Containment of SARS-CoV-2 Delta strain in Guangzhou, China by quarantine and social distancing: a modelling study.

China detected the first case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with Delta variant in May 2021. We assessed control strategies against this variant of concern. We constructed a robust transmission model to assess the effectiveness of interventions against the Delta variant in Guangzhou with initial quarantine/isolation, followed by social distancing. We also assessed the effectiveness of alternative strategies and that against potentially more infectious variants. The effective reproduction number (Rt) fell below 1 when the average daily number of close contacts was reduced to ≤ 7 and quarantine/isolation was implemented on average at the same day of symptom onset in Guangzhou. Simulations showed that the outbreak could still be contained when quarantine is implemented on average 1 day after symptom onset while the average daily number of close contacts was reduced to ≤ 9 per person one week after the outbreak's beginning. Early quarantine and reduction of close contacts were found to be important for containment of the outbreaks. Early implementation of quarantine/isolation along with social distancing measures could effectively suppress spread of the Delta and more infectious variants.

A Mouse-Adapted Model of HCoV-OC43 and Its Usage to the Evaluation of Antiviral Drugs.

The human coronavirus OC43 (HCoV-OC43) is one of the most common causes of common cold but can lead to fatal pneumonia in children and elderly. However, the available animal models of HCoV-OC43 did not show respiratory symptoms that are insufficient to assist in screening antiviral agents for respiratory diseases. In this study, we adapted the HCoV-OC43 VR-1558 strain by serial passage in suckling C57BL/6 mice and the resulting mouse-adapted virus at passage 9 (P9) contained 8 coding mutations in polyprotein 1ab, spike (S) protein, and nucleocapsid (N) protein. Pups infected with the P9 virus significantly lost body weight and died within 5 dpi. In cerebral and pulmonary tissues, the P9 virus replication induced the production of G-CSF, IFN-γ, IL-6, CXCL1, MCP-1, MIP-1α, RANTES, IP-10, MIP-1ß, and TNF-α, as well as pathological alterations including reduction of neuronal cells and typical symptoms of viral pneumonia. We found that the treatment of arbidol hydrochloride (ARB) or Qingwenjiere Mixture (QJM) efficiently improved the symptoms and decreased n gene expression, inflammatory response, and pathological changes. Furthermore, treating with QJM or ARB raised the P9-infected mice's survival rate within a 15 day observation period. These findings suggested that the new mouse-adapted HCoV-OC43 model is applicable and reproducible for antiviral studies of HCoV-OC43.

Broad antiviral and anti-inflammatory activity of Qingwenjiere mixture against SARS-CoV-2 and other human coronavirus infections.

BACKGROUND: Qingwenjiere Mixture (QJM) is a traditional Chinese medicine (TCM) that has been shown to have remarkable clinical efficacy against COVID-19. However, little is known about the antiviral and anti-inflammatory activities of QJM against a wider range of human coronavirus (HCoV) strains. PURPOSE: The study aims to investigate the antiviral and anti-inflammatory activities of QJM, as well as the underlying mechanisms against HCoV infections. METHODS: The chemical compositions from QJM were analyzed by LC-MS. The inhibitory effect of QJM on infections of HCoV-OC43, HCoV-229E, HCoV-NL63, and SARS-CoV-2 was evaluated in HRT-18 cells, Huh7 cells, LLC-MK2 cells, and Vero-E6 cells, respectively, by using cytopathic effect (CPE) inhibition assay or RT-qPCR detection of viral n, s, or RdRp/Hel genes. The expression of pro-inflammatory cytokines induced by HCoV-OC43, HCoV-229E, and SARS-CoV-2, as well as the host ace2 gene was also determined by RT-qPCR assay. Furthermore, the expression of key molecules in the NF-κB/MAPKs signaling pathways was determined by western blot. RESULTS: In alcohol-extraction groups of QJM and reference decoction pieces, 53 similar ion peaks were identified, the majority of which were phenylpropanoids, iridoids, and flavonoids. In addition, QJM reduced CPE caused by HCoVs and the expression of viral n genes or N protein. Pretreatment with QJM also exerted inhibitory effect on viral n gene expression. QJM also inhibited the expression of RdRp/Hel and s genes of SARS-CoV-2, as well as the host ace2 gene. Besides, QJM markedly reduced virus-induced mRNA expression of a panel of pro-inflammatory cytokines, such as IL-6, CXCL-8/IL-8, CXCL-10/IP-10, CCL-5/RANTES, TNF-α, IFN-α, CCL-2/MCP-1, CXCL-9/MIG, and IL1-α. We further showed that QJM inhibited the phosphorylation of NF-κB p65, and JNK, ERK 1/2, and p38 MAPKs in HCoV-OC43-infected HRT-18 cells. CONCLUSIONS: QJM has broad antiviral and anti-inflammatory activity against both common and newly emerged HCoVs possibly by inhibiting the activation of key components in NF-κB/MAPKs signaling pathway. QJM also has a prevention effect against HCoV infections and inhibits the host receptor required for virus entry. These results indicate that QJM may have the therapeutic potential in the treatment of diseases caused by a broad range of HCoVs.

ß-sitosterol ameliorates influenza A virus-induced proinflammatory response and acute lung injury in mice by disrupting the cross-talk between RIG-I and IFN/STAT signaling.

ß-Sitosterol (24-ethyl-5-cholestene-3-ol) is a common phytosterol Chinese medical plants that has been shown to possess antioxidant and anti-inflammatory activity. In this study we investigated the effects of ß-sitosterol on influenza virus-induced inflammation and acute lung injury and the molecular mechanisms. We demonstrate that ß-sitosterol (150-450 µg/mL) dose-dependently suppresses inflammatory response through NF-κB and p38 mitogen-activated protein kinase (MAPK) signaling in influenza A virus (IAV)-infected cells, which was accompanied by decreased induction of interferons (IFNs) (including Type I and III IFN). Furthermore, we revealed that the anti-inflammatory effect of ß-sitosterol resulted from its inhibitory effect on retinoic acid-inducible gene I (RIG-I) signaling, led to decreased STAT1 signaling, thus affecting the transcriptional activity of ISGF3 (interferon-stimulated gene factor 3) complexes and resulting in abrogation of the IAV-induced proinflammatory amplification effect in IFN-sensitized cells. Moreover, ß-sitosterol treatment attenuated RIG-I-mediated apoptotic injury of alveolar epithelial cells (AEC) via downregulation of pro-apoptotic factors. In a mouse model of influenza, pre-administration of ß-sitosterol (50, 200 mg·kg-1·d-1, i.g., for 2 days) dose-dependently ameliorated IAV-mediated recruitment of pathogenic cytotoxic T cells and immune dysregulation. In addition, pre-administration of ß-sitosterol protected mice from lethal IAV infection. Our data suggest that ß-sitosterol blocks the immune response mediated by RIG-I signaling and deleterious IFN production, providing a potential benefit for the treatment of influenza.