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1.
J Med Virol ; 93(4): 2396-2405, 2021 04.
Article in English | MEDLINE | ID: covidwho-1217389

ABSTRACT

SARS-CoV-2 triggers a dysregulated innate immune system activation. As the mevalonate pathway (MVP) prevents the activation of inflammasomes and cytokine release and regulates endosomal transport, compromised signaling could be associated with the pathobiology of COVID-19. Prior transcriptomic studies of host cells in response to SARS-CoV-2 infection have not reported to date the effects of SARS-CoV-2 on the MVP. In this study, we accessed public data sets to report in silico investigations into gene expression. In addition, we proposed candidate genes that are thought to have a direct association with the pathogenesis of COVID-19, and which may be dependent on signals derived from the MVP. Our results revealed dysregulation of genes involved in the MVP. These results were not found when investigating the gene expression data from host cells infected with H3N2 influenza virus, H1N1 influenza virus, or respiratory syncytial virus. Our manually curated gene set showed significant gene expression variability in A549 cells infected with SARS-CoV-2, as per Blanco-Melo et al. data set (GSE147507). In light of the present findings, SARS-CoV-2 could hijack the MVP, leading to hyperinflammatory responses. Prompt reconstitution of this pathway with available agents should be considered in future studies.


Subject(s)
COVID-19/metabolism , Mevalonic Acid/metabolism , SARS-CoV-2/metabolism , A549 Cells , Autophagy , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Computer Simulation , Cytokines/immunology , Cytokines/metabolism , HMGB1 Protein/genetics , HMGB1 Protein/metabolism , Host-Pathogen Interactions , Humans , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/metabolism , Influenza A Virus, H3N2 Subtype/genetics , Influenza A Virus, H3N2 Subtype/metabolism , Influenza, Human/immunology , Influenza, Human/metabolism , SAM Domain and HD Domain-Containing Protein 1/genetics , SAM Domain and HD Domain-Containing Protein 1/metabolism , SARS-CoV-2/genetics , Signal Transduction , Transcriptome , Virus Replication
2.
Am J Trop Med Hyg ; 105(1): 73-80, 2021 05 03.
Article in English | MEDLINE | ID: covidwho-1212055

ABSTRACT

Exuberant inflammation manifesting as a "cytokine storm" has been suggested as a central feature in the pathogenesis of severe coronavirus disease 2019 (COVID-19). This study investigated two prognostic biomarkers, the high mobility group box 1 (HMGB1) and interleukin-6 (IL-6), in patients with severe COVID-19 at the time of admission in the intensive care unit (ICU). Of 60 ICU patients with COVID-19 enrolled and analyzed in this prospective cohort study, 48 patients (80%) were alive at ICU discharge. HMGB1 and IL-6 plasma levels at ICU admission were elevated compared with a healthy control, both in ICU nonsurvivors and ICU survivors. HMGB1 and IL-6 plasma levels were higher in patients with a higher Sequential Organ Failure Assessment (SOFA) score (> 10), and the presence of septic shock or acute kidney injury. HMGB1 and IL-6 plasma levels were also higher in patients with a poor oxygenation status (PaO2/FiO2 < 150 mm Hg) and a longer duration of ventilation (> 7 days). Plasma HMGB1 and IL-6 levels at ICU admission also correlated with other prognostic markers, including the maximum neutrophil/lymphocyte ratio, D-dimer levels, and C-reactive protein levels. Plasma HMGB1 and IL-6 levels at ICU admission predicted ICU mortality with comparable accuracy to the SOFA score and the COVID-GRAM risk score. Higher HMGB1 and IL-6 were not independently associated with ICU mortality after adjustment for age, gender, and comorbidities in multivariate analysis models. In conclusion, plasma HMGB1 and IL6 at ICU admission may serve as prognostic biomarkers in critically ill COVID-19 patients.


