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Integrin αvβ5 internalizes Zika virus during neural stem cells infection and is a target for antiviral therapy

ABSTRACT: Here, we performed the first CRISPR-Cas9 genome-wide screen in glioblastoma stem cells (GSCs) to identify factors determining ZIKV neurotropism. Using a ZIKV-ZsGreen reporter virus, a new strategy was developed to sort infection-resistant cells, expand, and enrich the resistant pool. Importantly, bioinformatics analysis and functional validation revealed integrin αvβ5 as an internalization factor for ZIKV. Expression of αvβ5 is correlated with ZIKV susceptibility in various cell lines and matched the cell tropism in developing human cerebral cortex. Blocking antibody against integrin αvβ5 but not αvβ3 efficiently inhibited ZIKV infection. Mechanistic evaluation showed that ZIKV binds to cells but fails to internalize when treated with integrin αvβ5 blocking antibody. αvβ5 directly binds to ZIKV virions, activates FAK (focal adhesion kinase), which is required for ZIKV infection. Strikingly, pharmaceutical inhibitors of αvβ5, SB273005 and cilengitide suppressed ZIKV infection at nanomolar concentrations. Finally, αvβ5 blocking antibody or inhibitors reduced ZIKV infection and alleviated ZIKV induced pathology in human neural stem cells (hNSC) and in mouse brain. This is the first study, to the best of our knowledge, identifying integrin αvβ5 is an internalization factor for ZIKV providing a new therapeutic target as well as two promising drug candidates that potentially can be used as prophylactics or treatments for ZIKV infections.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139142 | GEO | 2020/01/22

REPOSITORIES: GEO

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MFAP4 is an integrin αVβ3/5 ligand involved in vascular remodeling

Project description:Arterial injury or occlusive arterial disease may stimulate healing responses, which when overexuberant, leads to restenosis of the injured vessel. This response is influenced by specific integrin signalling in vascular smooth muscle cells (VSMCs). Microfibril-associated protein 4 (MFAP4) colocates in blood vessels with elastic fibers. MFAP4 contains an N-terminal RGD-motiv, which is a potential integrin binding site. The role for MFAP4 in vascularproliferative disease is so far unknown and the subject for these investigations. Here we show that MFAP4 is expressed and secreted by VSMCs and binds elastin and collagen. MFAP4 mediated adhesion, and migration, and proliferation of VSMCs in an integrin αVβ3/5 dependent manner and the effects were inhibited by MFAP4 blocking antibodies. MFAP4 deficient mutant mice were generated and appeared with a normal cardiophysiological phenotype. When challenged by carotid artery ligation, the MFAP4 deficient mice had delayed neointimal formation and the compensatory outward remodeling of the vessel diameter and thus the vessel lumen was reduced. MFAP4 expression appeared unaffected by the induced pathology. HUMANE DATA This new MFAP4 mediated molecular mechanism for regulation of integrin αVβ3/5 signalling may have therapeutic implications in diseases where VSMC migration and proliferation are involved in the pathogenesis.

2013-04-01 | GSE40480 | GEO

Integrin αvβ3 acting as membrane receptor for thyroid hormones mediates angiogenesis in malignant T cells

2015-02-18 | GSE63122 | GEO

The impact of Zika virus exposure on the placental proteomic profile

Project description:Zika virus (ZIKV) infection has caused severe unexpected clinical outcomes in neonates and adults during the recent outbreak in Latin America, particularly in Brazil. Congenital malformations associated with ZIKV have been frequently reported; nevertheless, the mechanism of vertical transmission and the involvement of placental cells remains unclear. In this study, we applied quantitative proteomics analysis in a floating explant model of chorionic villi of human placental tissues incubated with ZIKV and with ZIKV pre-adsorbed with anti-ZIKV envelope protein. The regulation of specific proteins was measured using immunofluorescence and immunoperoxidase assays. Altered levels of proteins were involved in cell proliferation, apoptosis, inflammatory processes, and the integrin-cytoskeleton complex. Antibody-opsonized ZIKV particles differentially modulated the pattern of protein expression in placental cells; this phenomenon may play a pivotal role in determining the course of infection and the role of mixed infections. These data fill gaps in our understanding of ZIKV in the placenta and help identify infection control targets.

2021-12-30 | PXD025764 | Pride

Integrin αvβ3 acting as membrane receptor for thyroid hormones mediates angiogenesis in malignant T cells

Project description:We have found that thyroid hormones (THs), acting as soluble integrin αvβ3 ligands, activate growth-related signaling pathways in T-cell lymphomas (TCL). Specifically, TH-activated αvβ3 integrin signaling promotes TCL proliferation and angiogenesis, in part, via the up-regulation of VEGF. CUTLL1 cells were treated with T3- and T4-bound agarose or agarose alone for 24hrs. Total RNA was harvested from cells and used for expression profiling via RNA-seq.

2015-02-18 | E-GEOD-63122 | biostudies-arrayexpress

Integrin beta 3 regulates cellular senescence by activating the TGFβ pathway

Project description:Cellular senescence is an important in vivo mechanism that prevents the propagation of damaged cells. However, the precise mechanism(s) regulating senescence are not well characterized. Here, we find that ITGB3 (integrin beta 3 or β3) is epigenetically regulated by the Polycomb protein CBX7. β3 expression accelerates the onset of senescence in human primary fibroblasts, by activating the TGFβ pathway in a cell autonomous and non-cell autonomous manner. β3 levels are dynamically increased during oncogeneinduced senescence (OIS) through CBX7 epigenetic regulation. DNA-damage and therapy-induced senescence (TIS) also induce β3 expression. In fact, downregulation of β3 levels override OIS and TIS, independently of its ligand-binding activity. Moreover, cilengitide, a αvβ3 antagonist, has the ability to block the SASP without affecting proliferation. Finally, we show an increase in β3 levels during aging in mice and humans. Altogether, our data show that integrin β3 subunit is a marker and regulator of senescence.

