A novel ex vivo model of West Nile virus infection in human lymphoid tissue

人体淋巴组织中西尼罗河病毒感染的新型离体模型

• 批准号: 8566428
• 负责人: Jean Kyou Lim
• 金额: $ 23.9万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-09 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566428
• 关键词: Address; Adult; Antiviral Agents; Antiviral Therapy; Arbovirus Encephalitis; Architecture; Australia; B-Lymphocytes; Categories; Cells; Cessation of life; Culicidae; Data; Disease; Disease Outbreaks; Environment; Enzyme-Linked Immunosorbent Assay; Epidemic; Event; Flavivirus; Flow Cytometry; Host Defense; Human; Immune response; Indigenous; Infection; Inflammatory Response; Lead; Licensing; Lymphoid Tissue; Measures; Modeling; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Nature; Neuraxis; North America; Outcome; Pathogenesis; Pathway interactions; Population; Predisposition; Relative (related person); Reporting; Research; Seasons; Site; System; T-Lymphocyte; Testing; Therapeutic; Tissue Model; Tissues; United States; Vaccines; Viral; Viral Pathogenesis; Viremia; Virulent; Virus; Virus Diseases; Virus Replication; West Nile virus; base; chemokine; clinical application; cytokine; defense response; in vivo; insight; lymph nodes; mortality; novel; pathogen; public health relevance; response; virus host interaction

DESCRIPTION (provided by applicant): West Nile virus (WNV) is a highly virulent human pathogen of the central nervous system (CNS) and the most common cause of epidemic encephalitis in the United States. Since there are no vaccines or specific antiviral treatments available for WNV, understanding its pathogenesis is a high priority. Following infection, WNV is transported to the local draining lymph nodes, where primary amplification of the virus and key host defense responses are triggered; however, there is very little known about the events that take place at this junction in humans. To study this, we developed an ex vivo human lymphoid tissue model of WNV infection. In preliminary studies, we show that WNV replicates robustly in all donors tested, and WNV-infected cells can be detected. In this application, we will use two strains of WNV that differ in their pathogenic potential in humans to characterize the cellular response to WNV infection and identify the permissive target cells within the lymphoid tissue (Aim 1), measure the inflammatory response during the infection (Aim 2), and determine the anatomical environment within the lymph node where virus replication preferentially occurs (Aim 3). Understanding these viral and cellular aspects in a human system and how these differ between a neuroinvasive and non-neuroinvasive strain of WNV will not only provide the first glimpse into early infection events, but also lead to new hypotheses for in vivo susceptibility in humans.

描述（由申请人提供）：西尼罗河病毒（WNV）是一种对中枢神经系统（CNS）具有高毒力的人类病原体，也是美国流行性脑炎的最常见原因。由于没有针对西尼罗河病毒的疫苗或特定的抗病毒治疗方法，因此了解其发病机制是当务之急。感染后，西尼罗河病毒被输送到局部引流淋巴结，在那里触发病毒的初级扩增和关键的宿主防御反应；然而，人们对人类这个连接点发生的事件知之甚少。为了研究这一点，我们开发了西尼罗河病毒感染的离体人体淋巴组织模型。在初步研究中，我们表明西尼罗河病毒在所有测试的供体中都能强劲复制，并且可以检测到西尼罗病毒感染的细胞。在此应用中，我们将使用两种对人类致病潜力不同的 WNV 毒株来表征对 WNV 感染的细胞反应，并识别淋巴组织内允许的靶细胞（目标 1），测量感染期间的炎症反应（目标 2)，并确定淋巴结内病毒复制优先发生的解剖环境（目标 3）。了解人体系统中的这些病毒和细胞方面，以及西尼罗河病毒的神经侵袭性和非神经侵袭性毒株之间的差异，不仅可以让人们首次了解早期感染事件，而且还可以提出关于人类体内易感性的新假设。