Brain pathology and function in a chronic mouse model of ZIKV transmission

项目摘要 寨卡病毒主要通过受感染的伊蚊蚊子叮咬传播给人 埃及伊蚊属，主要是埃及伊蚊，尽管该病毒也可以通过性交传播。的确有 科学共识认为ZIKV是小头畸形的病原体，小头畸形是感染病毒出生的儿童的出生缺陷 母亲和感染成人的神经免疫性格林-巴利综合征。更令人不安的是，垂直 寨卡病毒的传播不仅限于小头畸形症，而且现在与多发性直接相关，尽管 严重的大脑和眼睛发育障碍，称为先天性寨卡综合征。 由于ZIKV继续在美洲蔓延，更好地了解ZIKV的病理以及 迫切需要一种有效的手段来治疗这种感染。因此，我们的MPI研究的重点是 建议大大提高我们对长期服用ZIKV引起的脑病理变化的了解 感染，以及通过改变用途以药理有益的方式控制病毒的实用手段 目前FDA批准的抗病毒和抗疟疾药物作为鸡尾酒。重要的是，一个 采用生理相关的SJL小鼠ZIKV垂直传播和慢性感染模型 我们的深入研究，而不是干扰素敲除动物在感染后几天内死亡。这 该项目以我们大量的初步数据为基础。我们的具体目标是：(1)确定 寨卡病毒垂直传播后胎脑感染动态及围产儿结局调查 SJL小鼠，(2)确定先天性ZIKV对成人大脑结构和功能的影响 SJL小鼠感染，以及(3)使用ZIKV抑制剂确定ZIKV感染的最佳治疗方案 病毒生命周期的不同阶段及其组合，以防止寨卡病毒的垂直传播。我们的 出色且平衡的多学科团队包括经验丰富的专业人员，他们具有互补的 在病毒学、生物化学、神经和干细胞生物学、药物设计、硅胶等不同领域的专业知识 建模和统计、大脑发育和磁共振显微镜。为了实现我们的目标 相互联系的具体目标的整体性和及时性，我们将使用过多的先进 细胞、分子和成像技术和方法，特别是如果结合在一起，不容易 可供许多其他用户使用。我们多才多艺的团队的另一个优势是我们广泛的、长达十年的 对黄病毒的研究。因为我们以ZIKV为中心的研究已经进行了两年多了 在此期间，我们的研究已经获得了显著的势头，这预示着这项研究的成功 提出研究课题。

Project Summary Zika virus (ZIKV) is primarily transmitted to people through the bite of an infected mosquito from the Aedes genus, mainly Aedes aegypti, although the virus can also be transmitted through sexual intercourse. There is scientific consensus that ZIKV is a causative agent of microcephaly, a birth defect in children born to infected mothers and neuroimmune Guillain-Barré syndrome in infected adults. Even more troubling, vertical transmission of ZIKV is not limited to microcephaly alone, but it is now directly linked to multiple, albeit still severe, dysfunctions in the development of the brain and the eyes, called the Congenital Zika Syndrome. Because ZIKV continues to spread through the Americas, a better understanding of ZIKV pathology along with an efficient means to treat the infection is urgently needed. Accordingly, the focus of our MPI research proposal is to greatly increase our understanding of the changes to brain pathology caused by long-term ZIKV infections, and a practical means to control the virus in a pharmacologically-beneficial manner by repurposing the current FDA-approved anti-viral and anti-malarial pharmaceuticals as cocktails. Importantly, a physiologically-relevant SJL mouse model of ZIKV vertical transmission and chronic infection is employed in our in-depth studies, rather than interferon-knockout animals that perish in a few days post-infection. This project is firmly grounded on volumes of our preliminary data. Our Specific Aims are: (1) Determine the dynamics of fetal brain infection and investigate perinatal consequences following ZIKV vertical transmission in SJL mice, (2) Determine structural and functional consequences to the adult brain following congenital ZIKV infection in SJL mice, and (3) Determine the best treatment regimens for ZIKV infection using inhibitors of different stages of the viral life cycle and their combinations to prevent vertical transmission of ZIKV. Our exceptional and well-balanced multidisciplinary team includes experienced professionals with complementary expertise in the diverse areas of virology, biochemistry, neuro- and stem cell biology, drug design, in silico modeling and statistics, brain development and magnetic resonance microscopy. To accomplish our interrelated Specific Aims in their entirety and in a timely fashion, we will use a plethora of the advanced cellular, molecular and imaging techniques and methodologies which, especially if combined, are not readily available for many others. An additional advantage of our multi-talented team is our extensive, decade-long, studies in flaviviruses. Because our ZIKV-centered research has been already on-going for over a 2-year period, we have already acquired significant momentum in our studies that bodes well for the success of this proposed research project.