Type I and III interferon responses in SARS-CoV-2 infection

Abstract

Coronavirus disease 2019 (COVID-19), the current pandemic disease, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Type I and III interferons (IFNs) are innate cytokines that are important in the first-line defense against viruses. Similar to many other viruses, SARS-CoV-2 has evolved mechanisms for evading the antiviral effects of type I and III IFNs at multiple levels, including the induction of IFN expression and cellular responses to IFNs. In this review, we describe the innate sensing mechanisms of SARS-CoV-2 and the mechanisms used by SARS-CoV-2 to evade type I and III IFN responses. We also discuss contradictory reports regarding impaired and robust type I IFN responses in patients with severe COVID-19. Finally, we discuss how delayed but exaggerated type I IFN responses can exacerbate inflammation and contribute to the severe progression of COVID-19.

Fig. 1. The receptors and downstream signaling pathways of type I, type II, and type III interferons (IFNs).

Type I and type III IFNs bind to the heterodimeric receptor complexes IFNAR1/IFNAR2 and IFNLR1/IL-10Rβ, respectively. Upon IFN binding, the receptor-associated kinases JAK1 and TYK2 phosphorylate STAT1 and STAT2. Together with IRF9, phosphorylated STAT1 and STAT2 form a trimeric complex called IFN-stimulated gene factor 3 (ISGF3). ISGF3 subsequently enters the nucleus and binds IFN-stimulated response elements (ISREs) to promote the transcription of hundreds of IFN-stimulated genes (ISGs). Type II IFN binds to the receptor complex composed of IFNGR1 and IFNGR2 and promotes the phosphorylation of STAT1 via JAK1 and JAK2. Phosphorylated STAT1 forms homodimers, which bind gamma-activated sequences (GASs) in the nucleus and induce proinflammatory gene expression. Unlike type III IFNs, type I IFNs can also signal via STAT1 homodimers and promote proinflammatory gene expression.

Fig. 2. The sensing of SARS-CoV-2 by innate immune receptors and signaling pathways leading to the production of type I and type III interferons.

The viral RNA genome and replication intermediates of SARS-CoV-2 can be sensed by Toll-like receptors (TLR3 and TLR7) and cytosolic RNA sensors (RIG-I and MDA-5). RNA-bound receptors induce the activation of the transcription factors NFκB and IRF3/IRF7 via the TRAF6/IKKα/β/γ and TRAF3-TBK1/IKKε pathways, respectively, and promote the expression of type I and type III interferons (IFNs).

Fig. 3. Hypothesis of how delayed but exaggerated type I IFN responses are involved in hyperinflammation and contribute to the severe progression of COVID-19.

After respiratory epithelial cells are infected (a), SARS-CoV-2 proteins block type I and III interferon (IFN) responses (b). The viral load increases (c) and uninfected innate immune cells, such as monocytes, macrophages, and dendritic cells, are stimulated by viral components via Toll-like receptors and produce type I and III IFNs (d). Type I and III IFNs further induce the accumulation and activation of monocytes and macrophages, leading to the production of large amounts of IFNs and proinflammatory cytokines (e). Type I IFNs also enhance TNF-mediated inflammation by disrupting TNF-induced tolerance to TLR stimulation in monocytes and macrophages.