Abstract
Exacerbated and persistent innate immune response marked by pro-inflammatory cytokine expression is thought to be a major driver of chronic COVID-19 pathology. Although macrophages are not the primary target cells of SARS-CoV-2 infection in humans, viral RNA and antigens in activated monocytes and macrophages have been detected in post-mortem samples, and dysfunctional monocytes and macrophages have been hypothesized to contribute to a protracted hyper-inflammatory state in COVID-19 patients. In this study, we demonstrate that CD169, a myeloid cell specific I-type lectin, facilitated ACE2-independent SARS-CoV-2 fusion and entry in macrophages. CD169-mediated SARS-CoV-2 entry in macrophages resulted in expression of viral genomic and subgenomic RNAs with minimal viral protein expression and no infectious viral particle release, suggesting a post-entry restriction of the SARS-CoV-2 replication cycle. Intriguingly this post-entry replication block was alleviated by exogenous ACE2 expression in macrophages. Restricted expression of viral genomic and subgenomic RNA in CD169+ macrophages elicited a pro-inflammatory cytokine expression (TNFα, IL-6 and IL-1β) in a RIG-I, MDA-5 and MAVS-dependent manner, which was suppressed by remdesivir treatment. These findings suggest that de novo expression of SARS-CoV-2 RNA in macrophages contributes to the pro-inflammatory cytokine signature and that blocking CD169-mediated ACE2 independent infection and subsequent activation of macrophages by viral RNA might alleviate COVID-19-associated hyperinflammatory response.
【초록키워드】 Treatment, SARS-CoV-2, Macrophage, ACE2, innate immune response, macrophages, IL-6, SARS-COV-2 infection, Infection, Remdesivir, Antigen, monocyte, RNA, Replication, humans, subgenomic RNA, RIG-I, Post-mortem, Viral RNA, genomic, expression, COVID-19 patients, CD169, IL-1β, Activation, Viral protein, SARS-CoV-2 entry, TNFα, pro-inflammatory cytokine, COVID-19 pathology, de novo, viral particle, myeloid cell, Hyperinflammatory, independent, MDA-5, thought, subsequent, activated, facilitated, contribute, suppressed, elicited, primary target cell, alleviate, CD169+ macrophage, exogenous ACE2, expression of SARS-CoV-2, Restricted, the SARS-CoV-2, 【제목키워드】 Macrophage, SARS-COV-2 infection, pro-inflammatory response, induce,