Ubiquitination of SARS-CoV-2 ORF7a Prevents Cell Death Induced by Recruiting BclXL To Activate ER Stress.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which has emerged in the last 2 years. The accessory protein ORF7a has been proposed as an immunomodulating factor that can cause dramatic inflammatory responses, but it is unknown how ORF7a interacts with host cells. We show that ORF7a induces cell apoptosis by recruiting the prosurvival factor BclXL to the endoplasmic reticulum (ER) via the exposed C-terminal residues Lys117 and Lys119. Simultaneously, ORF7a activates ER stress via the PERK-elF2α-CHOP pathway and inhibits the expression of endogenous BclXL, resulting in enhanced cell apoptosis. Ubiquitination of ORF7a interrupts the interaction with BclXL in the ER and weakens the activation of ER stress, which to some extent rescues the cells. Our work demonstrates that SARS-CoV-2 ORF7a hires antiapoptosis protein and aggregates on the ER, resulting in ER stress and apoptosis initiation. On the other hand, ORF7a utilizes the ubiquitin system to impede and escape host elimination, providing a promising potential target for developing strategies for minimizing the COVID-19 pandemic. IMPORTANCE Viruses struggle to reproduce after infecting cells, and the host eliminates infected cells through apoptosis to prevent virus spread. Cells adopt a special ubiquitination code to protect against viral infection, while ORF7a manipulates and exploits the ubiquitin system to eliminate host cells' effect on apoptosis and redirect cellular pathways in favor of virus survival. Our results revealed that SARS-CoV-2-encoded accessory protein ORF7a recruits prosurvival factor BclXL to the ER and activates the cellular ER stress response resulting in the initiation of programmed death to remove virus-infected cells. Ubiquitination of ORF7a blocked the recruitment of BclXL and suppressed the ER stress response, which helps to counteract cell apoptosis and rescue cell fate. These findings help us understand the mechanism of SARS-CoV-2 invasion and contribute to a theoretical foundation for the clinical prevention of COVID-19.

The research progress and function of SARS-CoV-2 accessory protein ORF8

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a genome similar to that of the SARSCoV, which has been circulating since 2002 and encodes multiple viral proteins. The accessory protein ORF8 has low sequence homology with SARS-CoV ORF8, and has characteristics of rapid evolution and mutation. It has functions of inhibiting type I interferon and down-regulating the expression of major histocompatibility complex I (MHC I). This paper reviews the structure and function of accessory protein ORF8 and the diagnostic and therapeutic prospects for COVID-19.

Host adaptation of codon usage in SARS-CoV-2 from mammals indicates potential natural selection and viral fitness.

SARS-CoV-2 infection, which is the cause of the COVID-19 pandemic, has expanded across various animal hosts, and the virus can be transmitted particularly efficiently in minks. It is still not clear how SARS-CoV-2 is selected and evolves in its hosts, or how mutations affect viral fitness. In this report, sequences of SARS-CoV-2 isolated from human and animal hosts were analyzed, and the binding energy and capacity of the spike protein to bind human ACE2 and the mink receptor were compared. Codon adaptation index (CAI) analysis indicated the optimization of viral codons in some animals such as bats and minks, and a neutrality plot demonstrated that natural selection had a greater influence on some SARS-CoV-2 sequences than mutational pressure. Molecular dynamics simulation results showed that the mutations Y453F and N501T in mink SARS-CoV-2 could enhance the binding of the viral spike to the mink receptor, indicating the involvement of these mutations in natural selection and viral fitness. Receptor binding analysis revealed that the mink SARS-CoV-2 spike interacted more strongly with the mink receptor than the human receptor. Tracking the variations and codon bias of SARS-CoV-2 is helpful for understanding the fitness of the virus in virus transmission, pathogenesis, and immune evasion.

Drivers of CO2 Emissions: A Debt Perspective.

CO2 emissions and debt accumulation are twin threats to sustainable development. To fill the gap that few studies can untangle the reasons behind CO2 emissions from the debt perspective, we illustrate debt can cause CO2 emissions through various channels. We then examined how debt-based drivers impact emission trajectories. We use the logarithmic mean Divisia index (LMDI) method to decompose the emission changes into five factors. We make decomposition analyses between different country groups to identify their respective characteristics. Further, to investigate the potential financial crisis impacts, we consider the full period 2001-2019 and two sub-periods (pre- and post-2008). The results show that the gross domestic product (GDP) is always the biggest contributor to emissions, whose effect on advanced economies saw a bigger decrease after 2008 than that on emerging economies. Debt-GDP is second only to GDP in contributing to emissions. It has a similar impact on emissions before and after 2008 for advanced economies, while it rockets after 2008 for emerging economies. Private debt financing of fossil fuels is the prominent inhibitor for both economies, especially for emerging economies. It has a stronger mitigation impact after 2008 than before for emerging economies, while has the opposite change for advanced economies. Debt structure and fossil CO2 intensity have relatively smaller effects on emissions. The crisis is an opportunity to promote low-carbon development. Since the COVID-19 pandemic is analogous to the 2008 crisis in terms of debt level and emission change, we provide recommendations for emission mitigation in the post-pandemic context.

