Modulation of B-cell exosome proteins by gamma herpesvirus infection

Lineberger Comprehensive Cancer Center, Program in Molecular Biology and Biotechnology, and Department of Microbiology-Immunology, University of North Carolina, Chapel Hill, NC 27599.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 07/2013; 110(31). DOI: 10.1073/pnas.1303906110
Source: PubMed

ABSTRACT The human gamma herpesviruses, Kaposi sarcoma-associated virus (KSHV) and EBV, are associated with multiple cancers. Recent evidence suggests that EBV and possibly other viruses can manipulate the tumor microenvironment through the secretion of specific viral and cellular components into exosomes, small endocytically derived vesicles that are released from cells. Exosomes produced by EBV-infected nasopharyngeal carcinoma cells contain high levels of the viral oncogene latent membrane protein 1 and viral microRNAs that activate critical signaling pathways in recipient cells. In this study, to determine the effects of EBV and KSHV on exosome content, quantitative proteomics techniques were performed on exosomes purified from 11 B-cell lines that are uninfected, infected with EBV or with KSHV, or infected with both viruses. Using mass spectrometry, 871 proteins were identified, of which ∼360 were unique to the viral exosomes. Analysis by 2D difference gel electrophoresis and spectral counting identified multiple significant changes compared with the uninfected control cells and between viral groups. These data predict that both EBV and KSHV exosomes likely modulate cell death and survival, ribosome function, protein synthesis, and mammalian target of rapamycin signaling. Distinct viral-specific effects on exosomes suggest that KSHV exosomes would affect cellular metabolism, whereas EBV exosomes would activate cellular signaling mediated through integrins, actin, IFN, and NFκB. The changes in exosome content identified in this study suggest ways that these oncogenic viruses modulate the tumor microenvironment and may provide diagnostic markers specific for EBV and KSHV associated malignancies.

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    • "However, there are multiple benefits in transplanting exosomes rather than in transplanting the whole " factory, " the cell, into the body. In contrast to exogenously administered cells delivered systemically, exosomes, given their nano dimension may readily enter the brain and easily pass through the blood brain barrier (BBB) (Alvarez-Erviti et al., 2011; Kooijmans et al., 2012; Anthony and Shiels, 2013; Gheldof et al., 2013; Meckes et al., 2013). Exogenously administered MSCs may have many adverse effects, i. e. tumor modulation and malignant transformation. "
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    • "While still a relatively new field of study, experiments performed in regard to the effect of viral infections on host exosomes have begun to delineate the alterations of exosomal composition and determine the biochemical mechanisms driving variation in exosomal content. A recent proteomic analysis of B cells infected with either Kaposi's sarcoma herpes virus (KSHV), Epstein–Barr Virus (EBV), or a dual infection showed major changes to the exosomal protein composition as compared to exosomes from the uninfected parental cell line (Meckes et al., 2013). Specifically , a total of 345 proteins were identified by mass spectrometry to be uniquely incorporated into the exosomes released from the infected cells. "
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