2017-03-09 | PXD005717 | Pride

ZIKV infection induces robust Th1-like Tfh cell and long-term protective antibody responses in immunocompetent mice

Project description:Induction of long-lived antibody responses during infection or vaccination is often essential for subsequent protection, but the relative contributions of T follicular helper (Tfh) cells and T helper 1 (Th1) cells for induction of antigen specific antibody responses to viruses are unclear. Here, we establish an acute Zika virus (ZIKV) infection model in immunocompetent mice, and show that ZIKV infection elicits robust Th1-like Tfh cell and protective antibody responses. While these Th1-like Tfh cells share phenotypic and transcriptomic profiles with both Tfh and Th1 cells, they also have unique surface markers and gene expression characteristics, and are dependent on T-bet for their development. Th1-like Tfh cells, but not Th1 cells, are essential for class switching of ZIKV-specific IgG2c antibodies and maintenance of long-term neutralizing antibody responses. Our study suggests that specific modulation of the Th1-like Tfh cell response during infection or vaccination may augment the induction of antiviral antibody response to ZIKV and other viruses.

2019-05-01 | GSE121250 | GEO

Natalizumab exerts direct signaling capacity and supports a pro-inflammatory phenotype in some patients with multiple sclerosis

Project description:Natalizumab is a recombinant monoclonal antibody raised against integrin alpha-4 (CD49d). It is approved for the treatment of patients with multiple sclerosis (MS), a chronic inflammatory autoimmune disease of the CNS. Natalizumab blocks leukocyte extravasation across the blood-brain barrier by inhibiting the molecular interaction between integrin alpha-4/beta-1 heterodimers expressed on leukocytes and VCAM-1 on inflammatory-activated CNS endothelium. Here we investigated whether binding of this adhesion-blocking antibody to T lymphocytes modulated their phenotype by direct induction of intracellular signaling events. Natalizumab induced a mild upregulation of IL-2, IFN-gamma and IL-17 expression in activated primary human CD4+ T cells propagated ex vivo from healthy donors, consistent with a pro-inflammatory costimulatory effect on lymphokine expression. Overall, the relative effect of natalizumab was more pronounced in less than in fully activated T cells. Along with this, natalizumab binding triggered rapid MAPK/ERK phosphorylation. Furthermore, it decreased CD49d surface expression on effector cells within a few hours. Sustained CD49d downregulation could be attributed to integrin internalization and degradation. Importantly, also CD4+ T cells from some MS patients receiving their very first dose of natalizumab produced more IL-2, IFN-gamma and IL-17 already 24 h after infusion. Together these data indicate that in addition to its adhesion-blocking mode of action, natalizumab possesses mild direct signaling capacities, which may support a pro-inflammatory phenotype of peripheral blood T lymphocytes. This might explain why a rebound of disease activity is observed in some MS patients after natalizumab cessation. Human CD4+ T cells from healthy donors were stimulated in the absence or presence of natalizumab for 10 days. To recall the developed program and induce cytokine expression, half of the cells were restimulated for a further 8 h.

2015-05-02 | E-GEOD-37783 | biostudies-arrayexpress

Repurposing an anti-cancer drug for the treatment of hypertrophic heart disease

Project description:Coronary microvascular dysfunction combined with maladaptive cardiomyocyte morphology and energetics are major contributors towards heart failure advancement. Thus dually enhancing cardiac angiogenesis and targeting cardiomyocyte function to slow, or reverse, the development of heart failure is a logical step towards improved therapy. We present evidence for the potential to repurpose a former anti-cancer Arg-Gly-Asp (RGD)-mimetic pentapeptide, Cilengitide, here used at low doses. Cilengitide targets avb3 integrin and this integrin is upregulated in human dilated and ischemic cardiomyopathies. Treatment of mice after transverse aortic constriction (TAC) surgery with low dose Cilengitide (ldCil) enhances coronary angiogenesis and directly affects cardiomyocyte hypertrophy with a correlating reduction disease severity. At a molecular level ldCil treatment has a direct effect on cardiac endothelial cell transcriptomic profiles with a significant enhancement of proangiogenic signalling pathways, corroborating the enhanced angiogenic phenotype after ldCil treatment.

2019-08-23 | GSE127854 | GEO

Lfc phospho-proteome (Lfc subcellular localization and activity is controlled by αv-class integrin)

Project description:Fibronectin (FN)-binding integrins control a variety of cellular responses through Rho GTPases. The FN-binding integrins, αvβ3 and α5β1, are known to induce different effects on cell morphology and motility. Here we report that FN-bound αvβ3 integrin, but not FN-bound α5β1 integrin, triggers the dissociation of the RhoA GEF Lfc (GEF-H1 in humans) from microtubules (MT), leading to the activation of RhoA, formation of stress fibres and maturation of focal adhesions (FAs). Conversely, loss of Lfc expression decreases RhoA activity, stress fibre formation and FA size, suggesting that Lfc is the major GEF downstream of FN-bound αvβ3 that controls RhoA activity. Mechanistically, FN-engaged αvβ3 integrin activates a kinase cascade involving MARK2/3, which in turn leads to phosphorylation of several phospho-sites on Lfc. In particular, S151 was identified as the main site involved in the regulation of Lfc localization and activity. Our findings indicate that activation of Lfc/RhoA is orchestrated in FN-adherent cells in an integrin-specific manner

2023-04-17 | PXD037633 | Pride

RhoA GEFs (Lfc subcellular localization and activity is controlled by αv-class integrin)

2023-04-17 | PXD037596 | Pride

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