Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can induce acute inflammatory response like acute lung inflammation (ALI) or acute respiratory distress syndrome, leading to severe progression and mortality. Therapeutics for treatment of SARS-CoV-2-triggered respiratory inflammation are urgent to be discovered. Our previous study shows that Salvianolic acid C potently inhibits SARS-CoV-2 infection. In this study, we investigated the antiviral effects of a Salvia miltiorrhiza compound, Danshensu, in vitro and in vivo, including the mechanism of S protein-mediated virus attachment and entry into target cells. In authentic and pseudo-typed virus assays in vitro, Danshensu displayed a potent antiviral activity against SARS-CoV-2 with EC50 of 0.97 μM, and potently inhibited the entry of SARS-CoV-2 S protein-pseudo-typed virus (SARS-CoV-2 S) into ACE2-overexpressed HEK-293T cells (IC50 = 0.31 μM) and Vero-E6 cell (IC50 = 4.97 μM). Mice received SARS-CoV-2 S via trachea to induce ALI, while the VSV-G treated mice served as controls. The mice were administered Danshensu (25, 50, 100 mg/kg, i.v., once) or Danshensu (25, 50, 100 mg·kg-1·d-1, oral administration, for 7 days) before SARS-CoV-2 S infection. We showed that SARS-CoV-2 S infection induced severe inflammatory cell infiltration, severely damaged lung tissue structure, highly expressed levels of inflammatory cytokines, and activated TLR4 and hyperphosphorylation of the NF-κB p65; the high expression of angiotensinogen (AGT) and low expression of ACE2 at the mRNA level in the lung tissue were also observed. Both oral and intravenous pretreatment with Danshensu dose-dependently alleviated the pathological alterations in mice infected with SARS-CoV-2 S. This study not only establishes a mouse model of pseudo-typed SARS-CoV-2 (SARS-CoV-2 S) induced ALI, but also demonstrates that Danshensu is a potential treatment for COVID-19 patients to inhibit the lung inflammatory response.
【초록키워드】 Treatment, SARS-CoV-2, ACE2, coronavirus, Mortality, Therapeutics, TLR4, SARS-COV-2 infection, Infection, progression, in vitro, antiviral activity, virus, Antiviral effect, mice, Inflammatory cytokines, in vivo, expression, mechanism, NF-κB, acute respiratory distress, administration, Potential treatment, AGT, COVID-19 patient, intravenous, target cells, acute respiratory syndrome, alteration, low expression, syndrome, lung tissue, SARS-CoV-2 S, respiratory inflammation, mRNA level, EC50, lung inflammatory response, inflammatory cell infiltration, Administered, VERO-E6, controls, Cell, acute inflammatory response, acute lung inflammation, investigated, inhibit, inhibited, treated, activated, expressed, induce, damaged, entry of SARS-CoV-2, HEK-293T cell, infected with SARS-CoV-2, Salvia miltiorrhiza, virus assay, VSV-G, 【제목키워드】 SARS-CoV-2, acute lung inflammation, alleviate,