Efficient immune responses against viral infection are determined by sufficient activation of nucleic acid sensor-mediated innate immunity 1,2 . Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains an ongoing global pandemic. It is an urgent challenge to clarify the innate recognition mechanism to control this virus. Here we show that retinoic acid-inducible gene-I (RIG-I) sufficiently restrains SARS-CoV-2 replication in human lung cells in a type I/III interferon (IFN)-independent manner. RIG-I recognizes the 3′ untranslated region of the SARS-CoV-2 RNA genome via the helicase domains, but not the C-terminal domain. This new mode of RIG-I recognition does not stimulate its ATPase, thereby aborting the activation of the conventional mitochondrial antiviral-signaling protein-dependent pathways, which is in accordance with lack of cytokine induction. Nevertheless, the interaction of RIG-I with the viral genome directly abrogates viral RNA-dependent RNA polymerase mediation of the first step of replication. Consistently, genetic ablation of RIG-I allows lung cells to produce viral particles that expressed the viral spike protein. By contrast, the anti-SARS-CoV-2 activity was restored by all-trans retinoic acid treatment through upregulation of RIG-I protein expression in primary lung cells derived from patients with chronic obstructive pulmonary disease. Thus, our findings demonstrate the distinctive role of RIG-I as a restraining factor in the early phase of SARS-CoV-2 infection in human lung cells.More than 140 million people around the world have been affected by coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2. COVID-19 varies from mild to severe, life-threatening respiratory infection with coagulopathy. Most (81%) people infected with SARS-CoV-2 show a mild and self-limited course 3 , while severe cases of disease are more likely to be present in older patients with underlying comorbidities, such as chronic obstructive pulmonary disease (COPD) 4-6 , compared to patients with mild disease. But even young healthy adults sometimes experience severe illness. Conversely, it has been reported that nearly 40-45% of patients with SARS-CoV-2 infections are asymptomatic 7 . The wide spectrum of clinical manifestations of COVID-19 suggests that individual immune responses to the underlying pathogen may play some crucial role in determining the clinical course. Currently, no efficient therapies and preventive measures exist for COVID-19, thus studies about host immune response against SARS-CoV-2 infection are required for a better understanding of the pathological processes for the rational development of countermeasures to control SARS-CoV-2 infection. There is also an urgent need to identify biomarkers that can predict which patients will deteriorate.Microbial invasion in our body is sensed by pattern-recognition receptors (PRRs) that are present in most types of cells, which initiate the activation of cell-intrinsic defense and innate immune responses. During ...

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