title: Role of miR-155 in the pathogenesis of herpetic stromal keratitis.
abstract: Ocular infection with herpes simplex virus 1 can result in a chronic immunoinflammatory stromal keratitis (SK) lesion that is a significant cause of human blindness. A key to controlling SK lesion severity is to identify cellular and molecular events responsible for tissue damage and to manipulate them therapeutically. Potential targets for therapy are miRNAs, but these are minimally explored especially in responses to infection. Here, we demonstrated that Mir155 expression was up-regulated after ocular herpes simplex virus 1 infection, with the increased Mir155 expression occurring mainly in macrophages and CD4(+) T cells and to a lesser extent in neutrophils. In vivo studies indicated that Mir155 knockout mice were more resistant to herpes SK with marked suppression of T helper cells type 1 and 17 responses both in the ocular lesions and the lymphoid organs. The reduced SK lesion severity was reflected by increased phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 and interferon-γ receptor α-chain levels in activated CD4(+) T cells in the lymph nodes. Finally, in vivo silencing of miR-155 by the provision of antagomir-155 nanoparticles to herpes simplex virus 1-infected mice led to diminished SK lesions and corneal vascularization. In conclusion, our results indicate that miR-155 contributes to the pathogenesis of SK and represents a promising target to control SK severity.
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee.
authors.forename: Siddheshvar
authors.initials: S
authors.lastname: Bhela
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee; Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sachin
authors.initials: S
authors.lastname: Mulik
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Gimenez
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee; Department of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia.
authors.forename: Pradeep B J
authors.initials: PB
authors.lastname: Reddy
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee.
authors.forename: Raphael L
authors.initials: RL
authors.lastname: Richardson
authors.affiliation: Department of Genome Science and Technology, University of Tennessee, Knoxville, Tennessee.
authors.forename: Siva Karthik
authors.initials: SK
authors.lastname: Varanasi
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee.
authors.forename: Ujjaldeep
authors.initials: U
authors.lastname: Jaggi
authors.affiliation: Sirnaomics, Inc., Gaithersburg, Maryland.
authors.forename: John
authors.initials: J
authors.lastname: Xu
authors.affiliation: Sirnaomics, Inc., Gaithersburg, Maryland.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Lu
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee. Electronic address: btr@utk.edu.
authors.forename: Barry T
authors.initials: BT
authors.lastname: Rouse
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D003319:Corneal Stroma / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D018259:Herpesvirus 1, Human / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D000072181:Inositol Polyphosphate 5-Phosphatases; D016849:Keratitis, Herpetic / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000821:virology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry; D009841:Oligonucleotides / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D017471:Receptors, Interferon / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects; D000096743:Interferon gamma Receptor
chemical_list: D018925:Chemokines; D000072181:Inositol Polyphosphate 5-Phosphatases; D035683:MicroRNAs; D009841:Oligonucleotides; D010744:Phosphoric Monoester Hydrolases; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C532623:Mirn155 microRNA, mouse