Subject(s)
COVID-19/metabolism , COVID-19/pathology , Critical Illness , HMGB1 Protein/metabolism , Interleukin-6/metabolism , SARS-CoV-2 , Biomarkers/blood , Gene Expression Regulation/immunology , HMGB1 Protein/genetics , Humans , Intensive Care Units , Interleukin-6/genetics
3.
Cytokine ; 142: 155496, 2021 06.
Article in English | MEDLINE | ID: covidwho-1152317

ABSTRACT

Efforts to understand host factors critical for COVID-19 pathogenesis have identified high mobility group box 1 (HMGB1) to be crucial for regulating susceptibility to SARS-CoV-2. COVID-19 disease severity is correlated with heightened inflammatory responses, and HMGB1 is an important extracellular mediator in inflammation processes.In this study, we evaluated the effect of HMGB1 inhibitor Glycyrrhizin on the cellular perturbations in lung cells expressing SARS-CoV-2 viral proteins. Pyroptosis in lung cells transfected with SARS-CoV-2 S-RBD and Orf3a, was accompanied by elevation of IL-1ß and extracellular HMGB1 levels. Glycyrrhizin mitigated viral proteins-induced lung cell pyroptosis and activation of macrophages. Heightened release of proinflammatory cytokines IL-1ß, IL-6 and IL-8, as well as ferritin from macrophages cultured in conditioned media from lung cells expressing SARS-CoV-2 S-RBD and Orf3a was attenuated by glycyrrhizin. Importantly, Glycyrrhizin inhibited SARS-CoV-2 replication in Vero E6 cells without exhibiting cytotoxicity at high doses. The dual ability of Glycyrrhizin to concomitantly halt virus replication and dampen proinflammatory mediators might constitute a viable therapeutic option in patients with SARS-CoV-2 infection.


Subject(s)
COVID-19/metabolism , Glycyrrhizic Acid/pharmacology , HMGB1 Protein/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Viroporin Proteins/metabolism , Virus Replication/drug effects , A549 Cells , COVID-19/drug therapy , COVID-19/genetics , HMGB1 Protein/genetics , Humans , Spike Glycoprotein, Coronavirus/genetics , U937 Cells , Viroporin Proteins/genetics
4.
J Cell Physiol ; 236(9): 6597-6606, 2021 09.
Article in English | MEDLINE | ID: covidwho-1098899

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 that causes coronavirus disease 2019 (COVID-19) binds to the angiotensin-converting enzyme 2 (ACE2) to gain cellular entry. Akt inhibitor triciribine (TCBN) has demonstrated promising results in promoting recovery from advanced-stage acute lung injury in preclinical studies. In the current study, we tested the direct effect of TCBN on ACE2 expression in human bronchial (H441) and lung alveolar (A549) epithelial cells. Treatment with TCBN resulted in the downregulation of both messenger RNA and protein levels of ACE2 in A549 cells. Since HMGB1 plays a vital role in the inflammatory response in COVID-19, and because hyperglycemia has been linked to increased COVID-19 infections, we determined if HMGB1 and hyperglycemia have any effect on ACE2 expression in lung epithelial cells and whether TCBN has any effect on reversing HMGB1- and hyperglycemia-induced ACE2 expression. We observed increased ACE2 expression with both HMGB1 and hyperglycemia treatment in A549 as well as H441 cells, which were blunted by TCBN treatment. Our findings from this study, combined with our previous reports on the potential benefits of TCBN in the treatment of acute lung injury, generate reasonable optimism on the potential utility of TCBN in the therapeutic management of patients with COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/drug therapy , HMGB1 Protein/genetics , Proto-Oncogene Proteins c-akt/genetics , A549 Cells , Bronchi/metabolism , Bronchi/pathology , Bronchi/virology , COVID-19/genetics , COVID-19/pathology , Epithelial Cells/drug effects , Epithelial Cells/virology , Gene Expression Regulation/drug effects , Humans , Lung/drug effects , Lung/pathology , RNA, Viral/genetics , Ribonucleosides/administration & dosage , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity
5.
Cell ; 184(1): 76-91.e13, 2021 01 07.
Article in English | MEDLINE | ID: covidwho-1064906

