Nodosome inhibition as a novel broad-spectrum antiviral strategy against arboviruses and SARS-CoV-2

Limonta, Daniel; L, Dyna-Dagman; Branton, William G.; Rw, Wozniak; Power, Christopher; Tc, Hobman

doi:10.1101/2020.11.05.370767

Cited by 2 publications

(2 citation statements)

References 41 publications

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“…A multiplicity of infection of 3 was used with 1 h of adsorption followed by incubation for 48 h followed by extraction of total cell RNA (Macherey-Nagel GmbH & Co., Düren, Germany) and collection of media for virus RNA quantitation by qRT-PCR [ 2 ] and viral titer determination by plaque assay in Vero E6 cells respectively. Lung endothelial cells on coverslips were also infected, using the same conditions before processing for indirect immunofluorescence and confocal microcopy analysis as described [ 98 ]. We observed very low titers (3–4.5 10^2 PFU/mL) together with modest viral RNA levels in infected endothelial cells ( Figure 2 A).…”

Section: Does Sars-cov-2 Infect Endothelial Cells?mentioning

confidence: 99%

Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19

Bernard

Limonta

Mahal

et al. 2020

Viruses

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152

130

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The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) poses a persistent threat to global public health. Although primarily a respiratory illness, extrapulmonary manifestations of COVID-19 include gastrointestinal, cardiovascular, renal and neurological diseases. Recent studies suggest that dysfunction of the endothelium during COVID-19 may exacerbate these deleterious events by inciting inflammatory and microvascular thrombotic processes. Although controversial, there is evidence that SARS-CoV-2 may infect endothelial cells by binding to the angiotensin-converting enzyme 2 (ACE2) cellular receptor using the viral Spike protein. In this review, we explore current insights into the relationship between SARS-CoV-2 infection, endothelial dysfunction due to ACE2 downregulation, and deleterious pulmonary and extra-pulmonary immunothrombotic complications in severe COVID-19. We also discuss preclinical and clinical development of therapeutic agents targeting SARS-CoV-2-mediated endothelial dysfunction. Finally, we present evidence of SARS-CoV-2 replication in primary human lung and cardiac microvascular endothelial cells. Accordingly, in striving to understand the parameters that lead to severe disease in COVID-19 patients, it is important to consider how direct infection of endothelial cells by SARS-CoV-2 may contribute to this process.

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Section: Does Sars-cov-2 Infect Endothelial Cells?mentioning

confidence: 99%

Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19

Bernard

Limonta

Mahal

et al. 2020

Viruses

Self Cite

152

130

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“…NOD-2 activation has been a striking finding arose during SARS-CoV2 pandemic research, documenting a Nodosome activation (NOD2-RIP2) during Zika virus, DENV and SARS-CoV2 infection in cell lines [37].…”

Section: Discussionmentioning

confidence: 98%

Dengue virus type 2 replication is limited by activation of NOD2 and its interactions with RIP2 and MAVS adaptors in THP-1 macrophage-like cells

Domínguez-Martínez¹,

Avellaneda²,

Cruz³

et al. 2021

Preprint

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The nucleotide-binding domain (NBD) and leucine-rich repeat receptors, such as NOD-like receptors (NLRs), have pivotal functions in the innate immune response to various viral infections participating during the recognition of pathogens and activation of signaling pathways. One NLR, NOD2, is a dynamic protein that is activated in the presence of viral genomes and metabolites. However, its participation in combating a dengue virus (DENV) infection remains unclear. The aim of this study was to determine the role of NOD2 in macrophage-like THP-1 cells during an in vitro infection with DENV type 2 (DENV2). The interactions of NOD2 with RIP2 and MAVS was examined in DENV2-infected and agonist-stimulated cells. The effects of downregulating NOD2 expression or signaling on virus loads was also evaluated. The cellular mRNA expression and protein levels of NOD2 on cells under the stimuli were quantified with RT-PCR, Western blot and indirect immunofluorescence. Both the mRNA and protein expression of NOD2 was enhanced in response to DENV-2 infection. Interactions of NOD2 with RIP2 and MAVS, analyzed with confocal microscopy and co-immunoprecipitation assays, were time-dependent and increased in the post-infection period, between 6 and 24 h. After silencing NOD2 expression, DENV2-infected cells displayed greater viral loads and decreased expression of IL-8 and IFN-α (measured in supernatants obtained from the cells), compared to the uninfected (mock control) cells or those transfected with irrelevant-siRNA. Thus, in response to a DENV2 infection, NOD2 was activated in THP-1 human macrophage-like cells, the production of IL-8 and IFN-α was enhanced, and viral replication was limited.

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Nodosome inhibition as a novel broad-spectrum antiviral strategy against arboviruses and SARS-CoV-2

Cited by 2 publications

References 41 publications

Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19

Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19

Dengue virus type 2 replication is limited by activation of NOD2 and its interactions with RIP2 and MAVS adaptors in THP-1 macrophage-like cells

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