Research Emphasis
Corneal Lymphatics and Adaptive Immunity.
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 HSV-1 infection, only hemangiogenesis has been investigated. Our published work convincingly demonstrates lymphangiogenesis is strongly induced by an immediate early gene product of he virus. Currently, we are investigating the contribution of soluble factors likely produced by resident cells found in the cornea that drive and maintain neovascularization after the viral insult has cleared (Fig. 1). Plans include investigating signal cascades activated by these soluble factors related to sprouting of vessels and movement of leukocytes in the cornea. This work is funded by R01 EY021238 through 2020.
The Neuroimmunology of HSV-1 infection
Herpes simplex virus type 1 (HSV-1) is one of the most common neurotropic pathogens in humans with a seroprevalence rate increasing up to 60-80% by the 5th decade of life. Clinical diseases associated with HSV-1 include herpetic stromal keratitis, the leading cause of infectious corneal blindness in the industrialized world, and frank sporadic encephalitis, a rare (1-2 cases/250,000 individuals/year) but debilitating disease that can result in death. Recently, we have identified a unique area of the brain, the ependyma (EP), that harbors lytic infection during viral latency at other peripheral and central nervous system sites (Fig. 2). Immunologically, we find resident memory T cells remain at relatively high levels in the EP but they develop an anergic profile over time. Further characterization of the adaptive immune response including B lymphocytes in this region is planned.
Ocular HSV-1 Vaccine
HSV-1 infection of the eye can have serious consequences including blindness. In the corneal clinic of the Dean McGee Eye Institute, we see between 800-1,000 patients/year due to ocular HSV-1 disease. There is no cure for HSV-1 infection as intervention does not clear the pathogen but only resolves the acute episode of disease. We are currently investigating a novel vaccine (termed HSV-1 0ΔNLS) that shows significant promise in preventing the acquisition of HSV-1 infection and the associated pathology in a mouse model (Fig. 3). The project consists of defining the immune components and mechanism(s) that correlate with the efficacy of the vaccine and preservation of the visual axis.
Current Laboratory Personnel:
Micaela Montgomery, Graduate Student
Derek Royer, Postdoctoral Fellow
Recent publications
Taken from 136 peer-reviewed articles:
Gurung, H.R., M.M. Carr, and D.J.J. Carr. 2017. Corneal lymphatics drive the CD8+ T cell immune response to HSV type 1. Immunol. Cell Biol., 95:87-98. PMCID: PMC5209249
Royer, D.J., M.M. Carr, A.J. Chucair-Elliott, W.P. Halford, and D.J.J. Carr. 2017. Impact of type 1 interferon on the safety and immunogenicity of an experimental live-attenuated herpes simplex virus type 1 vaccine in mice. J. Virol. 91(7). pii: e02342-16. PMCID: PMC5355590.
Chucair-Elliott, A.J., M.M. Carr, and D.J.J. Carr. 2017. Long-term consequences of topical dexamethasone treatment during acute cornea HSV-1 infection on the immune system. J. Leukoc. Biol. 101:1253-1261. PMCID: PMC5380376
Menendez, C.M. and D.J.J. Carr. 2017. Herpes Simplex Virus-1 infects the olfactory bulb shortly following ocular infection and exhibits a long-term inflammatory profile in the form of effector and HSV-1 specific T cells. J. Neuroinflamm. 14:124.
Royer, D.J., M.M. Carr, H.R. Gurung, W.P. Halford, and D.J.J. Carr. 2017. The neonatal Fc receptor (FcRn) and complement fixation facilitate prophylactic vaccine-mediated humoral protection against viral infection in the ocular mucosa. J. Immunol. 199:1898-1911.
Chucair-Elliott, A.J., H.R. Gurung, M.M. Carr, and D.J.J. Carr. 2017. Colony Stimulating Factor-1 Receptor Expressing cells infiltrating the cornea control corneal nerve degeneration in response to HSV-1 infection. Invest. Ophthalmol. Vis. Sci. 58:4670-4682.
Gurung, H.R., M.M. Carr, K. Bryant, A.J. Chucair-Elliott, and D.J.J. Carr. 2017. Neutralization of fibroblast growth factor-2 (FGF-2) blocks HSV-1-induced corneal lymphangiogenesis. Mucosal Immunol. In press.