SARS-CoV-2 Accessory Protein ORF7b Mediates Tumor Necrosis Factor-α-Induced Apoptosis in Cells.

The accessory proteins of coronaviruses are essential for virus-host interactions and the modulation of host immune responses. It has been reported that accessory protein ORF3a encoded by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can induce apoptosis, and accessory protein ORF6 and ORF8 could be inhibitors of the type-I interferon (IFN) signaling pathway. However, the function of accessory protein ORF7b is largely unknown. We investigated the apoptosis-inducing activity of ORF7b in cells. Cytokine levels and host innate immune responses, including expression of interferon regulatory transcription factor (IRF)-3, signal transducer and activator of transcription (STAT)-1, interferon (IFN)-ß, tumor necrosis factor (TNF)-α, and interleukin (IL)-6, were also investigated. We found that ORF7b promoted expression of IFN-ß, TNF-α, and IL-6, activated type-I IFN signaling through IRF3 phosphorylation, and activated TNFα-induced apoptosis in HEK293T cells and Vero E6 cells. These results could provide deeper understanding about the pathogenicity of SARS-CoV-2 as well as the interaction between the accessory protein ORF7b with host immune responses.

Comparison of Clinical Features and Outcomes of Medically Attended COVID-19 and Influenza Patients in a Defined Population in the 2020 Respiratory Virus Season.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), which is causing the coronavirus disease-2019 (COVID-19) pandemic, poses a global health threat. However, it is easy to confuse COVID-19 with seasonal influenza in preliminary clinical diagnosis. In this study, the differences between influenza and COVID-19 in epidemiological features, clinical manifestations, comorbidities and pathogen biology were comprehensively compared and analyzed. SARS-CoV-2 causes a higher proportion of pneumonia (90.67 vs. 17.07%) and acute respiratory distress syndrome (12.00 vs. 0%) than influenza A virus. The proportion of leukopenia for influenza patients was 31.71% compared with 12.00% for COVID-19 patients (P = 0.0096). The creatinine and creatine kinase were significantly elevated when there were COVID-19 patients. The basic reproductive number (R0) for SARS-CoV-2 is 2.38 compared with 1.28 for seasonal influenza A virus. The mutation rate of SARS-CoV-2 ranges from 1.12 × 10-3 to 6.25 × 10-3, while seasonal influenza virus has a lower evolutionary rate (0.60-2.00 × 10-6). Overall, this study compared the clinical features and outcomes of medically attended COVID-19 and influenza patients. In addition, the S477N and N439K mutations on spike may affect the affinity with receptor ACE2. This study will contribute to COVID-19 control and epidemic surveillance in the future.

Epidemiological and Clinical Characteristics of Patients With Coronavirus Disease-2019 in Shiyan City, China.

To investigate the early epidemic of COVID-19, a total of 176 confirmed COVID-19 cases in Shiyan city, Hubei province, China were surveyed. Our data indicated that the rate of emergence of early confirmed COVID-19 cases in Hubei province outside Wuhan was dependent on migration population, and the second-generation of patients were family clusters originating from Wuhan travelers. Epidemiological investigation indicated that the reproductive number (R0) under containment strategies was 1.81, and asymptomatic SARS-CoV-2 carriers were contagious with a transmission rate of 10.7%. Among the 176 patients, 53 were admitted to the Renmin Hospital of Hubei University of Medicine. The clinical characteristics of these 53 patients were collected and compared based on a positive RT-PCR test and presence of pneumonia. Clinical data showed that 47.2% (25/53) of COVID-19 patients were co-infected with Mycoplasma pneumoniae, and COVID-19 patients coinfected with M. pneumoniae had a higher percentage of monocytes (P < 0.0044) and a lower neutrophils percentage (P < 0.0264). Therefore, it is important to assess the transmissibility of infected asymptomatic individuals for SARS-CoV-2 transmission; moreover, clinicians should be alert to the high incidence of co-infection with M. pneumoniae in COVID-19 patients.

Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2.

From the beginning of 2002 and 2012, severe respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) crossed the species barriers to infect humans, causing thousands of infections and hundreds of deaths, respectively. Currently, a novel coronavirus (SARS-CoV-2), which has become the cause of the outbreak of Coronavirus Disease 2019 (COVID-19), was discovered. Until 18 February 2020, there were 72 533 confirmed COVID-19 cases (including 10 644 severe cases) and 1872 deaths in China. SARS-CoV-2 is spreading among the public and causing substantial burden due to its human-to-human transmission. However, the intermediate host of SARS-CoV-2 is still unclear. Finding the possible intermediate host of SARS-CoV-2 is imperative to prevent further spread of the epidemic. In this study, we used systematic comparison and analysis to predict the interaction between the receptor-binding domain (RBD) of coronavirus spike protein and the host receptor, angiotensin-converting enzyme 2 (ACE2). The interaction between the key amino acids of S protein RBD and ACE2 indicated that, other than pangolins and snakes, as previously suggested, turtles (Chrysemys picta bellii, Chelonia mydas, and Pelodiscus sinensis) may act as the potential intermediate hosts transmitting SARS-CoV-2 to humans.