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CX3CR1-CX3CL1-dependent cell-to-cell Japanese encephalitis virus transmission by human microglial cells.

ABSTRACT: The neurotropic Japanese encephalitis virus (JEV) is responsible for Japanese encephalitis, an uncontrolled inflammatory disease of the central nervous system. Microglia cells are the unique innate immune cell type populating the brain that cross-communicate with neurons via the CX3CR1-CX3CL1 axis. However, microglia may serve as a viral reservoir for JEV. Human microglia are able to transmit JEV infectivity to neighbouring cells in a cell-to-cell contact-dependent manner. Using JEV-treated human blood monocyte-derived microglia, the present study investigates molecular mechanisms behind cell-to-cell virus transmission by human microglia. For that purpose, JEV-associated microglia were co-cultured with JEV susceptible baby hamster kidney cells under various conditions. Here, we show that microglia hosting JEV for up to 10 days were able to transmit the virus to susceptible cells. Interestingly, neutralizing anti-JEV antibodies did not completely abrogate cell-to-cell virus transmission. Hence, intracellular viral RNA could be a contributing source of infectious virus material upon intercellular interactions. Importantly, the CX3CL1-CX3CR1 axis was a key regulator of cell-to-cell virus transmission from JEV-hosting human microglia. Our findings suggest that human microglia may be a source of infection for neuronal populations and sustain JEV brain pathogenesis in long-term infection. Moreover, the present work emphasizes on the critical role of the CX3CR1-CX3CL1 axis in JEV pathogenesis mediating transmission of infectious genomic JEV RNA.

SUBMITTER: Lannes N

PROVIDER: S-EPMC6423114 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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CX3CR1-CX3CL1-dependent cell-to-cell Japanese encephalitis virus transmission by human microglial cells.

Lannes Nils N Garcia-Nicolàs Obdullio O Démoulins Thomas T Summerfield Artur A Filgueira Luis L

Scientific reports 20190318 1

The neurotropic Japanese encephalitis virus (JEV) is responsible for Japanese encephalitis, an uncontrolled inflammatory disease of the central nervous system. Microglia cells are the unique innate immune cell type populating the brain that cross-communicate with neurons via the CX3CR1-CX3CL1 axis. However, microglia may serve as a viral reservoir for JEV. Human microglia are able to transmit JEV infectivity to neighbouring cells in a cell-to-cell contact-dependent manner. ...[more]

PMID: 30886214

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Project description:Natural killer (NK) cell can inhibit tumor initiation and regulates metastatic dissemination, acting as key mediators of the innate immune response. Intrinsic factors modulating NK cells infiltration and its anticancer activity remain poorly characterized. We investigated the roles of dysregulation of micro(mi)RNAs and NK cells in progression of hepatocellular carcinoma (HCC). Methods: Small RNA sequencing were used to detect the miRNA profiles of tumor tissues from HCC patients with (n=14) or without (n=13) pulmonary metastasis and HCC cell lines with different pulmonary metastatic potentials. Chemokine expression profiling and bioinformatics were used to detect the downstream target of candidate target. In gain- and loss-of-function assays were used to investigate the role of miRNA in HCC progression. Different subsets of NK cells were isolated and used for chemotaxis and functional assays in vivo and in vitro. In situ hybridization and immunohistochemical analyses were performed to detect the expression of miRNA in tumor tissues from 242 HCC patients undergoing curative resection from 2010. Results: Three miRNAs (miR-137, miR-149-5p, and miR-561-5p) were identified to be associated with pulmonary metastasis in patients with HCC. miR-561-5p was most highly overexpressed in metastatic HCC tissues and high-metastatic-potential HCC cell lines. In gain- and loss-of-function assays in a murine model, miR-561-5p promoted tumor growth and spread to the lungs. Yet, miR-561-5p did not appear to affect cellular proliferation and migration in vitro. Bioinformatics and chemokine expression profiling identified chemokine (C-X3-C motif) ligand 1 (CX3CL1) as a potential target of miR-561-5p. Furthermore, miR-561-5p promoted tumorigenesis and metastasis via CX3CL1-dependent regulation of CX3CR1+ NK cell infiltration and function. CX3CR1+ NK cells demonstrated stronger in vivo anti-metastatic activity relative to CX3CR1- NK cells. CX3CL1 stimulated chemotactic migration and cytotoxicity in CX3CR1+ NK cells via STAT3 signaling. Blockade of CX3CL1, CX3CR1, or of pSTAT3 signaling pathways attenuated the antitumor responses. Clinical samples exhibited a negative correlation between miR-561-5p expression and levels of CX3CL1 and CX3CR1+ NK cells. High miR-561-5p abundance, low CX3CL1 levels, and low numbers of CX3CR1+ NK cells were associated with adverse prognosis. Conclusion: We delineated a miR-561-5p/CX3CL1/NK cell axis that drives HCC metastasis and demonstrated that CX3CR1+ NK cells serve as potent antitumor therapeutic effectors.

Project description:BackgroundAngiostrongylus cantonensis (A. cantonensis), is a food-borne zoonotic parasite that can cause central nervous system (CNS) injury characterized by eosinophilic meningitis. However, the pathogenesis of angiostrongylosis remains elusive. Natural killer cells (NK cells) are unique innate lymphocytes important in early defense against pathogens. The aim of this study was to investigate the role of NK cells in A. cantonensis infection and to elucidate the key factors that recruit NK cells into the CNS.MethodsMouse model of A. cantonensis infection was established by intragastric administration of third-stage larvae. The expression of cytokines and chemokines at gene and protein levels was analyzed by qRT-PCR and ELISA. Distribution of NK cells was observed by immunohistochemistry and flow cytometry. NK cell-mediated cytotoxicity against YAC-1 cells was detected by LDH release assay. The ability of NK cells to secrete cytokines was determined by intracellular flow cytometry and ELISA. Depletion and adoptive transfer of NK cells in vivo was induced by tail vein injection of anti-asialo GM1 rabbit serum and purified splenic NK cells, respectively. CX3CL1 neutralization experiment was performed by intraperitoneal injection of anti-CX3CL1 rat IgG.ResultsThe infiltration of NK cells in the CNS of A. cantonensis-infected mice was observed from 14 dpi and reached the peak on 18 and 22 dpi. Compared with uninfected splenic NK cells, the CNS-infiltrated NK cells of infected mice showed enhanced cytotoxicity and increased IFN-γ and TNF-α production ability. Depletion of NK cells alleviated brain injury, whereas adoptive transfer of NK cells exacerbated brain damage in A. cantonensis-infected mice. The expression of CX3CL1 in the brain tissue and its receptor CX3CR1 on the CNS-infiltrated NK cells were both elevated after A. cantonensis infection. CX3CL1 neutralization reduced the percentage and absolute number of the CNS-infiltrated NK cells and relieved brain damage caused by A. cantonensis infection.ConclusionsOur results demonstrate that the up-regulated CX3CL1 in the brain tissue recruits NK cells into the CNS and aggravates brain damage caused by A. cantonensis infection. The findings improve the understanding of the pathogenesis of angiostrongyliasis and expand the therapeutic intervention in CNS disease.

Dataset Information

CX3CR1-CX3CL1-dependent cell-to-cell Japanese encephalitis virus transmission by human microglial cells.

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CX<sub>3</sub>CR1-CX<sub>3</sub>CL1-dependent cell-to-cell Japanese encephalitis virus transmission by human microglial cells.

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