Integrating population-level and cell-based signatures for drug repositioning (preprint)

Drug repositioning presents a streamlined and cost-efficient way to expand the range of therapeutic possibilities. Furthermore, drugs with genetic evidence are more likely to progress successfully through clinical trials towards FDA approval. Exploiting these developments, single gene-based drug repositioning methods have been implemented, but approaches leveraging the entire spectrum of molecular signatures are critically underexplored. Most multi-gene-based approaches rely on differential gene expression (DGE) analysis, which is prone to identify the molecular consequence of disease and renders causal inference challenging. We propose a framework TReD (Transcriptome-informed Reversal Distance) that integrates population-level disease signatures robust to reverse causality and cell-based drug-induced transcriptome response profiles. TReD embeds the disease signature and drug profile in a high-dimensional normed space, quantifying the reversal potential of candidate drugs in a disease-related cell screen assay. The robustness is ensured by evaluation in additional cell screens. For an application, we implement the framework to identify potential drugs against COVID-19. Taking transcriptome-wide association study (TWAS) results from four relevant tissues and three DGE results as disease features, we identify 37 drugs showing potential reversal roles in at least four of the seven disease signatures. Notably, over 70% (27/37) of the drugs have been linked to COVID-19 from other studies, and among them, eight drugs are supported by ongoing/completed clinical trials. For example, TReD identifies the well-studied JAK1/JAK2 inhibitor baricitinib, the first FDA-approved immunomodulatory treatment for COVID-19. Novel potential candidates, including enzastaurin, a selective inhibitor of PKC-beta which can be activated by SARS-CoV-2, are also identified. In summary, we propose a comprehensive genetics-anchored framework integrating population-level signatures and cell-based screens that can accelerate the search for new therapeutic strategies.

SARS-CoV-2 S protein antagonizes type I interferon downstream signal pathway through interacting and attenuating phosphorylation of STAT1/STAT2 (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may keep patients in a clinically asymptomatic state by blocking cellular innate antiviral immunity, but the molecular mechanism remains unclear. Here, we screened the viral proteins of SARS-CoV-2 and found that the spike (S) protein inhibits the activation of interferon-stimulated genes (ISGs) and even reduces the expression of these genes to below background values. Mechanistically, the S protein interacted with STAT1, STAT2, and IRF9 and impedes the phosphorylation of STAT1/STAT2, thus preventing the formation of the interferon-stimulating gene factor 3 (ISGF3) complex and inhibiting the downstream production of Interferon-stimulated genes (ISGs). Remarkably, we also have found that the inhibitory mechanism of the S protein was conservative among SARS-CoV-2 variants and other human coronaviruses, including SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63, and HCoV-HKU1. Truncation studies indicated that the most conserved S2 domain played a major inhibitory role. Altogether, our findings unveil a new mechanism by which SARS-CoV-2 S protein attenuated the host's antiviral immune response and provide new insights into the pathogenic mechanism of coronavirus.

Construction of a potent pan-vaccine based on the evolutionary tendency of SARS-CoV-2 spike protein. (preprint)

SARS-CoV-2 continued to spread globally along with different variants. Here, we systemically analyzed viral infectivity and immune-resistance of SARS-CoV-2 variants to explore the underlying rationale of viral mutagenesis. We found that the Beta variant harbors both high infectivity and strong immune resistance, while the Delta variant is the most infectious with only a mild immune-escape ability. Remarkably, the Omicron variant is even more immune-resistant than the Beta variant, but its infectivity increases only in Vero E6 cells implying a probable preference for the endocytic pathway. A comprehensive analysis revealed that SARS-CoV-2 spike protein evolved into distinct evolutionary paths of either high infectivity plus low immune resistance or low infectivity plus high immune resistance, resulting in a narrow spectrum of the current single-strain vaccine. In light of these findings and the phylogenetic analysis of 2674 SARS-CoV-2 S-protein sequences, we generated a consensus antigen (S6) taking the most frequent mutations as a pan-vaccine against heterogeneous variants. As compared to the ancestry SWT vaccine with significantly declined neutralizations to emerging variants, the S6 vaccine elicits broadly neutralizing antibodies and full protections to a wide range of variants. Our work highlights the importance and feasibility of a universal vaccine strategy to fight against antigen drift of SARS-CoV-2.

Presymptomatic transmission of COVID-19 in a cluster of cases occurred in confined space: a case report (preprint)

Background: COVID-19 is spreading rapidly intercity and international despite rigid public health prevention and control measures been taken.Case presentation: In a cluster of infection, six out of seven participants engaged in persistent singing and talking in confined space were later diagnosed COVID-19 patients. One of the cases was asymptomatic with no SARS-CoV-2 nucleic acid detected, but positive for anti-SARS-CoV-2 IgG. None of the household contacts was infected during the following month.Conclusions: This epidemiological evidence revealed that asymptomatic patients transmitted the coronavirus in confined space with relatively high efficiency, suggesting that it is important to provide better ventilation in public buildings to prevent COVID-19 transmission.

COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression ;Journal of Antimicrobial Chemotherapy ;Oxford Academic

A novel coronavirus disease (COVID-19), caused by infection with SARS-CoV-2, has swept across 31 provinces in China and over 40 countries worldwide. The transition from first symptoms to acute respiratory distress syndrome (ARDS) is highly likely to be due to uncontrolled cytokine release. There is an urgent need to identify safe and effective drugs for treatment. Chloroquine (CQ) exhibits a promising inhibitory effect. However, the clinical use of CQ can cause severe side effects. We propose that hydroxychloroquine (HCQ), which exhibits an antiviral effect highly similar to that of CQ, could serve as a better therapeutic approach. HCQ is likely to attenuate the severe progression of COVID-19, inhibiting the cytokine storm by suppressing T cell activation. It has a safer clinical profile and is suitable for those who are pregnant. It is cheaper and more readily available in China. We herein strongly urge that clinical trials are performed to assess the preventive effects of HCQ in both disease infection and progression.