A Dual Role for Corneal Dendritic Cells in Herpes Simplex Keratitis: Local Suppression of Corneal Damage and Promotion of Systemic Viral Dissemination.
The cornea is the shield to the foreign world and thus, a primary site for peripheral infections. However, transparency and vision are incompatible with inflammation and scarring that may result from infections. Thus, the cornea is required to perform a delicate balance between fighting infections and preserving vision. To date, little is known about the specific role of antigen-presenting cells in viral keratitis. In this study, utilizing an established murine model of primary acute herpes simplex virus (HSV)-1 keratitis, we demonstrate that primary HSV keratitis results in increased conventional dendritic cells (cDCs) and macrophages within 24 hours after infection. Local depletion of cDCs in CD11c-DTR mice by subconjuntival diphtheria toxin injections, led to increased viral proliferation, and influx of inflammatory cells, resulting in increased scarring and clinical keratitis. In addition, while HSV infection resulted in significant corneal nerve destruction, local depletion of cDCs resulted in a much more severe loss of corneal nerves. Further, local cDC depletion resulted in decreased corneal nerve infection, and subsequently decreased and delayed systemic viral transmission in the trigeminal ganglion and draining lymph node, resulting in decreased mortality of mice. In contrast, sham depletion or depletion of macrophages through local injection of clodronate liposomes had neither a significant impact on the cornea, nor an effect on systemic viral transmission. In conclusion, we demonstrate that corneal cDCs may play a primary role in local corneal defense during viral keratitis and preserve vision, at the cost of inducing systemic viral dissemination, leading to increased mortality.
Schepens Eye Research Institute, Massachusetts Eye & Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America; Cornea Service, Massachusetts Eye & Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America; Immune Disease Institute, Program in Cellular and Molecular Medicine at Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, United States of America.
Kai
K
Hu
Schepens Eye Research Institute, Massachusetts Eye & Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America; Immune Disease Institute, Program in Cellular and Molecular Medicine at Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, United States of America; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
Deshea L
DL
Harris
Schepens Eye Research Institute, Massachusetts Eye & Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America; Cornea Service, Massachusetts Eye & Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America; Immune Disease Institute, Program in Cellular and Molecular Medicine at Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, United States of America.
Takefumi
T
Yamaguchi
Immune Disease Institute, Program in Cellular and Molecular Medicine at Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, United States of America; Division of Immunology, Department of Microbiology & Immunobiology, Harvard Medical School, Boston, Massachusetts, United States of America.
Ulrich H
UH
von Andrian
Schepens Eye Research Institute, Massachusetts Eye & Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America; Cornea Service, Massachusetts Eye & Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America; Immune Disease Institute, Program in Cellular and Molecular Medicine at Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, United States of America; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
Pedram
P
Hamrah
D000818:Animals; D003315:Cornea / Q000294:innervation; D003713:Dendritic Cells / Q000276:immunology*; D003714:Denervation; D018259:Herpesvirus 1, Human / Q000472:pathogenicity / Q000502:physiology; D016849:Keratitis, Herpetic / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014779:Virus Replication