- Open Access
Antiviral activity of salivary microRNAs for ophthalmic herpes zoster
© Irmak et al.; licensee BioMed Central Ltd. 2012
- Received: 18 April 2012
- Accepted: 25 May 2012
- Published: 7 June 2012
Ophthalmic herpes zoster is a common ocular infection caused by the varicella-zoster virus (VZV). Viral mRNA transcripts play a major role in the replicative cycle of the virus and current antiviral agents have little effect in preventing and treating the complications. Therapeutic use of saliva for certain painful ocular diseases such as ophthalmic herpes zoster is a well-known public practice in our region. We thought that antiviral activity of saliva may stem from salivary microvesicles and we aimed to look for molecules with antiviral activity in these vesicles. As a possible candidate for antiviral activity, salivary microvesicles contain at least 20 microRNAs (miRNAs), small noncoding RNAs, which suppress the translation of target mRNAs. miRNAs not only participate in maintenance of normal cell functions, but are also involved in host–virus interactions and limit the replication of certain virus types. Thus, miRNA gene therapy by targeting mRNAs required for VZV survival may find a niche in the treatment of ophthalmic herpes zoster. But, how could salivary microvesicles reach into the corneal cells to demonstrate their antiviral activity. We suggest that human salivary microvesicles can be effective carriers of miRNA for corneal cells, because they contain a molecular machinery for vesicle trafficking and fusion allowing them to be endocytosed by target cells. After binding to the plasma membrane, microvesicles seem to enter into the corneal cells through the clathrin-mediated endocytosis. In the cytosol, human salivary miRNAs base-pair with specific viral mRNAs and inhibit their translation, thus limiting the replication of the virus.
- Antiviral Activity
- Herpes Zoster
- Antiviral Agent
- Corneal Cell
- Vesicle Trafficking
Herpes zoster is a common infection caused by the varicella-zoster virus (VZV). Approximately 20% of the world's population suffers from herpes zoster at least once in a lifetime, with 10% to 20% having ophthalmic involvement (ophthalmic herpes zoster) limited mainly to the cornea [1, 2]. Ophthalmic herpes zoster has a very variable course; some cases resolve without trace after a minimum of treatment, others become indolent with chronic cellular and lipid infiltration. These patients present with varying degrees of decreased vision, pain, and light sensitivity . Unfortunately this tends to occur more in young people and therefore these lesions should be observed and treated carefully . Viral DNA is mainly found in mononuclear cells, in keratocytes, and in epithelial cells of the cornea . Antiviral agents have demonstrated some success in resolving early signs and symptoms, but they have little effect in preventing and treating late complications .
Extensive transcription mapping showed that VZV contains 78 different mRNA transcripts of 6.8 kb or less . After the entry of VZV into the cells, early viral mRNA transcripts are produced in the nucleus, translated in the cytoplasm, and proteins they encode are transported back to the nucleus, where they facilitate viral DNA replication . Thereafter, late viral mRNAs are transcribed, translated, and proteins they encode are transported back to the nucleus for assembly into nascent capsids. Newly replicated DNA is then packaged into capsids in the nucleus, enveloped in the cytosol and transported to the cytoplasmic membrane, where the virions are released .
Membrane-bound compartments newly formed from the corneal cell surface normally enter the endosomal/lysosomal network, which is an inhospitable environment . Viruses which are valuable models of cellular entry and intracellular trafficking pathways avoid lysosomal degradation, which is a dead end for many particles in a classic endocytic pathway. Entry of adenovirus into the corneal cells is emerging as a useful paradigm in the field. After adenovirus is internalized through clathrin-mediated endocytosis; it is entrapped in the endosomes . Protein VI of the adenovirus causes membrane disintegration and allows adenovirus to escape the endosomes by forming pores [31–34]. In cytosol, heat shock protein 70 facilitates the disassembly of the coat protein from the virus (decoating of adenovirus) . Similarly salivary microvesicles contain a molecular machinery for clathrin mediated endocytosis and are capable to decoat the microvesicular membrane by heat shock protein 70 . Therefore, after cellular uptake, these microvesicles are able to harbor a mechanism that mimics that used by adenoviral particles to escape from the endosomal/lysosomal pathway and proceed to the cytosol.