ABSTRACT

Identification of host genes essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may reveal novel therapeutic targets and inform our understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here we performed genome-wide CRISPR screens in Vero-E6 cells with SARS-CoV-2, Middle East respiratory syndrome CoV (MERS-CoV), bat CoV HKU5 expressing the SARS-CoV-1 spike, and vesicular stomatitis virus (VSV) expressing the SARS-CoV-2 spike. We identified known SARS-CoV-2 host factors, including the receptor ACE2 and protease Cathepsin L. We additionally discovered pro-viral genes and pathways, including HMGB1 and the SWI/SNF chromatin remodeling complex, that are SARS lineage and pan-coronavirus specific, respectively. We show that HMGB1 regulates ACE2 expression and is critical for entry of SARS-CoV-2, SARS-CoV-1, and NL63. We also show that small-molecule antagonists of identified gene products inhibited SARS-CoV-2 infection in monkey and human cells, demonstrating the conserved role of these genetic hits across species. This identifies potential therapeutic targets for SARS-CoV-2 and reveals SARS lineage-specific and pan-CoV host factors that regulate susceptibility to highly pathogenic CoVs.


Subject(s)
Coronavirus Infections/genetics , Genome-Wide Association Study , Host-Pathogen Interactions , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/immunology , COVID-19/virology , Cell Line , Chlorocebus aethiops , Clustered Regularly Interspaced Short Palindromic Repeats , Coronavirus/classification , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Gene Knockout Techniques , Gene Regulatory Networks , HEK293 Cells , HMGB1 Protein/genetics , HMGB1 Protein/metabolism , Host-Pathogen Interactions/drug effects , Humans , Vero Cells , Virus Internalization
6.
Cell Mol Immunol ; 17(9): 992-994, 2020 09.
Article in English | MEDLINE | ID: covidwho-630398
7.
Mol Med ; 26(1): 63, 2020 06 29.
Article in English | MEDLINE | ID: covidwho-617382

ABSTRACT

BACKGROUND: Oxygen therapy, using supraphysiological concentrations of oxygen (hyperoxia), is routinely administered to patients who require respiratory support including mechanical ventilation (MV). However, prolonged exposure to hyperoxia results in acute lung injury (ALI) and accumulation of high mobility group box 1 (HMGB1) in the airways. We previously showed that airway HMGB1 mediates hyperoxia-induced lung injury in a mouse model of ALI. Cholinergic signaling through the α7 nicotinic acetylcholine receptor (α7nAChR) attenuates several inflammatory conditions. The aim of this study was to determine whether 3-(2,4 dimethoxy-benzylidene)-anabaseine dihydrochloride, GTS-21, an α7nAChR partial agonist, inhibits hyperoxia-induced HMGB1 accumulation in the airways and circulation, and consequently attenuates inflammatory lung injury. METHODS: Mice were exposed to hyperoxia (≥99% O2) for 3 days and treated concurrently with GTS-21 (0.04, 0.4 and 4 mg/kg, i.p.) or the control vehicle, saline. RESULTS: The systemic administration of GTS-21 (4 mg/kg) significantly decreased levels of HMGB1 in the airways and the serum. Moreover, GTS-21 (4 mg/kg) significantly reduced hyperoxia-induced acute inflammatory lung injury, as indicated by the decreased total protein content in the airways, reduced infiltration of inflammatory monocytes/macrophages and neutrophils into the lung tissue and airways, and improved lung injury histopathology. CONCLUSIONS: Our results indicate that GTS-21 can attenuate hyperoxia-induced ALI by inhibiting extracellular HMGB1-mediated inflammatory responses. This suggests that the α7nAChR represents a potential pharmacological target for the treatment regimen of oxidative inflammatory lung injury in patients receiving oxygen therapy.


Subject(s)
Acute Lung Injury/etiology , Acute Lung Injury/metabolism , Benzylidene Compounds/pharmacology , HMGB1 Protein/metabolism , Hyperoxia/complications , Nicotinic Agonists/pharmacology , Pyridines/pharmacology , Acute Lung Injury/drug therapy , Acute Lung Injury/pathology , Animals , Biomarkers , Disease Susceptibility , HMGB1 Protein/blood , HMGB1 Protein/genetics , Immunohistochemistry , Male , Mice , Models, Biological
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