The Notch Pathway: A Link Between COVID-19 Pathophysiology and Its Cardiovascular Complications

Breikaa, Randa M.; Lilly, Brenda

doi:10.3389/fcvm.2021.681948

Cited by 35 publications

(31 citation statements)

References 167 publications

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“…Notch signaling has also been known to facilitate viral infectivity of RNA viruses including influenza virus, respiratory syncytial virus (RSV), HCV, etc. ( Breikaa and Lilly, 2021 ) and have regulatory roles in inflammation ( Shang et al, 2016 ). Our study is concordant with an earlier study that reported the downregulation of the Notch signaling in CCHFV-infection at the transcript level ( Arslan et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Multi-omics insights into host-viral response and pathogenesis in Crimean-Congo hemorrhagic fever viruses for novel therapeutic target

Neogi

Elaldı

Appelberg

et al. 2022

eLife

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The pathogenesis and host-viral interactions of the Crimean–Congo hemorrhagic fever orthonairovirus (CCHFV) are convoluted and not well evaluated. Application of the multi-omics system biology approaches, including biological network analysis in elucidating the complex host-viral response, interrogates the viral pathogenesis. The present study aimed to fingerprint the system-level alterations during acute CCHFV-infection and the cellular immune responses during productive CCHFV-replication in vitro. We used system-wide network-based system biology analysis of peripheral blood mononuclear cells (PBMCs) from a longitudinal cohort of CCHF patients during the acute phase of infection and after one year of recovery (convalescent phase) followed by untargeted quantitative proteomics analysis of the most permissive CCHFV-infected Huh7 and SW13 cells. In the RNAseq analysis of the PBMCs, comparing the acute and convalescent-phase, we observed system-level host’s metabolic reprogramming towards central carbon and energy metabolism (CCEM) with distinct upregulation of oxidative phosphorylation (OXPHOS) during CCHFV-infection. Upon application of network-based system biology methods, negative coordination of the biological signaling systems like FOXO/Notch axis and Akt/mTOR/HIF-1 signaling with metabolic pathways during CCHFV-infection were observed. The temporal quantitative proteomics in Huh7 showed a dynamic change in the CCEM over time and concordant with the cross-sectional proteomics in SW13 cells. By blocking the two key CCEM pathways, glycolysis and glutaminolysis, viral replication was inhibited in vitro. Activation of key interferon stimulating genes during infection suggested the role of type I and II interferon-mediated antiviral mechanisms both at the system level and during progressive replication.

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Section: Discussionmentioning

confidence: 99%

Multi-omics insights into host-viral response and pathogenesis in Crimean-Congo hemorrhagic fever viruses for novel therapeutic target

Neogi

Elaldı

Appelberg

et al. 2022

eLife

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“…Hypoxia has also been implicated in contributing to the development of cytokine storm in COVID-19 patients, a signaling pathway for which we could also identify several putative viral inducers ( Table 1 ) [ 23 ]. Similarly, the role of the Notch pathway in promoting the pro-inflammatory microenvironment and cardiovascular diseases (e.g., myocarditis, thrombosis) that are associated with COVID-19 is well-established, but it is still unknown which SARS-CoV-2 factors are involved in the dysregulation of the Notch pathway [ 24 , 25 ]. We identified at least five viral inducers that could play a role in the regulation of the Notch signaling pathway in SARS-CoV-2-infected cells ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Signaling Pathway Reporter Screen with SARS-CoV-2 Proteins Identifies nsp5 as a Repressor of p53 Activity

Kumar

Grams

Bloom

et al. 2022

Viruses

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The dysregulation of host signaling pathways plays a critical role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and viral pathogenesis. While a number of viral proteins that can block type I IFN signaling have been identified, a comprehensive analysis of SARS-CoV-2 proteins in the regulation of other signaling pathways that can be critical for viral infection and its pathophysiology is still lacking. Here, we screened the effect of 21 SARS-CoV-2 proteins on 10 different host signaling pathways, namely, Wnt, p53, TGFβ, c-Myc, Hypoxia, Hippo, AP-1, Notch, Oct4/Sox2, and NF-κB, using a luciferase reporter assay. As a result, we identified several SARS-CoV-2 proteins that could act as activators or inhibitors for distinct signaling pathways in the context of overexpression in HEK293T cells. We also provided evidence for p53 being an intrinsic host restriction factor of SARS-CoV-2. We found that the overexpression of p53 is capable of reducing virus production, while the main viral protease nsp5 can repress the transcriptional activity of p53, which depends on the protease function of nsp5. Taken together, our results provide a foundation for future studies, which can explore how the dysregulation of specific signaling pathways by SARS-CoV-2 proteins can control viral infection and pathogenesis.

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“…The presence of a high autoantibody response to these proteins suggests that they are overproduced during a pathological condition, such as cancer or a cardiovascular complication 39, 40 . For example, notch signally protein RBPJ has been associated with COVID-19 pathophysiology and cardiovascular complication 41 . Similarly, keratin family proteins (KRT19 and KRT15) that are responsible for epithelial cell structural integrity are linked to COVID-19 pathogenesis and disease severity 42 .…”

Section: Discussionmentioning

confidence: 99%

Auto-Immunoproteomics Analysis of COVID-19 ICU Patients Revealed Increased Levels of Autoantibodies Related to Male Reproductive System

Schmidt

Abdesselem

Suhre

et al. 2022

Preprint

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The role of autoantibodies in coronavirus disease (COVID-19) complications is not yet fully understood. The current investigation screened two independent cohorts of 97 COVID-19 patients (Discovery (Disc) cohort from Qatar (n = 49) and Replication (Rep) cohort from New York (n = 48)) utilizing high-throughput KoRectly Expressed (KREX) immunome protein-array technology. Autoantibody responses to 57 proteins were significantly altered in the COVID-19 Disc cohort compared to healthy controls (P ≤ 0.05). The Rep cohort had altered autoantibody responses against 26 proteins compared to non-COVID-19 ICU patients that served as controls. Both cohorts showed substantial similarities (r2 = 0.73) and exhibited higher autoantibodies responses to numerous transcription factors, immunomodulatory proteins, and human disease markers. Analysis of the combined cohorts revealed elevated autoantibody responses against SPANXN4, STK25, ATF4, PRKD2, and CHMP3 proteins in COVID-19 patients. KREX analysis of the specific IgG autoantibody responses indicates that the targeted host proteins are supposedly increased in COVID-19 patients. The autoantigen-autoantibody response was cross-validated for SPANXN4 and STK25 proteins using Uniprot BLASTP and sequence alignment tools. SPANXN4 is essential for spermiogenesis and male fertility, which may predict a potential role for this protein in COVID-19 associated male reproductive tract complications and warrants further research.

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The Notch Pathway: A Link Between COVID-19 Pathophysiology and Its Cardiovascular Complications

Cited by 35 publications

References 167 publications

Multi-omics insights into host-viral response and pathogenesis in Crimean-Congo hemorrhagic fever viruses for novel therapeutic target

Multi-omics insights into host-viral response and pathogenesis in Crimean-Congo hemorrhagic fever viruses for novel therapeutic target

Signaling Pathway Reporter Screen with SARS-CoV-2 Proteins Identifies nsp5 as a Repressor of p53 Activity

Auto-Immunoproteomics Analysis of COVID-19 ICU Patients Revealed Increased Levels of Autoantibodies Related to Male Reproductive System

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