After binding to the plasma membrane, microvesicles enter the corneal cells through the clathrin-mediated endocytosis. After penetration into the cell, microvesicles translocate Rab5 proteins to the outer surface of the vacuolar membrane by a syringe-like mechanism while moving toward the endosome . These proteins help the microvesicles to pass from membrane to the endosome and vacuoles containing microvesicles fuse with endosome. In the endosome, some other proteins take role for the microvesicles to escape into the cytosol . In cytosol, decoating of the microvesicular membrane occurs with the help of heat shock protein 70 and the released mRNA is translocated into the cytosol directly together with miRNA. In the cytosol, the linear copy of the microvesicular mRNA is translated into proteins by the cellular enzymes. In this way, about 500 transcripts representing the microvesicular transcriptome from saliva can be expressed in the corneal cells . Human salivary microvesicles also express more than 20 different miRNAs with a potential to repress the viral mRNA transcripts directly . These miRNAs base-pair with specific viral mRNAs and inhibit their translation, thus limiting the replication of the virus. Since a single miRNA can act to repress many complementary viral mRNAs, this method may allow saliva to be a useful tool in the treatment of the ophthalmic herpes zoster .
This work is dedicated to Dear Ali whose painful ocular disease was treated by the saliva of his lovely Cousin.
- Pavan-Langston D: Herpes zoster antivirals and pain management. Ophthalmol. 2008, 115: S13-S20. 10.1016/j.ophtha.2007.10.012.View ArticleGoogle Scholar
- Karbassi M, Raizman MB, Schuman JS: Herpes zoster ophthalmicus. Surv Ophthalmol. 1992, 36: 395-410. 10.1016/S0039-6257(05)80021-9.View ArticlePubMedGoogle Scholar
- Shaikh S, Ta CN: Evaluation and management of herpes zoster ophthalmicus. Am Fam Physician. 2002, 66: 1723-1730.PubMedGoogle Scholar
- Marsh RJ: Ophthalmic zoster. Br J Ophthalmol. 1992, 76: 244-245. 10.1136/bjo.76.4.244.PubMed CentralView ArticlePubMedGoogle Scholar
- Wenkel H, Rummelt C, Rummelt V, Jahn G, Fleckenstein B, Naumann GO: Detection of varicella zoster virus DNA and viral antigen in human cornea after herpes zoster ophthalmicus. Cornea. 1993, 12: 131-317. 10.1097/00003226-199303000-00007.View ArticlePubMedGoogle Scholar
- Reinhold WC, Straus SE, Ostrove JM: Directionality and further mapping of varicella zoster virus transcripts. Virus Res. 1988, 9: 249-261. 10.1016/0168-1702(88)90034-2.View ArticlePubMedGoogle Scholar
- Cohen JI, Straus SE, Arvin AM: Varicella-zoster virus. Fields Virology. Edited by: Knipe DM, Howley PM, Griffin DE, Lamb RA, Martin MA, Roizman B, Straus SE. 2007, Lippincott Williams & Wilkins, Philadelphia, 2773-2818. 5Google Scholar
- Irmak MK, Oztas Y, Oztas E: RNA-based gene delivery system hidden in breast milk microvesicles. J Exp Integr Med. 2012, 2: 125-136.Google Scholar
