Immunity to Live Mosquito Probing and Flavivirus Infection in Human Skin

人类皮肤对活蚊探测和黄病毒感染的免疫力

• 批准号: 9807252
• 负责人: Simon M Barratt-Boyes
• 金额: $ 21.06万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807252
• 关键词: Address; Aedes; Affect; Arbovirus Infections; Arboviruses; Area; Arthropods; Biology; Blood; Cell Communication; Cells; Complex; Culicidae; Cutaneous; Dengue Infection; Dengue Virus; Deposition; Epidermis; Event; Flavivirus; Flavivirus Infections; Foundations; Funding Opportunities; Future; Goals; Health; Human; Immune response; Immunity; Immunologics; Immunology; Individual; Infection; Inflammatory Response; Innate Immune Response; Insect Vectors; Interferons; International; Mediating; Modeling; Mus; Myeloid Cells; Needles; Organism; Pathogenesis; Pathogenicity; Publications; Recruitment Activity; Research; Research Personnel; Risk; Role; Salivary Glands; Skin; Structure; System; Thick; Time; Translating; Vascular blood supply; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; Work; ZIKV infection; Zika Virus; arbovirus disease; boys; clinically relevant; dynamic system; feeding; human morbidity; human mortality; innovation; keratinocyte; migration; mosquito-borne; mouse model; pathogenic virus; recruit; response; therapy development; transmission process; vaccine development; vector; vector transmission; vector-borne; vector-borne infection; vector-borne pathogen; viral transmission; virus host interaction

Abstract Arthropod-borne viruses represent a major threat to humans on a global scale, and of these flaviviruses transmitted by Aedes aegypti mosquitoes are the most significant risk to human health. Understanding the immunologic events that take place in the human host, particularly in the skin where virus is transmitted during mosquito feeding, represents a major gap in our understanding of arbovirus disease. Addressing this gap is a central theme of the Funding Opportunity PAR-18-860, “Immune Response to Arthropod Blood Feeding”, and is the goal of the current proposal. To best define these events, we propose a transdisciplinary study between the Barratt-Boyes lab, with expertise in human skin immunology, and the Vasilakis lab, with expertise in arbovirology and mosquito-virus-host interactions. The Barratt-Boyes group has established an ex vivo model of dengue (DENV) and Zika virus (ZIKV) infection in human skin using large-area explants from anonymous healthy donors, and have defined the immunologic events that occur in skin in the absence of mosquito probing. The unique access of the Vasilakis group to insectary facilities approved for working with live Aedes spp. infected with DENV or ZIKV allows us to now explore the contribution of the mosquito to viral pathogenesis. Thus, we will bring together three essential components – live mosquitoes, human skin, and pathogenic viruses – to address for the first time the immunologic events that occur during vector-borne transmission of flaviviruses in human skin. This is a truly innovative proposal; to our knowledge, no publications exist describing the response of human skin to pathogenic flaviviruses transmitted by live mosquitoes, and no other research group has an experimental system such as ours to fill this research gap. We have two specific aims: (1) what is the immune response of human skin to mosquito probing in the absence of virus, and (2) how does mosquito probing affect DENV and ZIKV replication and spread in human skin. The results of our study will have a strong and lasting impact on the field of immunology and transmission of vector-borne pathogens. The work will establish the ex vivo mosquito-skin-virus system as a foundation for future studies on pathogenesis, therapy and vaccine development.

抽象的 节肢动物传播的病毒是全球范围内对人类的主要威胁，其中黄病毒 由埃及伊蚊传播的蚊子对人类健康构成最重大的风险。 人类宿主中发生的免疫事件，特别是在病毒传播的皮肤中 蚊子喂养是我们对虫媒病毒疾病理解的一个重大差距。 资助机会 PAR-18-860 的中心主题“对节肢动物血液喂养的免疫反应”，以及 是当前提案的目标，为了最好地定义这些事件，我们提出了一项跨学科研究。 Barratt-Boyes 实验室在人类皮肤免疫学方面拥有专业知识，而 Vasilakis 实验室在 Barratt-Boyes 小组建立了虫媒病毒学和蚊子-病毒-宿主相互作用。 使用来自匿名的大面积外植体检测人类皮肤中的登革热 (DENV) 和寨卡病毒 (ZIKV) 感染 健康捐赠者，并定义了在没有蚊子的情况下皮肤中发生的免疫事件 Vasilakis 小组拥有进入经批准可用于活伊蚊工作的昆虫设施的独特通道。 感染 DENV 或 ZIKV 的蚊子现在可以让我们探索蚊子对病毒的贡献 因此，我们将把三个基本组成部分结合在一起——蚊子的生命、人类的皮肤和 病原病毒——首次解决媒介传播过程中发生的免疫事件 据我们所知，这是一个真正创新的提议； 现有出版物描述了人类皮肤对活体传播的致病性黄病毒的反应 蚊子，没有其他研究小组拥有像我们这样的实验系统来填补这一研究空白。 我们有两个具体目标：（1）人体皮肤对蚊子探测的免疫反应是什么？ 不存在病毒，以及（2）蚊子探测如何影响 DENV 和 ZIKV 在人类中的复制和传播 我们的研究结果将对免疫学和传播领域产生强烈而持久的影响。 这项工作将为建立离体蚊子皮肤病毒系统作为基础。 未来关于发病机制、治疗和疫苗开发的研究。