SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation.

Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a mechanism by which the SARS-CoV-2 virus coopts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-ß. We reveal that the SARS-CoV-2 encoded nonstructural protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-ß production, which inhibits SARS-CoV-2 replication. Our findings reveal a target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.

Transcriptome Analysis Reveals Hub Genes Regulating Autophagy in Patients With Severe COVID-19.

Background: The COVID-19 pandemic has currently developed into a worldwide threat to humankind. Importantly, patients with severe COVID-19 are believed to have a higher mortality risk than those with mild conditions. However, despite the urgent need to develop novel therapeutic strategies, the biological features and pathogenic mechanisms of severe COVID-19 are poorly understood. Methods: Here, peripheral blood mononuclear cells (PBMCs) from four patients with severe COVID-19, four patients with mild COVID-19, and four healthy controls were examined by RNA sequencing (RNA-Seq). We conducted gene expression analysis and Venn diagrams to detect specific differentially expressed genes (DEGs) in patients with severe disease compared with those with mild conditions. Gene Ontology (GO) enrichment analysis was performed to identify the significant biological processes, and protein-protein interaction networks were constructed to extract hub genes. These hub genes were then subjected to regulatory signatures and protein-chemical interaction analysis for certain regulatory checkpoints and identification of potent chemical agents. Finally, to demonstrate the cell type-specific expression of these genes, we performed single-cell RNA-Seq analyses using an online platform. Results: A total of 144 DEGs were specifically expressed in severe COVID-19, and GO enrichment analysis revealed a significant association of these specific DEGs with autophagy. Hub genes such as MVB12A, CHMP6, STAM, and VPS37B were then found to be most significantly involved in the biological processes of autophagy at the transcriptome level. In addition, six transcription factors, including SRF, YY1, CREB1, PPARG, NFIC, and GATA2, as well as miRNAs, namely, hsa-mir-1-3p, and potent chemical agents such as copper sulfate and cobalt chloride, may cooperate in regulating the autophagy hub genes. Furthermore, classical monocytes may play a central role in severe COVID-19. Conclusion: We suggest that autophagy plays a crucial role in severe COVID-19. This study might facilitate a more profound knowledge of the biological characteristics and progression of COVID-19 and the development of novel therapeutic approaches to achieve a breakthrough in the current COVID-19 pandemic.

Transcriptome Analysis Reveals Hub Genes Regulating Autophagy in Patients With Severe COVID-19

Background: The COVID-19 pandemic has currently developed into a worldwide threat to humankind. Importantly, patients with severe COVID-19 are believed to have a higher mortality risk than those with mild conditions. However, despite the urgent need to develop novel therapeutic strategies, the biological features and pathogenic mechanisms of severe COVID-19 are poorly understood. Methods: Here, peripheral blood mononuclear cells (PBMCs) from four patients with severe COVID-19, four patients with mild COVID-19, and four healthy controls were examined by RNA sequencing (RNA-Seq). We conducted gene expression analysis and Venn diagrams to detect specific differentially expressed genes (DEGs) in patients with severe disease compared with those with mild conditions. Gene Ontology (GO) enrichment analysis was performed to identify the significant biological processes, and protein–protein interaction networks were constructed to extract hub genes. These hub genes were then subjected to regulatory signatures and protein–chemical interaction analysis for certain regulatory checkpoints and identification of potent chemical agents. Finally, to demonstrate the cell type-specific expression of these genes, we performed single-cell RNA-Seq analyses using an online platform. Results: A total of 144 DEGs were specifically expressed in severe COVID-19, and GO enrichment analysis revealed a significant association of these specific DEGs with autophagy. Hub genes such as MVB12A, CHMP6, STAM, and VPS37B were then found to be most significantly involved in the biological processes of autophagy at the transcriptome level. In addition, six transcription factors, including SRF, YY1, CREB1, PPARG, NFIC, and GATA2, as well as miRNAs, namely, hsa-mir-1-3p, and potent chemical agents such as copper sulfate and cobalt chloride, may cooperate in regulating the autophagy hub genes. Furthermore, classical monocytes may play a central role in severe COVID-19. Conclusion: We suggest that autophagy plays a crucial role in severe COVID-19. This study might facilitate a more profound knowledge of the biological characteristics and progression of COVID-19 and the development of novel therapeutic approaches to achieve a breakthrough in the current COVID-19 pandemic.

