title: HSV-1 targets lymphatic vessels in the eye and draining lymph node of mice leading to edema in the absence of a functional type I interferon response.
abstract: Herpes simplex virus type-1 (HSV-1) induces new lymphatic vessel growth (lymphangiogenesis) in the cornea via expression of vascular endothelial growth factor by virally infected epithelial cells. Here, we extend this observation to demonstrate the selective targeting of corneal lymphatics by HSV-1 in the absence of functional type I interferon (IFN) pathway. Specifically, we examined the impact of HSV-1 replication on angiogenesis using type I IFN receptor deficient (CD118(-/-)) mice. HSV-1-induced lymphatic and blood vessel growth into the cornea proper was time-dependent in immunocompetent animals. In contrast, there was an initial robust growth of lymphatic vessels into the cornea of HSV-1-infected CD118(-/-)mice, but such vessels disappeared by day 5 postinfection. The loss was selective as blood vessel integrity remained intact. Magnetic resonance imaging and confocal microscopy analysis of the draining lymph nodes of CD118(-/-) mice revealed extensive edema and loss of lymphatics compared with wild-type mice. In addition to a loss of lymphatic vessels in CD118(-/-) mice, HSV-1 infection resulted in epithelial thinning associated with geographic lesions and edema within the cornea, which is consistent with a loss of lymphatic vasculature. These results underscore the key role functional type I IFN pathway plays in the maintenance of structural integrity within the cornea in addition to the anti-viral characteristics often ascribed to the type I IFN cytokine family.
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Bryant-Hudson
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Ana J
authors.initials: AJ
authors.lastname: Chucair-Elliott
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Conrady
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Alex
authors.initials: A
authors.lastname: Cohen
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Electronic address: dan-carr@ouhsc.edu.
authors.forename: Daniel J J
authors.initials: DJJ
authors.lastname: Carr
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism; D003315:Cornea / Q000473:pathology / Q000821:virology; D004198:Disease Susceptibility; D004487:Edema / Q000473:pathology* / Q000821:virology; D005123:Eye / Q000473:pathology* / Q000821:virology*; D006410:Hematopoiesis; D006561:Herpes Simplex / Q000473:pathology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000502:physiology*; D007370:Interferon Type I / Q000378:metabolism*; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000172:deficiency / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology / Q000821:virology*; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000473:pathology / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D018925:Chemokines; D007370:Interferon Type I; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2
references.citation: Herpesviridae. 2011 Mar 15;2(1):5
references.pmid: 21429183
references.citation: Ocul Immunol Inflamm. 2006 Oct;14(5):257-66
references.pmid: 17056459
references.citation: Annu Rev Pathol. 2008;3:367-97
references.pmid: 18039141
references.citation: Nat Med. 2004 Aug;10(8):813-5
references.pmid: 15235599
references.citation: J Clin Microbiol. 2003 Jan;41(1):84-9
references.pmid: 12517830
references.citation: J Immunol. 2013 Mar 15;190(6):2807-17
references.pmid: 23382563
references.citation: J Immunol. 2012 Apr 15;188(8):4065-80
references.pmid: 22430738
references.citation: Microcirculation. 2011 Oct;18(7):517-31
references.pmid: 21575093
references.citation: Curr Top Microbiol Immunol. 2006;303:47-65
references.pmid: 16570856
references.citation: J Immunol. 2010 Jan 15;184(2):535-9
references.pmid: 20018627
references.citation: Immunity. 2006 Feb;24(2):203-15
references.pmid: 16473832
references.citation: J Interferon Cytokine Res. 2008 Apr;28(4):245-51
references.pmid: 18439102
references.citation: Mucosal Immunol. 2012 Mar;5(2):173-83
references.pmid: 22236996
references.citation: Curr Opin Immunol. 2002 Feb;14(1):129-35
references.pmid: 11790543
references.citation: Mucosal Immunol. 2013 Jan;6(1):45-55
references.pmid: 22692455
references.citation: Invest Ophthalmol Vis Sci. 2000 May;41(6):1402-9
references.pmid: 10798656
references.citation: J Immunol. 2011 Mar 15;186(6):3653-65
references.pmid: 21325621
references.citation: J Immunol. 2009 Mar 15;182(6):3678-87
references.pmid: 19265146
references.citation: Prog Retin Eye Res. 2013 May;34:89-124
references.pmid: 23348581
references.citation: Arch Virol. 2000;145(2):385-96
references.pmid: 10752560
references.citation: PLoS One. 2010 Jun 08;5(6):e10975
references.pmid: 20544015
references.citation: Cell Immunol. 2006 Oct;243(2):83-9
references.pmid: 17296171
references.citation: Virology. 2001 Apr 25;283(1):69-77
references.pmid: 11312663
references.citation: Int Rev Immunol. 2002 Mar-Jun;21(2-3):173-96
references.pmid: 12424842
references.citation: J Biol Chem. 1989 Mar 5;264(7):4133-7
references.pmid: 2917992
references.citation: Prog Retin Eye Res. 2013 Jan;32:88-101
references.pmid: 22944008
references.citation: Invest Ophthalmol Vis Sci. 2012 Oct 01;53(11):6785-92
references.pmid: 22952118
references.citation: PLoS Pathog. 2011 Oct;7(10):e1002278
references.pmid: 21998580
references.citation: J Virol. 1996 Feb;70(2):898-904
references.pmid: 8551629
references.citation: Invest Ophthalmol Vis Sci. 1998 Sep;39(10):1854-62
references.pmid: 9727408
references.citation: Front Biosci. 2002 Mar 01;7:d752-64
references.pmid: 11861220
references.citation: Immunol Cell Biol. 2011 Feb;89(2):207-15
references.pmid: 21221121
references.citation: Exp Cell Res. 2011 Mar 10;317(5):620-31
references.pmid: 21376175
references.citation: Blood. 2007 Nov 1;110(9):3158-67
references.pmid: 17625067
references.citation: J Immunol. 2005 Oct 1;175(7):4735-44
references.pmid: 16177121
references.citation: J Exp Med. 2010 Jan 18;207(1):101-15
references.pmid: 20026662
references.citation: Immunity. 2011 Jan 28;34(1):96-107
references.pmid: 21256057
references.citation: Invest Ophthalmol Vis Sci. 2010 Jan;51(1):160-71
references.pmid: 19710407