Host-Viral Infection Maps Reveal Signatures of Severe COVID-19 Patients

Bost, Pierre; Giladi, Amir; Liu, Yang; Bendjelal, Yanis; Xu, Gang; David, Eyal; Blecher‐Gonen, Ronnie; Cohen, Michal; Medaglia, Chiara; Li, Hanjie; Deczkowska, Aleksandra; Zhang, Shuye; Schwikowski, Benno; Zhang, Zheng

doi:10.1016/j.cell.2020.05.006

Cited by 451 publications

(627 citation statements)

References 77 publications

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“…In particular, tissue resident immune populations of the myeloid lineage in the heart, esophagus and lung also collectively express many of the predicted target genes (Supplementary Figure 3B,4). This is particularly interesting given the recent reports that myeloid lineage and epithelial cells are affected in severe SARS-CoV-2 infection cases 19 .…”

Section: Drugs That Reduce Ace-2 Regulate Steroid Signaling and Peptimentioning

confidence: 91%

Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men

Ghazizadeh

Majd

Richter

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to a global health crisis, and yet our understanding of the disease pathophysiology and potential treatment options remains limited. SARS-CoV-2 infection occurs through binding and internalization of the viral spike protein to angiotensin converting enzyme 2 (ACE2) on the host cell membrane. Lethal complications are caused by damage and failure of vital organs that express high levels of ACE2, including the lungs, the heart and the kidneys. Here, we established a high-throughput drug screening strategy to identify therapeutic candidates that reduce ACE2 levels in human embryonic stem cell (hESC) derived cardiac cells. Drug target analysis of validated hit compounds, including 5 alpha reductase inhibitors, revealed androgen signaling as a key modulator of ACE2 levels. Treatment with the 5 alpha reductase inhibitor dutasteride reduced ACE2 levels and internalization of recombinant spike receptor binding domain (Spike-RBD) in hESC-derived cardiac cells and human alveolar epithelial cells. Finally, clinical data on coronavirus disease 2019 (COVID-19) patients demonstrated that abnormal androgen states are significantly associated with severe disease complications and cardiac injury as measured by blood troponin T levels. These findings provide important insights on the mechanism of increased disease susceptibility in male COVID-19 patients and identify androgen receptor inhibition as a potential therapeutic strategy.

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Section: Drugs That Reduce Ace-2 Regulate Steroid Signaling and Peptimentioning

confidence: 91%

Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men

Ghazizadeh

Majd

Richter

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…18 Viral-Track, which allows unsupervised detection of viral RNA in single-cell RNA-seq datasets, also found evidence of SARS-COV-2 infection in monocytes/macrophages in severe patients. 19 In addition, viral antigens were also detected in macrophages infiltrated into the alveolar interstitium and cavities of SARS-CoV-2-infected hACE2-expressing mice. 20 Moreover, immunofluorescent double staining showed that IL-6 is primarily produced by infected macrophages.…”

Section: Ade Can Explain Characteristics Of Severe Covid-19mentioning

confidence: 94%

Immunoregulation with mTOR inhibitors to prevent COVID‐19 severity: A novel intervention strategy beyond vaccines and specific antiviral medicines

Zheng¹,

Liu

2020

Journal of Medical Virology

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Coronavirus disease 2019 (COVID-19) has become a major global public health concern. The mortality rate for critically ill patients is up to 60%, and, thus, reducing the disease severity and case mortality is a top priority. Currently, cytokine storms are considered as the major cause of critical illness and death due to COVID-19.After a systematical review of the literature, we propose that cross-reactive antibodies associated with antibody-dependent enhancement (ADE) may actually be the cause of cytokine storms. It would be more difficult to develop vaccines for highly pathogenic human coronaviruses (CoVs) if ADE characteristics are taken into consideration. Therefore, it is urgent to find an effective way to prevent the occurrence of severe illness as severe acute respiratory syndrome CoV-2 specific drugs or vaccines are still in development. If the activation of memory B cells can be selectively inhibited in high-risk patients at an early stage of COVID-19 to reduce the production of cross-reactive antibodies against the virus, we speculate that ADE can be circumvented and severe symptoms can be prevented. The mammalian target of rapamycin (mTOR) inhibitors satisfy such needs and it is recommended to conduct clinical trials for mTOR inhibitors in preventing the severity of COVID-19. K E Y W O R D S ADE, antibody-dependent enhancement, coronavirus, cross-reactive antibody, cytokine storm, immunity, mTOR inhibitors, rapamycin How to cite this article: Zheng Y, Li R, Liu S. Immunoregulation with mTOR inhibitors to prevent COVID-19 severity: A novel intervention strategy beyond vaccines and specific antiviral medicines.

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“…Liver scRNA-seq data processing and estimation of the abundance of liver cell type The healthy liver and cirrhotic liver 10X scRNA-seq matrices were downloaded from GSE136103 (13), and the HBV liver 10X scRNA-seq matrix was obtained from Ido Amit Lab (14). The unsupervised clustering and visualization were performed in the Seurat R package v3.1.1 (15).…”

Section: Resultsmentioning

confidence: 99%

Implications of Liver Injury in Risk-Stratification and Management of Patients with COVID-19

Shao

Liang

et al. 2020

Preprint

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BackgroundInfection with SARS-CoV-2 has been associated with liver dysfunction, aggravation of liver burden, and liver injury. This study aimed to assess the effects of liver injuries on the clinical outcomes of patients with COVID-19.MethodsA total of 1,564 patients with severe or critical COVID-19 from Huoshenshan Hospital, Wuhan, were enrolled. Chronic liver disease (CLD) was confirmed by consensus diagnostic criteria. Laboratory test results were compared between different groups. scRNA-seq data and bulk gene expression profiles were used to identify cell types associated with liver injury.ResultsA total of 10.98% of patients with severe or critical COVID-19 developed liver injury after admission that was associated with significantly higher rates of mortality (21.74%, p<0.001) and intensive care unit admission (26.71%, p<0.001). A pre-existing CLD was not associated with a higher risk. However, fatty liver disease and cirrhosis were associated with higher risks, supported by evidences from single cell and bulk transcriptome analysis that showed more TMPRSS2+ cells in these tissues. By generating a model, we were able to predict the risk and severity of liver injury during hospitalization.ConclusionWe demonstrate that liver injury occurring during therapy in patients with COVID-19 is significantly associated with the severity of disease and mortality, but the presence of CLD is not associated. We provide a risk-score model that can predict whether patients with COVID-19 will develop liver injury or proceed to higher risk stages during subsequent hospitalizations. These findings may prove beneficial for the clinical management of patients infected with SARS-CoV-2.

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Host-Viral Infection Maps Reveal Signatures of Severe COVID-19 Patients

Cited by 451 publications

References 77 publications

Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men

Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men

Immunoregulation with mTOR inhibitors to prevent COVID‐19 severity: A novel intervention strategy beyond vaccines and specific antiviral medicines

Implications of Liver Injury in Risk-Stratification and Management of Patients with COVID-19

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