- Michael A, Bajracharya SD, Yuen PS, Zhou H, Star RA, Illei GG, Alevizos I: Exosomes from human saliva as a source of microRNA biomarkers. Oral Dis. 2010, 16: 34-38. 10.1111/j.1601-0825.2009.01604.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Ogawa Y, Miura Y, Harazono A, Kanai-Azuma M, Akimoto Y, Kawakami H, Yamaguchi T, Toda T, Endo T, Tsubuki M, Yanoshita R: Proteomic analysis of two types of exosomes in human whole saliva. Biol Pharm Bull. 2011, 34: 13-23. 10.1248/bpb.34.13.View ArticlePubMedGoogle Scholar
- Broderick JA, Zamore PD: MicroRNA therapeutics. Gene Ther. 2011, 18: 1104-1110. 10.1038/gt.2011.50.PubMed CentralView ArticlePubMedGoogle Scholar
- Bartel DP: MicroRNAs: target recognition and regulatory functions. Cell. 2009, 136: 215-233. 10.1016/j.cell.2009.01.002.PubMed CentralView ArticlePubMedGoogle Scholar
- Umbach JL, Cullen BR: The role of RNAi and microRNAs in animal virus replication and antiviral immunity. Genes Dev. 2009, 23: 1151-1164. 10.1101/gad.1793309.PubMed CentralView ArticlePubMedGoogle Scholar
- Lecellier CH, Dunoyer P, Arar K, Lehmann-Che J, Eyquem S, Himber C, Saïb A, Voinnet O: A cellular microRNA mediates antiviral defense in human cells. Science. 2005, 308: 557-560. 10.1126/science.1108784.View ArticlePubMedGoogle Scholar
- Triboulet R, Mari B, Lin YL, Chable-Bessia C, Bennasser Y, Lebrigand K, Cardinaud B, Maurin T, Barbry P, Baillat V, Reynes J, Corbeau P, Jeang KT, Benkirane M: Suppression of microRNA-silencing pathway by HIV-1 during virus replication. Science. 2007, 315: 1579-1582. 10.1126/science.1136319.View ArticlePubMedGoogle Scholar
- Yeung ML, Bennasser Y, Myers TG, Jiang G, Benkirane M, Jeang KT: Changes in microRNA expression profiles in HIV-1-transfected human cells. Retrovirology. 2005, 28: 2-81.Google Scholar
- Lagos D, Pollara G, Henderson S, Gratrix F, Fabani M, Milne RS, Gotch F, Boshoff C: miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator. Nat Cell Biol. 2010, 12: 513-519. 10.1038/ncb2054.View ArticlePubMedGoogle Scholar
- Zheng SQ, Li YX, Zhang Y, Li X, Tang H: MiR-101 regulates HSV-1 replication by targeting ATP5B. Antiviral Res. 2011, 89: 219-226. 10.1016/j.antiviral.2011.01.008.View ArticlePubMedGoogle Scholar
- Williams KA, Coster DJ: Gene therapy for diseases of the cornea - a review. Clin Experiment Ophthalmol. 2010, 38: 93-103.PubMedGoogle Scholar
- Mohan RR, Tovey JC, Sharma A, Tandon A: Gene therapy in the Cornea: 2005-present. Prog Retin Eye Res. 2011, 31: 43-64.PubMed CentralView ArticlePubMedGoogle Scholar
- Jun EJ, Won MA, Ahn J, Ko A, Moon H, Tchah H, Kim YK, Lee H: An antiviral small-interfering RNA simultaneously effective against the most prevalent enteroviruses causing acute hemorrhagic conjunctivitis. Invest Ophthalmol Vis Sci. 2011, 52: 58-63. 10.1167/iovs.09-5051.View ArticlePubMedGoogle Scholar
- Tong YC, Chang SF, Liu CY, Kao WW, Huang CH, Liaw J: Eye drop delivery of nano-polymeric micelle formulated genes with cornea-specific promoters. J Gene Med. 2007, 9: 956-966. 10.1002/jgm.1093.View ArticlePubMedGoogle Scholar
- Contreras-Ruiz L, de la Fuente M, Párraga JE, López-García A, Fernández I, Seijo B, Sánchez A, Calonge M, Diebold Y: Intracellular trafficking of hyaluronic acid-chitosan oligomer-based nanoparticles in cultured human ocular surface cells. Mol Vis. 2011, 17: 279-290.PubMed CentralPubMedGoogle Scholar
