Suppression of ACE2 SUMOylation protects against SARS-CoV-2 infection through TOLLIP-mediated selective autophagy.

In addition to investigating the virology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), discovering the host-virus dependencies are essential to identify and design effective antiviral therapy strategy. Here, we report that the SARS-CoV-2 entry receptor, ACE2, conjugates with small ubiquitin-like modifier 3 (SUMO3) and provide evidence indicating that prevention of ACE2 SUMOylation can block SARS-CoV-2 infection. E3 SUMO ligase PIAS4 prompts the SUMOylation and stabilization of ACE2, whereas deSUMOylation enzyme SENP3 reverses this process. Conjugation of SUMO3 with ACE2 at lysine (K) 187 hampers the K48-linked ubiquitination of ACE2, thus suppressing its subsequent cargo receptor TOLLIP-dependent autophagic degradation. TOLLIP deficiency results in the stabilization of ACE2 and elevated SARS-CoV-2 infection. In conclusion, our findings suggest selective autophagic degradation of ACE2 orchestrated by SUMOylation and ubiquitination as a potential way to combat SARS-CoV-2 infection.

SARS-CoV-2 infection activates a subset of intrinsic pathways to inhibit type I interferons in vitro and in vivo.

SARS-CoV-2 infection poses a global challenge to human health. Upon viral infection, host cells initiate the innate antiviral response, which primarily involves type I interferons (I-IFNs), to enable rapid elimination of the invading virus. Previous studies revealed that SARS-CoV-2 infection limits the expression of I-IFNs in vitro and in vivo, but the underlying mechanism remains incompletely elucidated. In the present study, we performed data mining and longitudinal data analysis using SARS-CoV-2-infected normal human bronchial epithelial (NHBE) cells and ferrets, and the results confirmed the strong inhibitory effect of SARS-CoV-2 on the induction of I-IFNs. Moreover, we identified genes that are negatively correlated with IFNB1 expression in vitro and in vivo based on Pearson correlation analysis. We found that SARS-CoV-2 activates numerous intrinsic pathways, such as the circadian rhythm, phosphatidylinositol signaling system, peroxisome, and TNF signaling pathways, to inhibit I-IFNs. These intrinsic inhibitory pathways jointly facilitate the successful immune evasion of SARS-CoV-2. Our study elucidates the underlying mechanism by which SARS-CoV-2 evades the host innate antiviral response in vitro and in vivo, providing theoretical evidence for targeting these immune evasion-associated pathways to combat SARS-CoV-2 infection.

Prevalence and risk factors of disability and anxiety in a retrospective cohort of 432 survivors of Coronavirus Disease-2019 (Covid-19) from China.

OBJECTIVE: To estimate the prevalence of disability and anxiety in Covid-19 survivors at discharge from hospital and analyze relative risk by exposures. DESIGN: Multi-center retrospective cohort study. SETTING: Twenty-eight hospitals located in eight provinces of China. METHODS: A total of 432 survivors with laboratory-confirmed SARS CoV-2 infection participated in this study. At discharge, we assessed instrumental activities of daily living (IADL) with Lawton's IADL scale, dependence in activities of daily living (ADL) with the Barthel Index, and anxiety with Zung's self-reported anxiety scale. Exposures included comorbidity, smoking, setting (Hubei vs. others), disease severity, symptoms, and length of hospital stay. Other risk factors considered were age, gender, and ethnicity (Han vs. Tibetan). RESULTS: Prevalence of at least one IADL problem was 36.81% (95% CI: 32.39-41.46). ADL dependence was present in 16.44% (95% CI: 13.23-20.23) and 28.70% (95% CI: 24.63-33.15) were screened positive for clinical anxiety. Adjusted risk ratio (RR) of IADL limitations (RR 2.48, 95% CI: 1.80-3.40), ADL dependence (RR 2.07, 95% CI 1.15-3.76), and probable clinical anxiety (RR 2.53, 95% CI 1.69-3.79) were consistently elevated in survivors with severe Covid-19. Age was an additional independent risk factor for IADL limitations and ADL dependence; and setting (Hubei) for IADL limitations and anxiety. Tibetan ethnicity was a protective factor for anxiety but a risk factor for IADL limitations. CONCLUSION: A significant proportion of Covid-19 survivors had disability and anxiety at discharge from hospital. Health systems need to be prepared for an additional burden resulting from rehabilitation needs of Covid-19 survivors.

