Dicoumarol is an effective post-exposure prophylactic for SARS-CoV-2 Omicron infection in human airway epithelium.

Repurposing existing drugs to inhibit SARS-CoV-2 infection in airway epithelial cells (AECs) is a quick way to find novel treatments for COVID-19. Computational screening has found dicoumarol (DCM), a natural anticoagulant, to be a potential SARS-CoV-2 inhibitor, but its inhibitory effects and possible working mechanisms remain unknown. Using air-liquid interface culture of primary human AECs, we demonstrated that DCM has potent antiviral activity against the infection of multiple Omicron variants (including BA.1, BQ.1 and XBB.1). Time-of-addition and drug withdrawal assays revealed that early treatment (continuously incubated after viral absorption) of DCM could markedly inhibit Omicron replication in AECs, but DCM did not affect the absorption, exocytosis and spread of viruses or directly eliminate viruses. Mechanistically, we performed single-cell sequencing analysis (a database of 77,969 cells from different airway locations from 10 healthy volunteers) and immunofluorescence staining, and showed that the expression of NAD(P)H quinone oxidoreductase 1 (NQO1), one of the known DCM targets, was predominantly localised in ciliated AECs. We further found that the NQO1 expression level was positively correlated with both the disease severity of COVID-19 patients and virus copy levels in cultured AECs. In addition, DCM treatment downregulated NQO1 expression and disrupted signalling pathways associated with SARS-CoV-2 disease outcomes (e.g., Endocytosis and COVID-19 signalling pathways) in cultured AECs. Collectively, we demonstrated that DCM is an effective post-exposure prophylactic for SARS-CoV-2 infection in the human AECs, and these findings could help physicians formulate novel treatment strategies for COVID-19.

Multi-omics evaluation of SARS-CoV-2 infected mouse lungs reveals dynamics of host responses.

The outbreak of Coronavirus disease 2019 (COVID-19) throughout the world has caused millions of death, while the dynamics of host responses and the underlying regulation mechanisms during SARS-CoV-2 infection are not well depicted. Lung tissues from a mouse model sensitized to SARS-CoV-2 infection were serially collected at different time points for evaluation of transcriptome, proteome, and phosphoproteome. We showed the ebb and flow of several host responses in the lung across the viral infection. The signaling pathways and kinases regulating networks were alternated at different phases of infection. This multiplex evaluation also revealed that many kinases of the CDK and MAPK family were interactive and served as functional hubs in mediating the signal transduction during SARS-CoV-2 infection. Our study not only revealed the dynamics of lung pathophysiology and their underlying molecular mechanisms during SARS-CoV-2 infection, but also highlighted some molecules and signaling pathways that might guide future investigations on COVID-19 therapies.

Virus infection induced pulmonary fibrosis.

Pulmonary fibrosis is the end stage of a broad range of heterogeneous interstitial lung diseases and more than 200 factors contribute to it. In recent years, the relationship between virus infection and pulmonary fibrosis is getting more and more attention, especially after the outbreak of SARS-CoV-2 in 2019, however, the mechanisms underlying the virus-induced pulmonary fibrosis are not fully understood. Here, we review the relationship between pulmonary fibrosis and several viruses such as Human T-cell leukemia virus (HTLV), Human immunodeficiency virus (HIV), Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Murine γ-herpesvirus 68 (MHV-68), Influenza virus, Avian influenza virus, Middle East Respiratory Syndrome (MERS)-CoV, Severe acute respiratory syndrome (SARS)-CoV and SARS-CoV-2 as well as the mechanisms underlying the virus infection induced pulmonary fibrosis. This may shed new light on the potential targets for anti-fibrotic therapy to treat pulmonary fibrosis induced by viruses including SARS-CoV-2.

Abnormal Airway Mucus Secretion Induced by Virus Infection.

The airway mucus barrier is a primary defensive layer at the airway surface. Mucins are the major structural components of airway mucus that protect the respiratory tract. Respiratory viruses invade human airways and often induce abnormal mucin overproduction and airway mucus secretion, leading to airway obstruction and disease. The mechanism underlying the virus-induced abnormal airway mucus secretion has not been fully studied so far. Understanding the mechanisms by which viruses induce airway mucus hypersecretion may open new avenues to treatment. In this article, we elaborate the clinical and experimental evidence that respiratory viruses cause abnormal airway mucus secretion, review the underlying mechanisms, and also discuss the current research advance as well as potential strategies to treat the abnormal airway mucus secretion caused by SARS-CoV-2.