Transcriptional response of signalling pathways to SARS-CoV-2 infection in normal human bronchial epithelial cells

Enes, Ak; Pir, Pınar

doi:10.1101/2020.06.20.163006

Cited by 4 publications

(4 citation statements)

References 35 publications

(25 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In bronchial epithelial cells infected with SARS-CoV-2, DEGs are enriched for members of pathways related to NF-κB, TNF-α, and IL-17 signaling. Specific genes shared by these pathways include MMP9 , ICAM1 , CSF3 , and IL6 ( Enes and Pir, 2020 ). A protein-protein interaction network of DEGs shared between COVID-19, MERS, SARS, H1N1, and Ebola identifies ICAM1 , VEGFA , MMP9 , IL6 , TNF , IL-8 , IL1B , STAT1 , TLR2 , TLR1 , IRF7 , and CXCL1 as hub genes ( Alsamman and Zayed, 2020 ).…”

Section: Adhesion and Tissue Retention Of Inflammatory Leukocytesmentioning

confidence: 99%

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

2020

View full text Add to dashboard Cite

With the objective of linking early findings relating to the novel SARS-CoV-2 coronavirus with potentially informative findings from prior research literature and to promote investigation toward therapeutic response, a coherent cellular and molecular pathway is proposed for COVID-19. The pathway is consistent with a broad range of observed clinical features and biological markers and captures key mediators of pathophysiology. In this proposed pathway, membrane fusion and cytoplasmic entry of SARS-CoV-2 virus via ACE2 and TMPRSS2-expressing respiratory epithelial cells, including pulmonary type-II pneumocytes, provoke an initial immune response featuring inflammatory cytokine production coupled with a weak interferon response, particularly in IFN-l-dependent epithelial defense. Differentiation of non-classic pathogenic T-cells and pro-inflammatory intermediate monocytes contributes to a skewed inflammatory profile, mediated by membrane-bound immune receptor subtypes (e.g., FcgRIIA) and downstream signaling pathways (e.g., NF-kB p65 and p38 MAPK), followed by chemotactic infiltration of monocyte-derived macrophages and neutrophils into lung tissue. Endothelial barrier degradation and capillary leakage contribute to alveolar cell damage. Inflammatory cytokine release, delayed neutrophil apoptosis, and NETosis contribute to pulmonary thrombosis and cytokine storm. These mechanisms are concordant with observed clinical markers in COVID-19, including high expression of inflammatory cytokines on the TNF-a/ IL-6 axis, elevated neutrophil-to-lymphocyte ratio (NLR), diffuse alveolar damage via cell apoptosis in respiratory epithelia and vascular endothelia, elevated lactate dehydrogenase (LDH) and CRP, high production of neutrophil extracellular traps (NETs), depressed platelet count, and thrombosis. Although certain elements are likely to be revised as new findings emerge, the proposed pathway suggests multiple points of investigation for potential therapeutic interventions. Initial candidate interventions include prophylaxis to augment epithelial defense (e.g., AT1 receptor blockade, type III and type I interferons, melatonin, calcitriol, camostat, and lopinavir) and to reduce viral load (e.g., remdesivir, ivermectin, emetine, Abelson kinase inhibitors, dopamine D2 antagonists, and selective estrogen receptor modulators). Additional interventions focus on tempering inflammatory signaling and injury (e.g., dexamethasone, doxycycline, Ang1-7, estradiol, alpha blockers,

show abstract

Section: Adhesion and Tissue Retention Of Inflammatory Leukocytesmentioning

confidence: 99%

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

2020

View full text Add to dashboard Cite

show abstract

“…In bronchial epithelial cells infected with SARS-CoV-2, DEGs are enriched for members of pathways related to NF-kB, TNF-a, and IL-17 signaling. Specific genes shared by these pathways include MMP9, ICAM1, CSF3, and IL6 (Enes and Pir, 2020). A protein-protein interaction network of DEGs shared between COVID-19, MERS, SARS, H1N1, and Ebola identifies ICAM1, VEGFA, MMP9, IL6, TNF, IL-8, IL1B, STAT1, TLR2, TLR1, IRF7, and CXCL1 as hub genes (Alsamman and Zayed, 2020).…”

