Modulation of B-cell exosome proteins by gamma herpesvirus infection (original) (raw)
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Pathogenic Role of Exosomes in Epstein-Barr Virus (EBV)-Associated Cancers
Exosomes are 40-to 100-nm membrane-bound small vesicles that carry a great variety of cellular cargoes including proteins, DNA, messenger RNAs (mRNAs), and microRNAs (miRNAs). These nanovesicles are detected in various biological fluids such as serum, urine, saliva, and seminal fluids. Exosomes serve as key mediators in intercellular communication by facilitating the transfer and exchange of cellular components from cells to cells. They contain various pathogenic factors whereby their adverse effects have been implicated in multiple viral infections and cancers. Interestingly, accumulating evidences showed that exosomes derived from tumour viruses or oncoviruses, exacerbate virus-associated cancers by remodelling the tumour microenvironment. In this review, we summarize the contributing factors of Epstein-Barr virus (EBV) products-containing exosomes in viral pathogenesis and their potential implications in EBV-driven malignancies. Understanding the biological role of these exosomes in the disease would undoubtedly boost the development of a more comprehensive strategy to combat EBV-associated cancers and to better predict the therapeutic outcomes. Furthermore, we also highlight the potentials and challenges of EBV products-containing exosomes being employed as diagnostic markers and therapeutic targets for EBV-related cancers. Since these aspects are rather underexplored, we attempt to underline interesting areas that warrant further investigations in the future.
Exosomes as the Promising Biomarker for Epstein-Barr Virus (EBV)-Associated Cancers
Exosomes are microvesicles with sizes ranging from 50 to 150 nm. These small vesicles are known to morphologically and functionally resemble virus particles from human immunodeficiency virus type I (HIV-I) and human T-lymphotropic virus type I (HTLV-I). The function of exosomes is to mainly mediate cell-to-cell communication by exchanging various macromolecules including proteins, lipids and nucleic acids in diverse cellular processes. Due to its size and structural simplicity, the transfer of pathogenic or virulent cellular factors across the cells mediated by exosomes is more efficient, hence facilitating the dissemination of viral infections and cancer diseases. The pathogenic role of exo-somes in various cancers such as lung and breast, and their potentials as biomarkers have been previously studied, yet limited information is known for Epstein-Barr virus (EBV)-associated cancers. In this chapter, we discuss current evidences that support the pathogenic roles of exosomes in EBV-related cancers and their potentials as biomarkers in cancer diagnostics and therapy response. Here, we also highlight the potential challenges in the development of exosome-based biomarkers for clinical application.
Cancer Letters, 2013
EBV is a human herpesvirus associated with a number of malignancies. Both lymphoblastoid cell lines (LCLs), and EBV-infected nasopharyngeal carcinoma (NPC) cells have been demonstrated to release exosomes containing the EBV-encoded latent membrane protein 1 (LMP1), and mature micro-RNAs (EBV-miRNAs). Here we analyze the EBV protein and nucleic acid content of exosomes from different EBV-infected cells (LCL, 721 and Daudi) and we show for the first time that exosomes released from LCLs and 721 also contain EBV-encoded latent phase mRNAs. This confirms and strengthens exosomes pathogenetic potential, and might provide insights for development of novel diagnostic and therapeutic strategies.
Journal of Virology, 2013
35 Epstein-Barr virus (EBV), a human gamma herpesvirus, establishes a life-long latent 36 infection in B lymphocytes and epithelial cells following primary infection. Several lines of 37 evidence suggest that exosomes derived from EBV-infected cells are internalized and transfer 38 viral factors including EBV-encoded latent membrane protein and micro RNAs to the recipient 39 cells. However the detailed mechanism by which exosomes are internalized and their 40 physiological impact on the recipient cells are still poorly understood. Here, we visualized the 41 internalization of fluorescently labeled exosomes derived from EBV-uninfected and 42 EBV-infected B cells of type I, and type III latency into EBV-negative epithelial cells. In this 43 way, we demonstrated that exosomes derived from all three cell types were internalized into the 44 target cells in a similar fashion. Internalization of exosomes was significantly suppressed by 45 treatment with an inhibitor of dynamin and also by the knockdown of caveolin-1. Labeled 46 exosomes were co-localized with caveolae, and subsequently trafficked through endocytic 47 pathways. Moreover, we observed that exosomes derived from type III latency cells 48 up-regulated proliferation and expression of intercellular adhesion molecule 1 (ICAM-1) in the 49 recipient cells more significantly than did those derived from EBV-negative and type I latency 50 cells. We also identified the EBV-encoded latent membrane protein 1 (LMP1) as a gene 51 on December 18, 2016 by guest http://jvi.asm.org/ Downloaded from 4 responsible for induction of ICAM-1 expression. Taken together, our data indicate that 52 exosomes released from EBV-infected B cells are internalized via caveolae-dependent 53 endocytosis, which in turn contribute to phenotypic changes in the recipient cells through 54 transferring one or more viral factors. 55 56 57 58 59 60 61 62 63 64 65 66 67 68 on December 18, 2016 by guest http://jvi.asm.org/ Downloaded from Introduction 69 Epstein-Barr virus (EBV), a human gamma herpesviruses, establishes a persistent, latent 70 infection in B lymphocytes and epithelial cells following primary infection (1). EBV has been 71 implicated as a cause of lymphomas and epithelial malignancies such as Burkitt's lymphoma 72 (BL), Hodgkin's disease (HD), nasopharyngeal carcinoma (NPC), and gastric carcinoma (GC).
