Abstract
Human cells respond to infection by SARS-CoV-2, the virus that causes COVID-19, by producing cytokines including type I and III interferons (IFNs) and proinflammatory factors such as IL6 and TNF. IFNs can limit SARS-CoV-2 replication but cytokine imbalance contributes to severe COVID-19. We studied how cells detect SARS-CoV-2 infection. We report that the cytosolic RNA sensor MDA5 was required for type I and III IFN induction in the lung cancer cell line Calu-3 upon SARS-CoV-2 infection. Type I and III IFN induction further required MAVS and IRF3. In contrast, induction of IL6 and TNF was independent of the MDA5-MAVS-IRF3 axis in this setting. We further found that SARS-CoV-2 infection inhibited the ability of cells to respond to IFNs. In sum, we identified MDA5 as a cellular sensor for SARS-CoV-2 infection that induced type I and III IFNs.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and is causing an ongoing global pandemic
Calu-3 cells expressed many of the proteins required for the major signalling pathways activated during viral infection: cGAMP synthase (cGAS) and stimulator of interferon genes (STING) (DNA sensing); retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated protein 5 (MDA5) and mitochondrial antiviral-signalling protein (MAVS) (RNA sensing); the Toll-like receptor (TLR) adaptor MyD88; the kinase TANK-binding kinase 1 (TBK1); and the transcription factors interferon regulatory factor 3 (IRF3) and STAT1/2 (Fig. 1B)
It has recently been suggested that high baseline levels of RIG-I present in cells such as A549 prevent SARSCoV-2 replication[24]
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and is causing an ongoing global pandemic. The main replication sites of SARS-CoV-2 in patients are the upper and lower respiratory tract, where the virus infects airway and alveolar epithelial cells, vascular endothelial cells, and alveolar macrophages[11] Uncovering how these cells detect SARS-CoV-2 infection to produce type I and III IFNs and other pro-inflammatory cytokines is of great importance to understanding the pathology of COVID-19. In some infections with RNA viruses such as Dengue virus, the cytosolic DNA sensing pathway involving cGAMP synthase (cGAS) and stimulator of interferon genes (STING) detects mitochondrial DNA leaked from damaged mitochondria and thereby contributes to IFN induction[17,18] Whether this happens during coronavirus infection is unknown. We further show that expression of the ISG MxA is mainly induced in bystander non-infected cells in this system
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