Abstract
Exosomes are small membrane-bound vesicles that carry biological macromolecules from the site of production to target sites either in the microenvironment or at distant sites away from the origin. Exosomal content of cells varies with the cell type that produces them as well as environmental factors that alter the normal state of the cell such as viral infection. Human DNA and RNA viruses alter the composition of host proteins as well as incorporate their own viral proteins and other cargo into the secreted exosomes. While numerous viruses can infect various cell types of the CNS and elicit damaging neuropathologies, few have been studied for their exosomal composition, content, and function on recipient cells. Therefore, there is a pressing need to understand how DNA and RNA viral infections in CNS control exosomal release. Some of the more recent studies including HIV-1, HTLV-1, and EBV-infected B cells indicate that exosomes from these infections contain viral miRNAs, viral transactivators, and a host of cytokines that can control the course of infection. Finally, because exosomes can serve as vehicles for the cellular delivery of proteins and RNA and given that the blood-brain barrier is a formidable challenge in delivering therapeutics to the brain, exosomes may be able to serve as ideal vehicles to deliver protein or RNA-based therapeutics to the brain.
Similar content being viewed by others
References
Agrawal L, Louboutin JP et al. (2012) HIV-1 Tat neurotoxicity: a model of acute and chronic exposure, and neuroprotection by gene delivery of antioxidant enzymes. Neurobiol Dis 45(2):657–670
Ali SA, Huang MB et al. (2010) Genetic characterization of HIV type 1 Nef-induced vesicle secretion. AIDS Res Hum Retrovir 26(2):173–192
Aline F, Bout D et al. (2004) Toxoplasma gondii antigen-pulsed-dendritic cell-derived exosomes induce a protective immune response against T. gondii infection. Infect Immun 72(7):4127–4137
Alvarez-Erviti L, Seow Y et al. (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29(4):341–345
Beatty WL (2008) Late endocytic multivesicular bodies intersect the chlamydial inclusion in the absence of CD63. Infect Immun 76(7):2872–2881
Becker H, Herzberg F et al. (2011) The carcinogenic potential of nanomaterials, their release from products, and options for regulating them. Int J Hyg Environ Health 214(3):231–238
Booth, AM, Fang Y et al. (2006) Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. J Cell Biol 172(6):923–935
Buzea C, Pacheco II et al. (2007) Nanomaterials and nanoparticles: sources and toxicity. Biointerphases 2(4):MR17–MR71
Campbell PE, Isayev O et al. (2012) Validation of a novel secretion modification region (SMR) of HIV-1 Nef using cohort sequence analysis and molecular modeling. J Mol Model 18(10):4603–4613
Colino J, Snapper CM (2007) Dendritic cell-derived exosomes express a Streptococcus pneumoniae capsular polysaccharide type 14 cross-reactive antigen that induces protective immunoglobulin responses against pneumococcal infection in mice. Infect Immun 75(1):220–230
Colombo, M., C. Moita, et al. (2013) Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. J Cell Sci
Dreux M, Garaigorta U et al. (2012) Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity. Cell Host Microbe 12(4):558–570
El-Andaloussi S, Lakhal S et al. (2013) Exosomes for targeted siRNA delivery across biological barriers. Adv Drug Deliv Rev 65(3):391–397
Escudier B, Dorval T et al. (2005) Vaccination of metastatic melanoma patients with autologous dendritic cell (DC)-derived exosomes: results of the first phase I clinical trial. J Transl Med 3(1):10
Faure J, Lachenal G et al. (2006) Exosomes are released by cultured cortical neurones. Mol Cell Neurosci 31(4):642–648
Fruhbeis C, Frohlich D et al. (2013) Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol 11(7):e1001604
Gendreau KL, Hall GF (2013) Tangles, toxicity, and tau secretion in AD—new approaches to a vexing problem. Front Neurol 4:160
Giri PK, Kruh NA et al. (2010) Proteomic analysis identifies highly antigenic proteins in exosomes from M. tuberculosis-infected and culture filtrate protein-treated macrophages. Proteomics 10(17):3190–3202
Heaton RK, Clifford DB et al. (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: charter study. Neurology 75(23):2087–2096
Heaton RK, Franklin DR et al. (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol 17(1):3–16
Henne WM, Buchkovich NJ et al. (2011) The ESCRT pathway. Dev Cell 21(1):77–91
Hooper C, Sainz-Fuertes R et al. (2012) Wnt3a induces exosome secretion from primary cultured rat microglia. BMC Neurosci 13:144
Hu G, Yao H et al. (2012) Exosome-mediated shuttling of microRNA-29 regulates HIV Tat and morphine-mediated neuronal dysfunction. Cell Death Dis 3:e381
Ikeda M, Longnecker R (2007) Cholesterol is critical for Epstein-Barr virus latent membrane protein 2A trafficking and protein stability. Virology 360(2):461–468
Izquierdo-Useros N, Naranjo-Gomez M et al. (2010) HIV and mature dendritic cells: Trojan exosomes riding the Trojan horse? PLoS Pathog 6(3):e1000740
Johnstone RM, Mathew A et al. (1991) Exosome formation during maturation of mammalian and avian reticulocytes: evidence that exosome release is a major route for externalization of obsolete membrane proteins. J Cell Physiol 147(1):27–36
Kadiu I, Narayanasamy P et al. (2012) Biochemical and biologic characterization of exosomes and microvesicles as facilitators of HIV-1 infection in macrophages. J Immunol 189(2):744–754
