SARS-CoV-2 ORF9c Is a Membrane-Associated Protein that Suppresses Antiviral Responses in Cells (preprint)

Disrupted antiviral immune responses are associated with severe COVID-19, the disease caused by SAR-CoV-2. Here, we show that the 73-amino-acid protein encoded by ORF9c of the viral genome contains a putative transmembrane domain, interacts with membrane proteins in multiple cellular compartments, and impairs antiviral processes in a lung epithelial cell line. Proteomic, interactome, and transcriptomic analyses, combined with bioinformatic analysis, revealed that expression of only this highly unstable small viral protein impaired interferon signaling, antigen presentation, and complement signaling, while inducing IL-6 signaling. Furthermore, we showed that interfering with ORF9c degradation by either proteasome inhibition or inhibition of the ATPase VCP blunted the effects of ORF9c. Our study indicated that ORF9c enables immune evasion and coordinates cellular changes essential for the SARS-CoV-2 life cycle. One-sentence summarySARS-CoV-2 ORF9c is the first human coronavirus protein localized to membrane, suppressing antiviral response, resembling full viral infection.

Identification of potential key genes for SARS-CoV-2 infected human bronchial organoids based on bioinformatics analysis (preprint)

There is an urgent need to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) that leads to COVID-19 and respiratory failure. Our study is to discover differentially expressed genes (DEGs) and biological signaling pathways by using a bioinformatics approach to elucidate their potential pathogenesis. The gene expression profiles of the GSE150819 datasets were originally produced using an Illumina NextSeq 500 (Homo sapiens). KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) were utilized to identify functional categories and significant pathways. KEGG and GO results suggested that the Cytokine-cytokine receptor interaction, P53 signaling pathway, and Apoptosis are the main signaling pathways in SARS-CoV-2 infected human bronchial organoids (hBOs). Furthermore, NFKBIA, C3, and CCL20 may be key genes in SARS-CoV-2 infected hBOs. Therefore, our study provides further insights into the therapy of COVID-19.

Multi-organ Proteomic Landscape of COVID-19 Autopsies (preprint)

The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report an in-depth multi-organ proteomic landscape of COVID-19 patient autopsy samples. By integrative analysis of proteomes of seven organs, namely lung, spleen, liver, heart, kidney, thyroid and testis, we characterized 11,394 proteins, in which 5336 were perturbed in COVID-19 patients compared to controls. Our data showed that CTSL, rather than ACE2, was significantly upregulated in the lung from COVID-19 patients. Dysregulation of protein translation, glucose metabolism, fatty acid metabolism was detected in multiple organs. Our data suggested upon SARS-CoV-2 infection, hyperinflammation might be triggered which in turn induces damage of gas exchange barrier in the lung, leading to hypoxia, angiogenesis, coagulation and fibrosis in the lung, kidney, spleen, liver, heart and thyroid. Evidence for testicular injuries included reduced Leydig cells, suppressed cholesterol biosynthesis and sperm mobility. In summary, this study depicts the multi-organ proteomic landscape of COVID-19 autopsies, and uncovered dysregulated proteins and biological processes, offering novel therapeutic clues. HIGHLIGHTSO_LICharacterization of 5336 regulated proteins out of 11,394 quantified proteins in the lung, spleen, liver, kidney, heart, thyroid and testis autopsies from 19 patients died from COVID-19. C_LIO_LICTSL, rather than ACE2, was significantly upregulated in the lung from COVID-19 patients. C_LIO_LIEvidence for suppression of glucose metabolism in the spleen, liver and kidney; suppression of fatty acid metabolism in the kidney; enhanced fatty acid metabolism in the lung, spleen, liver, heart and thyroid from COVID-19 patients; enhanced protein translation initiation in the lung, liver, renal medulla and thyroid. C_LIO_LITentative model for multi-organ injuries in patients died from COVID-19: SARS-CoV-2 infection triggers hyperinflammatory which in turn induces damage of gas exchange barrier in the lung, leading to hypoxia, angiogenesis, coagulation and fibrosis in the lung, kidney, spleen, liver, heart, kidney and thyroid. C_LIO_LITesticular injuries in COVID-19 patients included reduced Leydig cells, suppressed cholesterol biosynthesis and sperm mobility. C_LI

NVX-CoV2373 vaccine protects cynomolgus macaque upper and lower airways against SARS-CoV-2 challenge (preprint)

There is an urgent need for a safe and protective vaccine to control the global spread of SARS-CoV-2 and prevent COVID-19. Here, we report the immunogenicity and protective efficacy of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) produced from the full-length SARS-CoV-2 spike (S) glycoprotein stabilized in the prefusion conformation. Cynomolgus macaques (Macaca fascicularis) immunized with NVX-CoV2373 and the saponin-based Matrix-M adjuvant induced anti-S antibody that was neutralizing and blocked binding to the human angiotensin-converting enzyme 2 (hACE2) receptor. Following intranasal and intratracheal challenge with SARS-CoV-2, immunized macaques were protected against upper and lower infection and pulmonary disease. These results support ongoing phase 1/2 clinical studies of the safety and immunogenicity of NVX-CoV2327 vaccine (NCT04368988). HighlightsO_LIFull-length SARS-CoV-2 prefusion spike with Matrix-M1 (NVX-CoV2373) vaccine. C_LIO_LIInduced hACE2 receptor blocking and neutralizing antibodies in macaques. C_LIO_LIVaccine protected against SARS-CoV-2 replication in the nose and lungs. C_LIO_LIAbsence of pulmonary pathology in NVX-CoV2373 vaccinated macaques. C_LI

