Gefitinib and pyrrolidine dithiocarbamate decrease viral replication and cytokine production in dengue virus infected human monocyte cultures

Durán, Anyelo; Valero, Nereida; Mosquera, Jesús; Fuenmayor, Elisabeth Mary Rubio; Álvarez‐Mon, Melchor

doi:10.1016/j.lfs.2017.10.027

Cited by 27 publications

(16 citation statements)

References 32 publications

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“…56 Several anti-GFR TKIs, including those targeting more specifically HER2, TrkA, and PDGFR, have already been shown to block multiple steps of the replication of both influenza virus 45 and dengue virus. 57 Evidently, such encouraging results should prompt further testing against emerging coronavirus species.…”

Section: Pharmacological Inhibitors Of the Tyrosine Kinase Activitymentioning

confidence: 99%

The role of growth factor receptors in viral infections: An opportunity for drug repurposing against emerging viral diseases such as COVID‐19?

2020

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Section: Pharmacological Inhibitors Of the Tyrosine Kinase Activitymentioning

confidence: 99%

The role of growth factor receptors in viral infections: An opportunity for drug repurposing against emerging viral diseases such as COVID‐19?

2020

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“…Gefitinib also exerts an off-target inhibitory activity on the expression of RIP2 [41], thus the inhibition of CXCL8 secretion may be due to blockage of NOD/RIP2 signaling alongside that of EGFR. In support to this hypothesis, EGFR/NOD cooperation has been recently involved in cytokine production in dengue virus infected monocytes [42]. Moreover, a growing body of literature highlights the importance of EGFR/ErbB in several bacterial and viral inflammatory responses [15,43] and in pathogenic angiogenesis [44].…”

Section: Discussionmentioning

confidence: 91%

“…Our finding indicates an important role of EGFR activation in Bartonella invasion; however, as these EGFR inhibitors do not completely abrogate Bartonella uptake by MSCs, it is likely that other receptors, other than EGFR, may play a role in Bartonella infection. Moreover, it remains to be investigated whether EGFR activation is due to the direct interaction of Bartonella with the EGFR extracellular domain or by its transactivation by EGFR ligands (i.e., EGF, HBEGF, TGFα, BTC, AREG, EREG and EPGN)[42] as shown for H. pylori…”

mentioning

confidence: 99%

Persistent Infection of Human Mesenchymal Stromal Cells With Bartonella Henselae Exerts a Proangiogenic Effect

Scutera¹,

Mitola²,

Sparti³

et al. 2020

Preprint

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Background B henselae is in humans the aetiologic agent of cat-scratch disease and of the vasculoproliferative disorders bacillary angiomatosis and bacillary peliosis. Although endothelial cells are crucial in the pathogenesis other cell types function as reservoir and contribute to pathological angiogenesis. Among them, mesenchymal stromal cells (MSCs) can sense pathogens and mount an appropriate cytokine/chemokine response through different Pattern Recognition Receptors (PRRs). MSCs exert direct antimicrobial effector function but may also shelter bacteria such as M. tuberculosis. Methods Adipose-derived MSCs were infected with B. henselae and analyzed for bacterial persistence by gentamicin protection assay, immunohistochemistry and immunofluorescence. Involvement of PRRs in bacterial infection was evaluated through gene and protein expression analysis. The effect of infection on MSC proliferation, apoptosis and release of soluble factors was assessed. The role of infected-MSC conditioned medium in promoting Bartonella infection of endothelial cells and angiogenesis was demonstrated using respectively gentamicin protection assay and different pro-angiogenic assays including spheroid, wound healing and morphogenesis. Results B. henselae can readily infect MSCs and survive in perinuclear bound vacuoles for up to 8 days. Bartonella infection stimulates MSC proliferation and upregulation of EGFR and of the two pattern recognition receptors (PRRs) TLR2 and NOD1. Specific inhibition of EGFR reduces bacterial internalization and treatment with anti-TLR2 neutralizing antibody or EGFR/NOD1 inhibitors significantly downmodulates CXCL8 production. Secretome analysis shows that, in addition to CXCL8, infected MSCs secrete higher levels of the proangiogenic factors VEGF, FGF-7, MMP-9, PIGF, serpin E1, TSP-1, uPA, IL-6, CCL5 and PDGF-D. Importantly, supernatants from B. henselae-infected MSCs increase the susceptibility of ECs to B. henselae infection while enhancing EC proangiogenic potential. Conclusions Altogether, these findings indicate that MSCs constitute a novel niche for B. henselae, which favors the persistence of vascular proliferative disorders.

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“…It works by reducing the activity of the epidermal growth factor receptor (EGFR) tyrosine kinase domains. Of note, this drug also inhibits the tyrosine kinase activity of RIPK2 (39) and has been shown to inhibit replication of DENV and release of pro-inflammatory cytokines from infected human primary monocytes (40). The authors suggested a role for EGFR/RIPK2 in DENV pathogenesis and that gefitinib may be beneficial in the treatment of dengue patients.…”

Section: Discussionmentioning

confidence: 99%

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

Limonta

Branton

et al. 2020

Preprint

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In the present report, we describe two small molecules with broad-spectrum antiviral activity. These drugs block formation of the nodosome. The studies were prompted by the observation that infection of human fetal brain cells with Zika virus (ZIKV) induces expression of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a host factor that was found to promote ZIKV replication and spread. A drug that targets NOD2 was shown to have potent broad-spectrum antiviral activity against other flaviviruses, alphaviruses and SARS-CoV-2, the causative agent of COVID-19. Another drug that inhibits the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) which functions downstream of NOD2, also decreased replication of these pathogenic RNA viruses. The broad-spectrum action of nodosome targeting drugs is mediated, at least in part, by enhancement of the interferon response. Together, these results suggest that further preclinical investigation of nodosome inhibitors as potential broad-spectrum antivirals is warranted.

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Gefitinib and pyrrolidine dithiocarbamate decrease viral replication and cytokine production in dengue virus infected human monocyte cultures

Cited by 27 publications

References 32 publications

The role of growth factor receptors in viral infections: An opportunity for drug repurposing against emerging viral diseases such as COVID‐19?

The role of growth factor receptors in viral infections: An opportunity for drug repurposing against emerging viral diseases such as COVID‐19?

Persistent Infection of Human Mesenchymal Stromal Cells With Bartonella Henselae Exerts a Proangiogenic Effect

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

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