ABSTRACT
As an enveloped virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delivers its viral genome into host cells via fusion of the viral and cell membranes. Here, we show that ANO6/TMEM16F-mediated cell surface exposure of phosphatidylserine is critical for SARS-CoV-2 entry and that ANO6-selective inhibitors are effective against SARS-CoV-2 infections. Application of the SARS-CoV-2 Spike pseudotyped virus (SARS2-PsV) evokes a cytosolic Ca2+ elevation and ANO6-dependent phosphatidylserine externalization in ACE2/TMPRSS2-positive mammalian cells. A high-throughput screening of drug-like chemical libraries identifies three different structural classes of chemicals showing ANO6 inhibitory effects. Among them, A6-001 displays the highest potency and ANO6 selectivity and it inhibits the single-round infection of SARS2-PsV in ACE2/TMPRSS2-positive HEK 293T cells. More importantly, A6-001 strongly inhibits authentic SARS-CoV-2-induced phosphatidylserine scrambling and SARS-CoV-2 viral replications in Vero, Calu-3, and primarily cultured human nasal epithelial cells. These results provide mechanistic insights into the viral entry process and offer a potential target for pharmacological intervention to protect against coronavirus disease 2019 (COVID-19).
Subject(s)
COVID-19 Drug Treatment , Angiotensin-Converting Enzyme 2 , Animals , Anoctamins , Humans , Mammals/metabolism , Phosphatidylserines , Phospholipid Transfer Proteins/metabolism , SARS-CoV-2 , Virus InternalizationABSTRACT
Experiences of infectious diseases cause stressful and traumatic life events, hence, coronavirus disease 2019 (COVID-19) patients could suffer from various mental health problems requiring psychological support services. This study investigates the severity of mental health problems among confirmed COVID-19 patients. From March to November 2020, we collected the data from 118 COVID-19 patients who voluntarily participated in the National Center for Disaster Trauma's online mental health assessment consisting of self-report scales like Primary Care of Posttraumatic Stress Disorder screen (PC-PTSD), Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Patient Health Questionnaire-15 (PHQ-15), and P4 Suicidality Screener. For control, 116 other disaster-experienced and 386 non-COVID-19-experienced participants were recruited. The COVID-19 patients showed more severe symptoms including post-traumatic symptoms, depression, anxiety, and somatic symptoms than control groups across all four screening scales (p < 0.001). Regarding high-risk, COVID-19 patients had an increased association with high-risk compared to the comparison groups (PC-PTSD: OR = 24.16, 95% CI = 13.52-43.16 p < 0.001; PHQ-9: OR = 14.45, 95% CI = 8.29-25.19, p < 0.001; GAD-7: OR=20.71, 95% CI = 10.74-39.96, p < 0.001; PHQ-15: OR = 5.65, 95% CI = 3.44-9.25, p < 0.001; P4: OR = 14.67, 95% CI = 8.95-25.07, p < 0.001). This study's results imply that there is a high-risk of overall mental health problems, especially stronger associations of post-traumatic stress symptoms, in COVID-19 patients. These findings help inform practitioners about the psychological responses to COVID-19 experiences and to prepare appropriate interventions and services for the incremental number of confirmed cases.