- Qaddoumi MG, Ueda H, Yang J, Davda J, Labhasetwar V, Lee VH: The characteristics and mechanisms of uptake of PLGA nanoparticles in rabbit conjunctival epithelial cell layers. Pharm Res. 2004, 21: 641-648.View ArticlePubMedGoogle Scholar
- Gonzalez-Begne M, Lu B, Han X, Hagen FK, Hand AR, Melvin JE, Yates JR: Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). J Proteome Res. 2009, 8: 1304-1314. 10.1021/pr800658c.PubMed CentralView ArticlePubMedGoogle Scholar
- Gorvel JP, Chavrier P, Zerial M, Gruenberg J: rab5 controls early endosome fusion in vitro. Cell. 1991, 64: 915-925. 10.1016/0092-8674(91)90316-Q.View ArticlePubMedGoogle Scholar
- Bucci C, Parton RG, Mather IH, Stunnenberg H, Simons K, Hoflack B, Zerial M: The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell. 1992, 70: 715-728. 10.1016/0092-8674(92)90306-W.View ArticlePubMedGoogle Scholar
- Sharma S, Rasool HI, Palanisamy V, Mathisen C, Schmidt M, Wong DT, Gimzewski JK: Structural-mechanical characterization of nanoparticle exosomes in human saliva, using correlative AFM, FESEM, and force spectroscopy. ACS Nano. 2010, 4: 1921-1926. 10.1021/nn901824n.PubMed CentralView ArticlePubMedGoogle Scholar
- Ziello JE, Huang Y, Jovin IS: Cellular endocytosis and gene delivery. Mol Med. 2010, 16: 222-229.PubMed CentralView ArticlePubMedGoogle Scholar
- Chailertvanitkul VA, Pouton CW: Adenovirus: a blueprint for non-viral gene delivery. Curr Opin Biotechnol. 2010, 21: 627-632. 10.1016/j.copbio.2010.06.011.View ArticlePubMedGoogle Scholar
- Rux JJ, Burnett RM: Adenovirus structure. Hum Gene Ther. 2004, 15: 1167-1176. 10.1089/hum.2004.15.1167.View ArticlePubMedGoogle Scholar
- Medina-Kauwe LK: Endocytosis of adenovirus and adenovirus capsid proteins. Ad Drug Deliv Rev. 2003, 55: 1485-1496. 10.1016/j.addr.2003.07.010.View ArticleGoogle Scholar
- Meier O, Boucke K, Hammer SV, Keller S, Stidwill RP, Hemmi S, Greber UF: Adenovirus triggers macropinocytosis and endosomal leakage together with its clathrin-mediated uptake. J Cell Biol. 2002, 158: 1119-1131. 10.1083/jcb.200112067.PubMed CentralView ArticlePubMedGoogle Scholar
- Prchla E, Plank C, Wagner E, Blaas D, Fuchs R: Virus-mediated release of endosomal content in vitro: different behaviour of adenovirus and rhinovirus serotype 2. J Cell Biol. 1995, 131: 111-123. 10.1083/jcb.131.1.111.View ArticlePubMedGoogle Scholar
- Meier O, Greber UF: Adenovirus endocytosis. J Gene Med. 2004, 6: S152-S163. 10.1002/jgm.553.View ArticlePubMedGoogle Scholar
- De Buck E, Anne J, Lammertyn E: The role of protein secretion systems in the virulence of the intracellular pathogen Legionella pneumophila. Microbiology. 2007, 153: 3948-3953. 10.1099/mic.0.2007/012039-0.View ArticlePubMedGoogle Scholar
- Gastaldelli M, Imelli N, Boucke K, Amstutz B, Meier O, Greber UF: Infectious adenovirus type 2 transport through early but not late endosomes. Traffic. 2008, 9: 2265-2278. 10.1111/j.1600-0854.2008.00835.x.View ArticlePubMedGoogle Scholar
- Guran S: Proceeded diagnosis and therapy in eye diseases under the light of developments in molecular biology and genetics. Gulhane Med J. 2011, 53: 74-76.Google Scholar
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