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

描述（由申请人提供）：西尼罗河病毒（WNV）是一种高毒性的中枢神经系统（CNS）人类病原体，是美国流行性脑炎的最常见原因。由于没有疫苗或特定的抗病毒治疗可用于西尼罗河病毒，了解其发病机制是一个高度优先事项。感染后，西尼罗河病毒被运送到局部引流淋巴结，在那里触发病毒的初级扩增和关键宿主防御反应;然而，对人类在这个交界处发生的事件知之甚少。为了研究这一点，我们开发了一个离体人淋巴组织模型的西尼罗河病毒感染。在初步研究中，我们发现WNV在所有测试的供体中复制稳健，并且可以检测到WNV感染的细胞。在本申请中，我们将使用两种在人类中致病潜力不同的WNV菌株来表征对WNV感染的细胞反应，并鉴定淋巴组织内的容许靶细胞（目的1），测量感染期间的炎症反应（目的2），并确定淋巴结内病毒复制优先发生的解剖环境（目的3）。了解人类系统中的这些病毒和细胞方面以及这些在WNV的神经侵袭性和非神经侵袭性菌株之间的差异，不仅可以首次了解早期感染事件，还可以为人类体内易感性提供新的假设。

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.