Section: Adhesion and Tissue Retention Of Inflammatory Leukocytesmentioning

confidence: 99%

Cellular and molecular pathways of COVID-19 and potential points of therapeutic intervention

Hussman¹

2020

Preprint

View full text Add to dashboard Cite

With the objective of linking early findings relating to the novel SARS-CoV-2 coronavirus with potentially informative findings from prior research literature, and to promote investigation toward therapeutic response, a coherent cellular and molecular pathway is proposed for COVID-19, consistent with a broad range of observed clinical features and biological markers, and capturing key mediators of pathophysiology. In this proposed pathway, membrane fusion and cytoplasmic entry of SARS-CoV-2 virus via ACE2 and TMPRSS2-expressing respiratory epithelial cells, including pulmonary type-II pneumocytes, provokes an initial immune response featuring inflammatory cytokine production coupled with a weak interferon response, particularly in Type III interferon-dependent epithelial defense. Differentiation of non-classic pathogenic T-cells and pro-inflammatory intermediate monocytes contributes to a skewed inflammatory profile, mediated by membrane-bound immune receptor subtypes (e.g. FcgRIIA) and downstream signaling pathways (e.g. NF-kB p65, p38 MAPK), followed by chemotactic infiltration of monocyte-derived macrophages and neutrophils into lung tissue, with inflammatory cytokine release, delayed neutrophil apoptosis, and NETosis contributing to pulmonary thrombosis and cytokine storm. These mechanisms are concordant with observed clinical markers in COVID-19, including high expression of inflammatory cytokines on the TNF-alpha/IL-6 axis, elevated neutrophil-to-lymphocyte ratio (NLR), diffuse alveolar damage via cell apoptosis in respiratory epithelia and vascular endothelia, elevated lactate dehydrogenase (LDH) and C-reactive protein (CRP), high production of neutrophil extracellular traps (NETs), depressed platelet count, and thrombosis. Although certain elements are likely to be revised as new findings emerge, the proposed pathway suggests multiple points of investigation for potential therapeutic interventions, including prophylaxis to augment epithelial defense (e.g. AT1 receptor blockade, Type III and Type I interferons, camostat), reduce viral load (e.g. remdesivir + emetine, lopinavir, Abelson kinase inhibition, dopamine D2 antagonists, selective estrogen receptor modulators), and temper pro-inflammatory signaling (e.g. Ang1-7, estradiol, alpha blockers, DHA/EPA, pasireotide), as well as therapeutics targeted toward molecular mediators of the maladaptive COVID-19 immune response (e.g. IL-6, TNF-alpha, IL-17, JAK, CDK9).

show abstract

“…In addition, in postmortem lung examinations of two severe and critically ill COVID-19 patients, the ACE2 protein levels were up-regulated, compared to the adjacent normal lung tissue [ 279 ]. In other recent studies, neither down- nor upregulation of ACE2 was observed in human cell lines infected with SARS-CoV-2 [ 228 , 229 , 280 ]. In COVID-19 patients, plasma levels and enzymatic activity of ACE2 were found increased [ 281 , 282 ] or not altered [ 278 , 283 , 284 ].…”

Section: The Roles Of Ace2 and Angiotensin II In Coronavirus-induced mentioning

confidence: 84%

Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury

Öz¹,

Lorke²

2021

Biomedicine & Pharmacotherapy

View full text Add to dashboard Cite

Transcriptional response of signalling pathways to SARS-CoV-2 infection in normal human bronchial epithelial cells

Cited by 4 publications

References 35 publications

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

Cellular and molecular pathways of COVID-19 and potential points of therapeutic intervention

Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury

Contact Info

Product

Resources

About