An Update on Innate Immune Responses during SARS-CoV-2 Infection

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the Coronaviridae family, which is responsible for the COVID-19 pandemic followed by unprecedented global societal and economic disruptive impact. The innate immune system is the body's first line of defense against invading pathogens and is induced by a variety of cellular receptors that sense viral components. However, various strategies are exploited by SARS-CoV-2 to disrupt the antiviral innate immune responses. Innate immune dysfunction is characterized by the weak generation of type I interferons (IFNs) and the hypersecretion of pro-inflammatory cytokines, leading to mortality and organ injury in patients with COVID-19. This review summarizes the existing understanding of the mutual effects between SARS-CoV-2 and the type I IFN (IFN-α/β) responses, emphasizing the relationship between host innate immune signaling and viral proteases with an insight on tackling potential therapeutic targets.

Keywords: SARS-CoV-2; innate immune response; type I interferons.

Figure 1

The SARS-CoV-2 lifecycle. (a–d), SARS-CoV-2 enters through membrane fusion and uncoating. The SARS-CoV-2 S protein combines with the ACE2 and TMPRSS2 to release RNA (b), and the genome RNA is translated into viral proteins (c). (d–g), these proteins will produce a viral replicase transcriptase complex to produce additional RNA (d). Subgenomic RNA transcription leads to the production of structural proteins and accessory proteins, which are translocated to endoplasmic reticulum (ER) membranes and go through the ER-Golgi intermediate compartment (ERGIC) to assemble a virus to produce new SARS-CoV-2 (e) and then will be released by exocytosis (f,g). ssRNA: single-stranded RNA; ACE2: angiotensin-converting enzyme 2; TMPRSS2: transmembrane serine protease 2; ORF1ab: open reading frame 1ab; ER: endoplasmic reticulum; ERGIC: ER-Golgi intermediate compartment.

Figure 2

The predictive model describing the innate immune responses to SARS-CoV-2. There is a simplified figure of the type I IFNs responses after sensing SARS-CoV-2. It has been suggested SARS-CoV-2 escape type I IFNs signaling pathway and ISGs by targeting type I IFNs signaling. Viral proteins with type I IFNs inhibitory activities are highlighted in red. RIG-I: retinoic-acid inducible gene I; MDA5: melanoma differentiation-associated gene 5; MAVS: mitochondrial antiviral signaling protein; nsp1: non-structural protein; TOM70: translocases of outer membrane 70; NLRP3: NLR family pyrin domain-containing 3; ASC: apoptosis-associated speck-like protein containing a CARD; pro-IL-18: pro-interleukin (IL)-18; TLR3: Toll-like receptors 3; TRIF: TIR domain-containing adaptor inducing interferon-β; TRAF3: tumour necrosis factor receptor-associated factor 3; TBK1: TANK-binding kinase 1; IKKε: inhibitor of κ-B kinase ε; IκBs: inhibitor κB; NF-κB: nuclear factor κB; IRF3: IFN regulatory factor 3; MyD88: myeloid differentiation primary response 88; IRAK3: interleukin-1-receptor-associated kinase 3; IFNAR1: IFN receptor type I; JAK1: Janus-activated kinase 1; TYK2: tyrosine kinase 2; STAT1: signal transducer and activator of transcription 1; ISGs: interferon-stimulated genes.