ECMO Therapy for Critically Ill Coronavirus Disease 2019 Patients in Wuhan, China: A Retrospective Multicenter Cohort Study (preprint)

Background The coronavirus disease 2019 (COVID-19) pandemic has led to surges in the demand for extracorporeal membrane oxygenation (ECMO) therapy. However, little in-depth evidence is known about the application of ECMO therapy in COVID-19 patients.Methods This retrospective multicenter cohort study included 88 patients who had been diagnosed with COVID-19 and received ECMO therapy at seven designated hospitals in Wuhan, China. The clinical characteristics, laboratory examinations, treatments, and outcomes were extracted from electronic medical records and compared between weaned and non-weaned ECMO patients. The patients were followed until June 30, 2020. Logistic regression analyses were performed to identify the risk factors associated with unsuccessful ECMO weaning. Propensity score matching was used to match patients who received veno-venous ECMO with those who received invasive mechanical ventilation (IMV)-only therapy. The primary endpoint, 120-day all-cause mortality after intensive care unit (ICU) admission during hospitalization, was compared using a mixed-effect Cox model.Results Of 88 patients who received ECMO therapy, 27 and 61 patients were and were not successfully weaned from ECMO, respectively. Additionally, 15, 15, and 65 patients were further weaned from IMV, discharged from hospital, or died during hospitalization, respectively. A lymphocyte count ≤ 0.5 × 109/L and D-dimer concentration > 4 × the upper limit of normal at ICU admission, a peak PaCO2 > 60 mmHg at 24 hours before ECMO initiation, and no tracheotomy performed during the ICU stay were independently associated with lower odds of ECMO weaning. In the propensity score-matched analysis, a mixed-effect Cox model detected a lower hazard ratio for 120-day all-cause mortality after ICU admission during hospitalization in the ECMO group, as compared with the IMV-only group.Conclusion Patients in Wuhan who received ECMO therapy had a relatively high mortality rate. This outcome may be largely attributable to resource-limited situations during the COVID-19 outbreak. In future, the presence of lymphocytopenia and higher D-dimer concentrations at ICU admission and hypercapnia at 24 hours before ECMO initiation could help to identify patients with a poor prognosis. Moreover, tracheotomy could facilitate weaning from ECMO. Despite the high mortality, ECMO was associated with improved outcomes relative to IMV-only therapy in critically ill COVID-19 patients.

The neutrophil-to-lymphocyte ratio determines clinical efficacy of corticosteroids therapy in patients with COVID-19 (preprint)

Preliminary results from the RECOVERY trial indicated that dexamethasone usage markedly reduced death rate in COVID-19 patients receiving invasive mechanical ventilation. However, the overall reduction for the entire patient cohort in that trial was much more modest, indicating highly variable effects of corticosteroid usage among COVID-19 patients. While steroid treatment is known to have both clinical efficacy and detrimental adverse-effects, defining a clinic parameter that could guide the beneficial corticosteroid usage for treating COVID-19 remains an elusive, urgent, and critical unmet need in COVID-19 therapy. Here, we undertook a multicentered retrospective study on a cohort of 12,862 confirmed COVID-19 cases from 21 hospitals in Hubei Province, China, including 3,254 received corticosteroid treatment and 9,608 received usual care without corticosteroid. We uncovered that the clinical benefits of corticosteroid use were closely associated with the neutrophil-to-lymphocyte ratio (NLR) measured at admission. Among participants with NLR > 6.12 at admission, corticosteroid treatment was significantly associated with a lower risk of 60-day all-cause mortality of COVID-19 based on both Cox model with time-varying exposure and Marginal Structural Model. However, in patients with NLR ≤ 6.12 at admission, corticosteroid treatment was no longer associated with reduced risk of all-cause death, but rather with increased risks of severe adverse effects, particularly in hyperglycemia and infection. In diabetic patients with COVID-19, corticosteroid treatment was associated with increased glycemia, but not with a higher risk of 60-day mortality. Therefore, our study has uncovered NLR as a clinical indicator to stratify COVID-19 patients in their response to corticosteroid therapy. This finding may assist clinical evaluation and future randomized controlled trials to establish proper guidelines for corticosteroid therapy in COVID-19 patients.

Difficulties and strategies of public hospitals in their participation in the prevention and control of novel coronavirus pneumonia / 中华医院管理杂志

Outbreak of the novel coronavirus pneumonia (NC) across the country has seriously threatened people's lives and health, endangering smooth operation of the national economy and social stability. An all-out campaign to save the NCP patients and reduce their mortality is not only one of the key tasks to fight against the epidemic, but also a major responsibility and mission of public hospitals. In view of the field practice of Wuhan Union Hospital in the epicenter, the authorsDescribed the challenges faced by such hospitals in the prevention and control, summarized its experiences and proposed improvement measures, for reference of other public hospitals and relevant authorities.