Keryer-Bibens C, Pioche-Durieu C et al. (2006) Exosomes released by EBV-infected nasopharyngeal carcinoma cells convey the viral latent membrane protein 1 and the immunomodulatory protein galectin 9. BMC Cancer 6:283
Klibi J, Niki T et al. (2009) Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein-Barr virus-infected nasopharyngeal carcinoma cells. Blood 113(9):1957–1966
Korkut C, Ataman B et al. (2009) Trans-synaptic transmission of vesicular Wnt signals through Evi/Wntless. Cell 139(2):393–404
Kramer-Albers EM, Bretz N et al. (2007) Oligodendrocytes secrete exosomes containing major myelin and stress-protective proteins: trophic support for axons? Proteomics Clin Appl 1(11):1446–1461
Kulshreshtha A, Ahmad T et al. (2013) "Proinflammatory role of epithelial cell-derived exosomes in allergic airway inflammation.". J Allergy Clin Immunol 131(4):1194–1203, 1203 e1191-1114
Laulagnier K, Motta C et al. (2004) Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization. Biochem J 380(Pt 1):161–171
Leblanc P, Alais S et al. (2006) Retrovirus infection strongly enhances scrapie infectivity release in cell culture. EMBO J 25(12):2674–2685
Luga V, Zhang L et al. (2012) Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 151(7):1542–1556
Mani KS, Mani AJ et al. (1969) A spastic paraplegic syndrome in South India. J Neurol Sci 9(1):179–199
Meckes DG Jr, Shair KH et al. (2010) Human tumor virus utilizes exosomes for intercellular communication. Proc Natl Acad Sci U S A 107(47):20370–20375
Meckes DG Jr, Gunawardena HP et al. (2013) Modulation of B-cell exosome proteins by gamma herpes virus infection. Proc Natl Acad Sci USA 110(31):E2925–E2933
Morse MA, Garst J et al. (2005) A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med 3(1):9
Narayanan A, Iordanskiy S et al. (2013) Exosomes derived from HIV-1-infected cells contain trans-activation response element RNA. J Biol Chem 288(27):20014–20033
Neumann J, Eis-Hubinger AM et al. (2003) Herpes simplex virus type 1 targets the MHC class II processing pathway for immune evasion. J Immunol 171(6):3075–3083
Osame M, Matsumoto M et al. (1987) Chronic progressive myelopathy associated with elevated antibodies to human T lymphotropic virus type I and adult T cell leukemia-like cells. Ann Neurol 21(2):117–122
Pegtel DM, Cosmopoulos K et al. (2010) Functional delivery of viral miRNAs via exosomes. Proc Natl Acad Sci U S A 107(14):6328–6333
Potolicchio I, Carven GJ et al. (2005) Proteomic analysis of microglia-derived exosomes: metabolic role of the aminopeptidase CD13 in neuropeptide catabolism. J Immunol 175(4):2237–2243
Ramakrishnaiah V, Thumann C et al. (2013) Exosome-mediated transmission of hepatitis C virus between human hepatoma Huh7.5 cells. Proc Natl Acad Sci U S A 110(32):13109–13113
Roman GC, Spencer PS et al. (1987) Tropical spastic paraparesis: HTLV-I antibodies in patients from the Seychelles. N Engl J Med 316(1):51
Shelton MN, Huang MB et al. (2012) Secretion modification region-derived peptide disrupts HIV-1 Nef's interaction with mortalin and blocks virus and Nef exosome release. J Virol 86(1):406–419
Skubis-Zegadlo J, Stachurska A et al. (2013) Vectrology of adeno-associated viruses (AAV). Med Wieku Rozwoj 17(3):202–206
Subra C, Laulagnier K et al. (2007) Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie 89(2):205–212
Sun D, Zhuang X et al. (2010) A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther 18(9):1606–1614
Taylor AR, Robinson MB et al. (2007) Regulation of heat shock protein 70 release in astrocytes: role of signaling kinases. Dev Neurobiol 67(13):1815–1829
Temme S, Eis-Hubinger AM et al. (2010) The herpes simplex virus-1 encoded glycoprotein B diverts HLA-DR into the exosome pathway. J Immunol 184(1):236–243
Thery, C., S. Amigorena, et al. (2006). "Isolation and characterization of exosomes from cell culture supernatants and biological fluids." Curr Protoc Cell Biol Chapter 3:3.22.1–3.22.29
Tian T, Wang Y et al. (2010) Visualizing of the cellular uptake and intracellular trafficking of exosomes by livecell microscopy. J Cell Biochem 111(2):488–496
Trajkovic K, Hsu C et al. (2008) Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319(5867):1244–1247
Vernant JC, Buisson GG et al. (1987) Can HTLV-1 lead to immunological disease? Lancet 2(8555):404
Viaud S, Thery C et al. (2010) Dendritic cell-derived exosomes for cancer immunotherapy: what's next? Cancer Res 70(4):1281–1285
Wang G, Dinkins M et al. (2012) Astrocytes secrete exosomes enriched with proapoptotic ceramide and prostate apoptosis response 4 (PAR-4): potential mechanism of apoptosis induction in Alzheimer disease (AD). J Biol Chem 287(25):21384–21395
Webber J, Clayton A (2013) How pure are your vesicles? J Extracell Vesicles 2:19861
Zhuang X, Xiang X et al. (2011) Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther 19(10):1769–1779
Acknowledgement
We would like to thank the members of the Kashanchi lab for assistance with the manuscript. This work was supported by NIH grant AI070740 to FK and the Geneva Foundation grant W81XWH-11-0126 to RMH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Geneva Foundation.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Gavin C Sampey and Shabana S Meyering contributed equally to this study.
Rights and permissions
About this article
Cite this article
Sampey, G.C., Meyering, S.S., Asad Zadeh, M. et al. Exosomes and their role in CNS viral infections. J. Neurovirol. 20, 199–208 (2014). https://doi.org/10.1007/s13365-014-0238-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13365-014-0238-6