Early human B cell signatures of the primary antibody response to mRNA vaccination.

Messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective at inducing protective immunity. However, weak antibody responses are seen in some individuals, and cellular correlates of immunity remain poorly defined, especially for B cells. Here we used unbiased approaches to longitudinally dissect primary antibody, plasmablast, and memory B cell (MBC) responses to the two-dose mRNA-1273 vaccine in SARS-CoV-2-naive adults. Coordinated immunoglobulin A (IgA) and IgG antibody responses were preceded by bursts of spike-specific plasmablasts after both doses but earlier and more intensely after dose 2. While antibody and B cell cellular responses were generally robust, they also varied within the cohort and decreased over time after a dose-2 peak. Both antigen-nonspecific postvaccination plasmablast frequency after dose 1 and their spike-specific counterparts early after dose 2 correlated with subsequent antibody levels. This correlation between early plasmablasts and antibodies remained for titers measured at 6 months after vaccination. Several distinct antigen-specific MBC populations emerged postvaccination with varying kinetics, including two MBC populations that correlated with 2- and 6-month antibody titers. Both were IgG-expressing MBCs: one less mature, appearing as a correlate after the first dose, while the other MBC correlate showed a more mature and resting phenotype, emerging as a correlate later after dose 2. This latter MBC was also a major contributor to the sustained spike-specific MBC response observed at month 6. Thus, these plasmablasts and MBCs that emerged after both the first and second doses with distinct kinetics are potential determinants of the magnitude and durability of antibodies in response to mRNA-based vaccination.

A multitask GNN-based interpretable model for discovery of selective JAK inhibitors.

The Janus kinase (JAK) family plays a pivotal role in most cytokine-mediated inflammatory and autoimmune responses via JAK/STAT signaling, and administration of JAK inhibitors is a promising therapeutic strategy for several diseases including COVID-19. However, to screen and design selective JAK inhibitors is a daunting task due to the extremely high homology among four JAK isoforms. In this study, we aimed to simultaneously predict pIC50 values of compounds for all JAK subtypes by constructing an interpretable GNN multitask regression model. The final model performance was positive, with R2 values of 0.96, 0.79 and 0.78 on the training, validation and test sets, respectively. Meanwhile, we calculated and visualized atom weights, followed by the rank sum tests and local mean comparisons to obtain key atoms and substructures that could be fine-tuned to design selective JAK inhibitors. Several successful case studies have demonstrated that our approach is feasible and our model could learn the interactions between proteins and small molecules well, which could provide practitioners with a novel way to discover and design JAK inhibitors with selectivity.

One dose of COVID-19 nanoparticle vaccine REVC-128 protects against SARS-CoV-2 challenge at two weeks post-immunization.

ABSTRACTA COVID-19 vaccine that can give early protection is needed to eliminate the viral spread efficiently. Here, we demonstrate the development of a nanoparticle vaccine candidate, REVC-128, in which multiple trimeric spike ectodomains with glycine (G) at position 614 were multimerized onto a nanoparticle. In-vitro characterization of this vaccine confirms its structural and antigenic integrity. In-vivo immunogenicity evaluation in mice indicates that a single dose of this vaccine induces potent serum neutralizing antibody titre at two weeks post-immunization. This is significantly higher than titre caused by trimeric spike protein without nanoparticle presentation. The comparison of serum binding to spike subunits between animals immunized by a spike with and without nanoparticle presentation indicates that nanoparticle prefers the display of spike RBD (Receptor-Binding Domain) over S2 subunit, likely resulting in a more neutralizing but less cross-reactive antibody response. Moreover, a Syrian golden hamster in-vivo model for the SARS-CoV-2 virus challenge was implemented two weeks post a single dose of REVC-128 immunization. The results showed that vaccination protects hamsters against the SARS-CoV-2 virus challenge with evidence of steady body weight, suppressed viral loads and alleviation of tissue damage for protected animals, compared with ∼10% weight loss, high viral loads and tissue damage in unprotected animals. Furthermore, the data showed that vaccine REVC-128 is thermostable at up to 37°C for at least 4 weeks. These findings, along with a history of safety for protein vaccines, suggest that the REVC-128 is a safe, stable and efficacious single-shot vaccine to give the earliest protection against SARS-CoV-2 infection.