Innate Immunity to Viral Infection of the Retina

视网膜对病毒感染的先天免疫

• 批准号: 10641586
• 负责人: Christopher Dale Conrady
• 金额: $ 23.47万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641586
• 关键词: Acute Disease; Acute Retinal Necrosis Syndrome; Acyclovir; Automobile Driving; Biopsy; Blindness; Brain; Cell Culture Techniques; Cells; Central Nervous System Infections; Cessation of life; Chimera organism; Chronic Disease; Clinical Treatment; Cornea; Data; Development; Development Plans; Disease; Faculty; Family; Functional disorder; Future; Goals; Herpesviridae; Herpesviridae Infections; Herpesvirus 1; Histopathology; Host Defense; Human; IFNAR1 gene; Image; Immune; Immune response; Immune signaling; Immunity; Infection; Inflammation; Inflammatory; Innate Immune Response; Institution; Interferon Type I; Interferons; Investigation; Knockout Mice; Leucocytic infiltrate; Medical center; Meningoencephalitis; Mentors; Mentorship; Microglia; Molecular; Mus; Natural Immunity; Nebraska; Necrosis Induction; Neurocognitive; Ophthalmology; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Primary Infection; Production; Productivity; Prognosis; Quality of life; Research; Research Personnel; Resources; Retina; Retinal Detachment; Retinal Diseases; Retinitis; Risk; Role; Sampling; Scientist; Signal Transduction; Simplexvirus; Source; Specimen; TLR3 gene; Testing; Therapeutic; Tissues; Toll-like receptors; Universities; Viral; Virus; Virus Activation; Virus Diseases; Virus Replication; Vision; Visual; Visual impairment; Wild Type Mouse; career development; cell type; chemokine; clinically significant; cytokine; fundus imaging; glial activation; human tissue; improved; in vivo; insight; laboratory facility; mouse model; neuroimmunology; neuroinflammation; novel; novel therapeutics; preservation; programs; response; retinal damage; sensor; skills; type I interferon receptor; vaginal mucosa; vision science

SUMMARY Alpha herpesviruses are a subfamily of ubiquitous viruses that can cause a spectrum of clinically-significant diseases including blindness from acute retinal necrosis (ARN). Unfortunately, even with timely antiviral treatment, irreversible pathological changes occur within the retina and significantly increase the risk of vision- threatening complications to further compromise an already poor visual prognosis. Since the advent of acyclovir, there have been no major advances in the treatment of clinically-significant herpes infections despite the vision-degrading complications and very little is known in regards to the immune response to the virus within the retina. This proposal will provide a fundamental understanding of the innate immune response to HSV-1 within the retina, while developing critical skills in career development. The long-term goal of this project is to acquire the scientific skills needed to enhance our understanding and pursue novel therapies to preserve vision and reduce complications related to ARN as an independent clinician-scientist. The scientific objective of this K08 proposal is to test the hypothesis that type I interferons (IFNs) are central to host defense to viral infection of the retina and that toll-like receptor-3 within retinal microglia activate this innate immune response. We propose evaluating the innate immune response to herpes virus infections of the retina by utilizing several immune knock-out mouse lines, human retinal cell cultures, and vitreous specimens from patients with ARN to assess the role of IFNs and their role in neuroinflammation. Three focused specific aims will be utilized to test our hypothesis: 1) Identify pathways and cell types responsible for HSV innate immunity within the retina; 2) Determine the role of downstream IFNs in host defense against viral infection of the retina; 3) Identify the predominate IFN subtype and cellular source in acute retinal necrosis from human samples. The career development objective is to develop the mentorship and expertise needed to become a productive and independent clinician-scientist. The Department of Ophthalmology and Visual Sciences and the University of Nebraska Medical Center have state-of-the-art laboratory facilities and world-class faculty with expertise in neuroimmunology, viral infections, and innate immune signaling to serve as the mentoring team. The institutional resources, mentorship team, and career development plan have been developed to specifically promote scientific independence in the study of neuroinflammation of the retina.

概括 α疱疹病毒是无处不在的病毒的亚家族，可能引起临床上显着的频谱 疾病，包括急性视网膜坏死（ARN）的失明。不幸的是，即使有及时的抗病毒 治疗，不可逆的病理变化发生在视网膜内，并显着增加了视力的风险 - 威胁并发症进一步损害已经差的视觉预后。自从出现以来 Acyclovir，尽管 关于病毒的免疫反应，降低视力的并发症和很少知道 在视网膜内。该建议将对对先天免疫反应的基本理解 在视网膜内的HSV-1，同时在职业发展方面发展了关键的技能。这个长期目标 项目是获得提高我们的理解并追求新颖疗法所需的科学技能 保持视力并减少与ARN相关的并发症，作为独立的临床医生科学家。 该K08提案的科学目标是检验I型干扰素（IFN）的假设 视网膜小胶质细胞激活的视网膜病毒感染的宿主防御和Toll样受体-3的中心 这种先天的免疫反应。我们建议评估对疱疹病毒感染的先天免疫反应 通过利用几种免疫敲除小鼠系，人类视网膜细胞培养和玻璃体来通过视网膜的 来自ARN患者的标本评估IFN的作用及其在神经炎症中的作用。三 专注的特定目标将用于检验我们的假设：1）确定负责的途径和细胞类型 视网膜内的HSV先天免疫； 2）确定下游IFN在宿主防御抗病毒中的作用 视网膜感染； 3）确定急性视网膜坏死中的主要IFN亚型和细胞源 来自人类样品。 职业发展目标是建立成为一个所需的指导和专业知识 生产和独立的临床医生科学家。眼科和视觉科学系以及 内布拉斯加州大学医学中心拥有最先进的实验室设施和世界一流的教职员工 神经免疫学，病毒感染和先天免疫信号的专业知识，可作为指导团队。 已经制定了机构资源，指导团队和职业发展计划 在视网膜神经炎症研究中特别促进了科学独立性。

项目成果

Type I Interferon Signaling Is Critical During the Innate Immune Response to HSV-1 Retinal Infection.

• DOI: 10.1167/iovs.63.13.28
• 发表时间: 2022-12-01
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4

Utility of a nitinol stone extractor for intraocular foreign body removal.

• DOI: 10.1016/j.ajoc.2023.101917
• 发表时间: 2023-12
• 期刊: American journal of ophthalmology case reports

The Host-Pathogen Interplay: A Tale of Two Stories within the Cornea and Posterior Segment.

• DOI: 10.3390/microorganisms11082074
• 发表时间: 2023-08-12
• 期刊: MICROORGANISMS
• 影响因子: 4.5
• 作者: Dempsey, Michael P.;Conrady, Christopher D.
• 通讯作者: Conrady, Christopher D.