Emerging role of exosomal secretory pathway in human tumour virus pathogenesis
Viruses are well known for their ability to hijack and manipulate the host cellular machinery to ensure immune evasion, viral survival and pathogenesis. Most animal viruses exhibit exclusive tropism and thus, infect only specific target cells. However, reports on the existence of virions and viral components in non-target cells suggest alternative mechanisms of viral spread. Studies on microvesicles and exosomes promise to provide justification for the presence of viruses at unrelated cell types. Exosomes have attracted the attention of not only cell biologist but also virologist as these vesicles can transport and deliver bioactive information (RNA, proteins, microRNA etc. including virus specific components from infected cells) to unrelated cell types and have the potential to regulate target cell function. Recent studies suggest that viruses can manipulate and hijack the exosome biogenesis and secretory pathway to manipulate the host microenvironment, evade immune response and increase viral accessibility. Here, we review the existing literature on viral interference and exploitation of exosome secretory mechanisms and correlate it with the increased virulence and spread of viruses in the host. Further, we discuss the prospects of exosomes as emerging biomarkers for virus induced pathology, potential of exosomes as delivery vehicles and also the new perspective to viral mediated pathogenesis.
Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma
Blood, 2018
Epstein-Barr virus (EBV) causes various diseases in the elderly including B-cell lymphoma such as Hodgkin's lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL). Here, we show that EBV acts in trans on non-infected macrophages in the tumor through exosome secretion and augments the development of lymphomas. In a humanized mouse model, the different formation of lymphoproliferative disease (LPD) between two EBV strains (Akata and B95-8) was evident. Furthermore, injection of Akata derived exosomes affected LPD severity possibly through the regulation of macrophage phenotype in vivo. Exosomes collected from Akata- lymphoblastoid cell lines (LCLs) reportedly contain EBV-derived non-coding RNAs such as BamHI fragment A rightward transcript (BART) miRNAs and EBV-encoded RNA (EBER). We focused on the exosome-mediated delivery of BART miRNAs. In vitro, BART miRNAs could induce the immune regulatory phenotype in macrophages characterized by the gene expressions of , , and , suggestin...
Cellular & Molecular Biology Letters
Exosomes, known as a type of extracellular vesicles (EVs), are lipid particles comprising heterogeneous contents such as nucleic acids, proteins, and DNA. These bi-layered particles are naturally released into the extracellular periphery by a variety of cells such as neoplastic cells. Given that exosomes have unique properties, they can be used as vectors and carriers of biological and medicinal particles like drugs for delivering to the desired areas. The proteins and RNAs being encompassed by the circulating exosomes in B-cell malignancies are deemed as the promising sources for diagnostic and prognostic biomarkers, as well as therapeutic agents. Exosomes can also provide a “snapshot” view of the tumor and metastatic landscape at any particular time. Further, clinical research has shown that exosomes are produced by immune cells such as dendritic cells can stimulate the immune system, so these exosomes can be used in antitumor vaccines. Despite the great potential of exosomes in t...
PLoS ONE, 2014
Epstein-Barr virus (EBV) is an oncogenic herpesvirus associated with a number of human malignancies of epithelial and lymphoid origin. However, the mechanism of oncogenesis is unclear. A number of viral products, including EBV latent proteins and non-protein coding RNAs have been implicated. Recently it was reported that EBV-encoded small RNAs (EBERs) are released from EBV infected cells and they can induce biological changes in cells via signaling from toll-like receptor 3. Here, we investigated if these abundantly expressed non-protein coding EBV RNAs (EBER-1 and EBER-2) are excreted from infected cells in exosomal fractions. Using differential ultracentrifugation we isolated exosomes from three EBV positive cell lines (B95-8, EBV-LCL, BL30-B95-8), one EBER-1 transfected cell line (293T-pHEBo-E1) and two EBV-negative cell lines (BL30, 293T-pHEBo). The identity of purified exosomes was determined by electron microscopy and western blotting for CD63. The presence of EBERs in cells, culture supernatants and purified exosomal fractions was determined using RT-PCR and confirmed by sequencing. Purified exosomal fractions were also tested for the presence of the EBER-1-binding protein La, using western blotting. Both EBER-1 and EBER-2 were found to be present not only in the culture supernatants, but also in the purified exosome fractions of all EBV-infected cell lines. EBER-1 could also be detected in exosomal fractions from EBER-1 transfected 293T cells whilst the fractions from vector only transfectants were clearly negative. Furthermore, purified exosomal fractions also contained the EBER-binding protein (La), supporting the notion that EBERs are most probably released from EBV infected cells in the form of EBER-La complex in exosomes.
Journal of General Virology, 2015
Epstein–Barr virus (EBV; human herpesvirus 4) is an oncogenic herpesvirus implicated in the pathogenesis of several human malignancies. A number of recent studies indicate that EBV can manipulate the local microenvironment by excreting viral and cellular components in nanovesicles called exosomes. In this study, we investigated the impact of EBV-derived exosomes on apoptosis of recipient cells and the molecular pathway involved in this process. Exosomes from EBV-infected but not from non-infected cells induced apoptosis in a number of different cell types, including B-cells, T-cells and epithelial cells. However, this phenomenon was not universal and the Burkitt's lymphoma-derived B-cell line BJAB was found to be resistant to apoptosis. Exosomes from both type I and type III EBV latently infected cells induced apoptosis in a dose- and time-dependent manner. Moreover, cells exposed to EBV exosomes did not form colonies in soft agar assays. We further show that fluorescently label...