Corneal Lymphatics & Adaptive Immunity

Summary

Principal Investigator: DANIEL J CARR
Affiliation: University of Oklahoma Health Sciences Center
Country: USA
Abstract: DESCRIPTION (provided by applicant): Neovascularization in the normally avascular cornea can lead to a compromised visual axis. Within the term "neovascularization" is a blood component referred to as hemangiogenesis and a lymphatic component referred to as lymphangiogenesis. Relative to herpes simplex virus type 1 (HSV-1) infection, only hemangiogenesis has been investigated. Recently, we have initiated a study on lymphangiogenesis following corneal infection with HSV-1 and discovered this process precedes hemangiogenesis. More importantly, we have discovered the genesis of lymphatic vessels in the cornea proper in response to HSV-1 infection operates thru a unique pathway distinct from what has been described following corneal transplantation. Specifically, we have found a robust vascular endothelial growth factor (VEGF) A response by corneal epithelium infected with HSV-1 elicits lymphangiogenesis thru a VEGF receptor 2 (VEGFR2)-mediated pathway. This process is independent of VEGF C, VEGF receptor 3, or monocytes/macrophages. We have also found the newly created lymphatic vessels are capable of transporting soluble antigen to the draining lymph node independent of hemangiogenesis. However, what remains unknown is the contribution of the newly created lymphatic conduit to the host immune response within the draining lymph node as well as other inflammatory mediators that contribute to corneal lymphangiogenesis. We hypothesize lymphatic vessel development driven principally by VEGF A and contributing pro-inflammatory molecules generated locally in response to infection are critical for the induction of the adaptive immune response found in the draining lymph node reflected by the severity in the development of herpetic stromal keratitis of HSV-1 infected mice. To address this hypothesis, two specific aims are proposed: Specific aim 1 will address the impact of viral replication and pro- inflammatory cytokine expression on corneal lymphangiogenesis following HSV-1 infection. In addition, trafficking of leukocyte subpopulations and antigen will be monitored as well. Specific aim 2 will address the significance of lymphangiogenesis relative to the genesis of the adaptive immune response in the draining lymph node and development of stromal keratitis following HSV-1 infection. It will further address the role of virus-induced VEGF A production on the production of CD4+ and CD8+ T effector cells that contribute in viral surveillance and corneal pathogenesis. It is anticipated in accomplishing these goals, we will eludicate the contribution of pro-lymphangiogenesis factors in the generation of the adaptive immune response critical for the ocular pathology that includes the debilitating and sometimes blinding stromal keratitis. PUBLIC HEALTH RELEVANCE: The role of lymphangiogenesis as a central force driving the adaptive immune response to ocular herpes simplex virus type 1 (HSV-1) infection has not been explored. In combination with HSV-1-induced vascular endothelial growth factor (VEGF)-A, a potent immunomodulatory molecule, it is anticipated the study will identify how HSV-1-induced lymphangiogenesis and VEGF-A production influence the immune response to the infection and in so doing, lead to a treatment strategy to alter the host response, attenuate the development of herpetic stromal keratitis, and preserve the visual axis.
Funding Period: ----------------2010 - ---------------2015-
more information: NIH RePORT

Top Publications

  1. pmc CD8+ T cells suppress viral replication in the cornea but contribute to VEGF-C-induced lymphatic vessel genesis
    Christopher D Conrady
    Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    J Immunol 189:425-32. 2012
  2. pmc CXCL1-deficient mice are highly sensitive to pseudomonas aeruginosa but not herpes simplex virus type 1 corneal infection
    Katie M Bryant-Hudson
    Department of Ophthalmology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
    Invest Ophthalmol Vis Sci 53:6785-92. 2012
  3. pmc Type I interferon and lymphangiogenesis in the HSV-1 infected cornea - are they beneficial to the host?
    Katie Bryant-Hudson
    Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    Prog Retin Eye Res 36:281-91. 2013
  4. pmc 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
    Katie M Bryant-Hudson
    Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
    Am J Pathol 183:1233-42. 2013
  5. pmc The herpes simplex virus-1 transactivator infected cell protein-4 drives VEGF-A dependent neovascularization
    Todd Wuest
    Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
    PLoS Pathog 7:e1002278. 2011
  6. pmc PD-L1-expressing dendritic cells contribute to viral resistance during acute HSV-1 infection
    Katie M Bryant-Hudson
    Department of Ophthalmology, Dean McGee Eye Institute, The University of Oklahoma Health Sciences Center, Room 415, 608 Stanton L Young Boulevard, Oklahoma, OK 73104, USA
    Clin Dev Immunol 2012:924619. 2012

Scientific Experts

  • DANIEL J CARR
  • Katie M Bryant-Hudson
  • Christopher D Conrady
  • Min Zheng
  • Katie Bryant-Hudson
  • Todd Wuest
  • Alex Cohen
  • Ana J Chucair-Elliott
  • Donald U Stone
  • William P Halford
  • Stacey Efstathiou

Detail Information

Publications6

  1. pmc CD8+ T cells suppress viral replication in the cornea but contribute to VEGF-C-induced lymphatic vessel genesis
    Christopher D Conrady
    Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    J Immunol 189:425-32. 2012
    ..Taken together, these results show that CD8(+) T cells are required to eliminate virus more efficiently from the cornea but play a minimal role in immunopathology as a source of VEGF-C...
  2. pmc CXCL1-deficient mice are highly sensitive to pseudomonas aeruginosa but not herpes simplex virus type 1 corneal infection
    Katie M Bryant-Hudson
    Department of Ophthalmology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
    Invest Ophthalmol Vis Sci 53:6785-92. 2012
    ..To determine the role of the chemokine CXCL1 on leukocyte recruitment, cytokine production and host resistance during HSV-1 and Pseudomonas aeruginosa infection...
  3. pmc Type I interferon and lymphangiogenesis in the HSV-1 infected cornea - are they beneficial to the host?
    Katie Bryant-Hudson
    Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    Prog Retin Eye Res 36:281-91. 2013
    ..This review will focus on these two innate immune events during acute HSV-1 infection of the cornea. ..
  4. pmc 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
    Katie M Bryant-Hudson
    Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
    Am J Pathol 183:1233-42. 2013
    ..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. ..
  5. pmc The herpes simplex virus-1 transactivator infected cell protein-4 drives VEGF-A dependent neovascularization
    Todd Wuest
    Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
    PLoS Pathog 7:e1002278. 2011
    ..Our results suggest that the neovascularization characteristic of ocular HSV-1 disease is a direct result of HSV-1's major transcriptional regulator, ICP4, and similarities between the VEGF-A promoter and those of HSV-1 early genes...
  6. pmc PD-L1-expressing dendritic cells contribute to viral resistance during acute HSV-1 infection
    Katie M Bryant-Hudson
    Department of Ophthalmology, Dean McGee Eye Institute, The University of Oklahoma Health Sciences Center, Room 415, 608 Stanton L Young Boulevard, Oklahoma, OK 73104, USA
    Clin Dev Immunol 2012:924619. 2012
    ..These studies indicate PD-L1-expressing dendritic cells are important for antiviral defense during acute HSV-1 infection...