Potential Effect of COVID-19 on Maternal and Infant Outcome: Lesson From SARS.

The coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is highly infectious and its ongoing outbreak has been declared a global pandemic by the WHO. Pregnant women are susceptible to respiratory pathogens and the development of severe pneumonia, suggesting the urgent need to assess the potential maternal and infant outcome of pregnancy with COVID-19. The intrauterine vertical transmission potential of SARS-CoV-2 also remains controversial. Herein, we discuss the potential effect of COVID-19 on maternal and infant outcomes based on current studies, including those published in Chinese, in a total of 80 mothers with COVID-19 and 80 infants. We also comprehensively explored the mother-to-child transmission routes of SARS-CoV-2, in particular the route of intrauterine vertical transmission. Given SARS-CoV-2 is a sister to SARS-CoV, of the SARS-related coronavirus species, we made a comprehensive comparison between them to learn from experiences with SARS. Although there is no evidence supporting the intrauterine vertical transmission of SARS-CoV-2, our comprehensive analysis suggests that the adverse maternal and infant outcomes caused by COVID-19 cannot be underestimated. Further, we speculated that the inconsistency between nucleic acids and serological characteristics IgM to SARS-CoV-2 of infants' specimens may be caused by the disruption of the amniotic barrier by the inflammatory factors induced by SARS-CoV-2 infection. Our review is beneficial to understand the effect of SARS-CoV-2 on maternal and infant outcomes.

Progress in the Research and Development of Anti-COVID-19 Drugs.

The outbreaks of COVID-19 due to SARS-CoV-2 has caused serious physical and psychological damage to global human health. COVID-19 spread rapidly around the world in a short time. Confronted with such a highly infectious respiratory disease, the research and development of anti-COVID-19 drugs became an urgent work due to the lack of specific drugs for the treatment of COVID-19. Nevertheless, several existing drugs are available to relieve the clinical symptoms of COVID-19. We reviewed information on selected anti-SARS-CoV-2 candidate therapeutic agents published until June 2, 2020. We also discussed the strategies of the development of anti-COVID-19 drugs in the future. Our review provides a novel insight into the future development of a safer, efficient, and toxic-less anti-COVID-19 drug.

A comprehensive investigation of the mRNA and protein level of ACE2, the putative receptor of SARS-CoV-2, in human tissues and blood cells.

The outbreak of pneumonia caused by SARS-CoV-2 posed a great threat to global human health, which urgently requires us to understand comprehensively the mechanism of SARS-CoV-2 infection. Angiotensin-converting enzyme 2 (ACE2) was identified as a functional receptor for SARS-CoV-2, distribution of which may indicate the risk of different human organs vulnerable to SARS-CoV-2 infection. Previous studies investigating the distribution of ACE2 mRNA in human tissues only involved a limited size of the samples and a lack of determination for ACE2 protein. Given the heterogeneity among humans, the datasets covering more tissues with a larger size of samples should be analyzed. Indeed, ACE2 is a membrane and secreted protein, while the expression of ACE2 in blood and common blood cells remains unknown. Herein, the proteomic data in HIPED and the antibody-based immunochemistry result in HPA were collected to analyze the distribution of ACE2 protein in human tissues. The bulk RNA-seq profiles from three separate public datasets including HPA tissue Atlas, GTEx, and FANTOM5 CAGE were also obtained to determine the expression of ACE2 in human tissues. Moreover, the abundance of ACE2 in human blood and blood cells was determined by analyzing the data in the PeptideAtlas and the HPA Blood Atlas. We found that the mRNA expression cannot reflect the abundance of ACE2 factor due to the strong differences between mRNA and protein quantities of ACE2 within and across tissues. Our results suggested that ACE2 protein is mainly expressed in the small intestine, kidney, gallbladder, and testis, while the abundance of which in brain-associated tissues and blood common cells is low. HIPED revealed enrichment of ACE2 protein in the placenta and ovary despite a low mRNA level. Further, human secretome shows that the average concentration of ACE2 protein in the plasma of males is higher than those in females. Our research will be beneficial for understanding the transmission routes and sex-based differences in susceptibility of SARS-CoV-2 infection.