Hippo Signaling Pathway Activation during SARS-CoV-2 Infection Contributes to Host Antiviral Response (preprint)

SARS-CoV-2, responsible for the COVID-19 pandemic, causes respiratory failure and damage to multiple organ systems. The emergence of viral variants poses a risk of vaccine failures and prolongation of the pandemic. However, our understanding of the molecular basis of SARS-CoV-2 infection and subsequent COVID-19 pathophysiology is limited. In this study, we have uncovered a critical role for the evolutionarily conserved Hippo signaling pathway in COVID-19 pathogenesis. Given the complexity of COVID-19 associated cell injury and immunopathogenesis processes, we investigated Hippo pathway dynamics in SARS-CoV-2 infection by utilizing COVID-19 lung samples, and human cell models based on pluripotent stem cell-derived cardiomyocytes (PSC-CMs) and human primary lung air-liquid interface (ALI) cultures. SARS-CoV-2 infection caused activation of the Hippo signaling pathway in COVID-19 lung and in vitro cultures. Both parental and Delta variant of concern (VOC) strains induced Hippo pathway. The chemical inhibition and gene knockdown of upstream kinases MST1/2 and LATS1 resulted in significantly enhanced SARS-CoV-2 replication, indicating antiviral roles. Verteporfin a pharmacological inhibitor of the Hippo pathway downstream transactivator, YAP, significantly reduced virus replication. These results delineate a direct antiviral role for Hippo signaling in SARS-CoV-2 infection and the potential for this pathway to be pharmacologically targeted to treat COVID-19.

Dynamic Public Health Interventions Consistent With the Development of COVID-19 Epidemic: The Targeted Prevention and Control Guidelines in Mainland, China (preprint)

Background: This study aims to describe the dynamic characteristics of COVID-19 transmission and the public health interventions in three phases in mainland, China.Methods: The number of daily reported new confirmed cases, severe cases and asymptomatic infected cases from Jan 10 to Jul 10 was analyzed. We calculated the effective reproduction number (Rt) to reflect the dynamic characteristics of epidemic transmission and intervention effect. According to the overall guidelines for prevention and control, we divided the past six months into three phases and summarized the features of main public health interventions in each phase.Results: The daily confirmed cases and severe cases of COVID-19 mainly concentrated in the first phase and the maximum Rt reached 10.75 (95%CI: 10.26-11.24). With the society-wide efforts and joint prevention and control strategy, Rt began to decline below 1.0 from Feb 19. In the second phase, the occurrence of imported infected cases caused small fluctuations. The preventive strategy, preventing both imported cases and local spread of epidemic, was mainly taken. In the third phase, the government adopted policies to prevent imported cases and domestic re-infections, responding to the regular epidemic prevention demands. Conclusion: Social isolation, wearing masks, digital management based on community and area hierarchical control were effective public health interventions in consistent with the development of COVID-19 epidemic. The targeted dynamic interventions in different phases could provide reference for other countries and regions to deal with COVID-19.

Host susceptibility to severe COVID-19: a retrospective analysis of 487 case outside Wuhan (preprint)

Background: The recent outbreak of SARS-CoV-2 infection results in a considerable morbidity and mortality, mainly in China. The study is to investigate the intrinstic features of infected patients that associated with severe type of this disease. Method: A total of 487 laboratory-confirmed COVID-19 patients were included in analysis. The demographic and epidemiological of patients representing as mild and severe at admission were compared. A step-wise multivariate logistic regression analysis were performed to identify significant risk factors associated with severe COVID-19 . A score systemc incorporating risk factors was established for risk stratification and validated in a small cohort during in-hospital follow-up. Results: Of all patients, 49 (10.1%) cases are severe at admission. Severe cases are elder [56(17) vs. 45(19), P<0.001), with more male (73.5% vs. 50.9%, P=0.003). They have a higher incidence of hypertension (53.1% vs. 16.7%, P<0.001), diabetes (14.3% vs. 5.0%, P=0.009), cardiovascular diseases (8.2% vs. 1.6%, P=0.003) and malignancy (4.1% vs. 0.7%, P=0.025), and less exposure to epidemic area (49.0% vs. 65.1%, P=0.027), but more infected familiy members(P=0.031). On multivariate analysis, elder age, male and presence of hypertension are independently associated with severe disease at admission. A host risk score, incorporating age, sex and hypertension history, clearly stratifies risk of developing severe type of COVID-19 both in patients at admission and during in-hospital follow-up. Conclusions: Elder age, male and presence of hypertension are associated with host susceptibility to developing severe COVID-19. The host risk score may be a useful tool to identify high risk indiviuals but requires validation.