; Nup93, nuclear pore complex protein 93; KPNA4, karyopherin-α4; KPNA2, karyopherin-α2; ISGF3, IFN-stimulated gene factor 3; IFNAR1, interferon-alpha/beta receptor alpha chain KPNA2, karyopherin-α2; ISG, interferon gene expression; JAK/STAT, Janus kinases/signal transducer and activator transcription proteins.

FIGURE 3

The major immune evasive strategies by HP-hCoVs as discussed in this review. The CoV-encoded proteins inhibit multiple aspects of the host innate immune signaling from sustaining viral replication and propagation. Different colors represent the proteins encoded by different viruses. Green represents SARS-CoV-2 encoded proteins, orange represents SARS-CoV encoded proteins, blue represents MERS-CoV encoded proteins, and black represents their common proteins. Virus antagonistic tactics are shown with black lines and arrows. (A) HP-hCoVs uses multiple gene products to impair IFN induction. To shield viral RNA (ssRNA and dsRNA) from recognition by PRRs, CoV replication takes place and DMVs are formed by NSP3, NSP4, and NSP6. In addition, NSP10, NSP13, NSP14, and NSP16 can modify the 5′-cap structure of viral RNA to mask viral PAMPs. HP-hCoVs interfere with the transmission of signals at almost every step. HP-hCoV N proteins interact with TRIM25, interfering with RIG-I signaling. MERS-CoV 4a and SARS-CoV N associate with PACT, sequestering the association of PACT and RIG-I/MDA5. SARS-CoV-2 NSP8 interacts with MDA5 to interfere with IFN induction. SARS-CoV-2 N is reported to associate with RIG-I, MDA5, and MAVS. SARS-CoV-2 and SARS-CoV M proteins are reported to associate with multiple adapters (not shown). SARS-CoV-2 and SARS-CoV 9b proteins interact with human TOM70 to block signaling downstream of MAVS. MERS-CoV ORF4b could specifically interact with TBK1 and IKKε, thereby blocking IRF3 phosphorylation. In addition, MERS-CoV ORF4b can associate karyopherin-α4 (KPNA4), out-competing NF-κB for KPNA4 binding and suppressing NF-κB nuclear transport. SARS-CoV NSP3 binds to IRF3 and inhibits the degradation of IκBα. SARS-CoV-2 NSP3 can cleave IRF3 directly. HP-hCoV NSP1 efficiently interferes with the cellular translation machinery. SARS-CoV-2 NSP16 disrupts mRNA splicing. SARS-CoV-2 NSP8 and NSP9 interfere with host protein trafficking. (B) HP-hCoVs use multiple gene products to impair IFN signaling. SARS-CoV 3a and SARS-CoV-2 NSP14 can degrade IFNAR1. SARS-CoV and SARS-CoV-2 ORF6 bind directly to Nup98 and Rae1 to prevent bidirectional nucleocytoplasmic transport. SARS-CoV ORF6 associates karyopherin-α2 (KPNA2), retaining KPNA2 in the cytoplasm and suppressing STAT1 nuclear import. SARS-CoV-2 NSP6, NSP13, NSP14, 3a, M, 7a, 7b, and N protein inhibit the phosphorylation of STAT1. HP-hCoV NSP1 inhibits the phosphorylation of STAT.