RESUMO
Type 1 interferons (IFNs; IFNα/ß) mediate immunological host resistance to numerous viral infections, including herpes simplex virus type 1 (HSV-1). The pathways responsible for IFNα/ß signaling during the innate immune response to acute HSV-1 infection in the cornea are incompletely understood. Using a murine ocular infection model, we hypothesized that the stimulator of IFN genes (STING) mediates resistance to HSV-1 infection at the ocular surface and preserves the structural integrity of this mucosal site. Viral pathogenesis, tissue pathology, and host immune responses during ocular HSV-1 infection were characterized by plaque assay, esthesiometry, pachymetry, immunohistochemistry, flow cytometry, and small interfering RNA transfection in wild-type C57BL/6 (WT), STING-deficient (STING(-/-)), and IFNα/ß receptor-deficient (CD118(-/-)) mice at days 3-5 postinfection. The presence of STING was critical for sustained control of HSV-1 replication in the corneal epithelium and resistance to viral neuroinvasion, but loss of STING had a negligible impact with respect to gross tissue pathology. Auxiliary STING-independent IFNα/ß signaling pathways were responsible for maintenance of corneal integrity. Lymphatic vessels, mast cells, and sensory innervation were compromised in CD118(-/-) mice concurrent with increased tissue edema. STING-dependent signaling led to the upregulation of tetherin, a viral restriction factor we identify is important in containing the spread of HSV-1 in vivo.
Assuntos
Antígenos CD/metabolismo , Córnea/imunologia , Herpes Simples/imunologia , Herpesvirus Humano 1/fisiologia , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/metabolismo , Animais , Antígenos CD/genética , Células Cultivadas , Córnea/virologia , Modelos Animais de Doenças , Humanos , Imunidade Inata , Interferon Tipo I/metabolismo , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Interferente Pequeno/genética , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais , Regulação para Cima , Replicação ViralRESUMO
HSV-1 continues to be the leading cause of infectious corneal blindness. Clinical trials for vaccines against genital HSV infection have been ongoing for more than three decades. Despite this, no approved vaccine exists, and no formal clinical trials have evaluated the impact of HSV vaccines on eye health. We review here the current state of development for an efficacious HSV-1 vaccine and call for involvement of ophthalmologists and vision researchers.