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NEUROPATHOGENESIS OF ZIKA VIRUS INFECTIONS

寨卡病毒感染的神经发病机制

基本信息

批准号：
9762238
负责人：
Robyn S Klein
金额：
$ 45.96万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762238
关键词：
Acute Address Adult Aedes Animals Appearance Autoimmune Process B-Lymphocytes Behavioral Brain CD8B1 gene Calcium Cell physiology Central America Central Nervous System Infections Cerebrum Cognition Cognitive Congenital Abnormality Culicidae Data Defect Demyelinations Dendritic Cells Development Disease Encephalitis Exhibits Fetal Growth Retardation Fetus Fibroblasts Flavivirus Functional Magnetic Resonance Imaging Gene Targeting Hemoglobin Human Humoral Immunities IFNGR1 gene Image Immune Impaired cognition Infection Infection Control Interferon Type II Interferons Lead Learning Literature Lymphocyte Magnetic Resonance Imaging Maps Mediating Memory Memory impairment Meningoencephalitis Methods Microcephaly Microglia Modeling Morphology Mus Neurological outcome Neurons Ocular Pathology Optics Pathogenesis Pathogenicity Play Pregnant Women Prospective Studies Public Health Publishing Radial Rag1 Mouse Receptor Signaling Reporter Reporting Risk Role Signal Transduction Skin South America Structural defect Structure Survivors Synaptic plasticity T-Cell Depletion T-Cell Receptor T-Lymphocyte Ultrasonography Viral Viral Load result Virus West Indies West Nile virus ZIKV infection Zika Virus adaptive immune response adult neurogenesis antigen-specific T cells calcification cell type cognitive function congenital infection cytokine experimental study fetal gulf coast immunopathology in utero in vivo keratinocyte monocyte neonate nerve stem cell neural correlate neurodevelopment neurogenesis neuroimaging pregnant progenitor receptor spatial memory virology

项目摘要

SUMMARY Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus of global public health concern due to its ability to cause severe congenital abnormalities during infections of pregnant women2, and meningoencephalitis or post-infectious autoimmune demyelination in infected, non-pregnant adults. Host-viral interactions that control infection and dissemination of ZIKV remain poorly characterized, as are post-infectious effects on brain development and function in congenital and adult infections, respectively. We have developed both congenital and adult models of ZIKV infection that have been instrumental in defining many pathogenic features of ZIKV infection. In preliminary studies, mice with deficiencies in lymphocytes (Rag1-/-), B cells (μMT-/-) or T cell function (TCR-/-) exhibited differential abilities to clear virus depending on the manner of exposure. Thus, μMT-/- mice exhibited increased pathogenesis in congenital models of ZIKV infection while Rag1-/- and TCR-/- adult mice exhibited decreased survival after intracranial infection with ZIKV. We hypothesize that antigen-specific T cells are required to eliminate ZIKV from the brain of adult mice, whereas humoral immunity plays the dominant role in clearance of ZIKV during congenital infection. Aim 1 we will define mechanisms of immune-mediated clearance during congenital and adult ZIKV infection of the CNS. While 30% of congenitally infected fetuses exhibit morphological abnormalities by ultrasound (e.g., microcephaly or brain calcifications)12, the majority of congenitally infected humans exhibit no morphological or structural abnormalities. Cognitive impairment and neurodevelopmental abnormalities are likely to occur after congenital ZIKV infection, but there may also be important effects on neurodevelopment after in utero infection. In addition, memory disturbances in adults that have recovered from acute ZIKV infection have recently been reported in the literature. One possible mechanism involves ZIKV infection of neural stem cells and early neural cell type progenitors. However, in preliminary studies of ZIKV-recovered adult mice, we observed persistent microglial activation, decreased SGZ neurogenesis and severe spatial learning defects, the latter of which is ameliorated by lack of signaling via the interferon-γ receptor (IFNγR). These studies suggest adaptive immune mechanisms may also contribute to memory dysfunction in adults recovering from ZIKV encephalitis. We hypothesize that congenital infection with ZIKV leads to alterations in cognition due to direct effects on neuronal progenitors and indirect disruption of radial glial function, leading to abnormalities in functional connectivity. We further hypothesize that the persistence of CD8+IFNγ+ T cells within the CNS of adult ZIKV- recovered animals promotes microglial activation, which alter neural correlates of learning and memory such as synaptic plasticity and adult neurogenesis. Aims 2 and 3 will define the mechanisms of spatial memory dysfunction during adult and congenital infection with ZIKV and determine the effects of congenital ZIKV infection on cerebral functional connectivity using optical neuroimaging.

总结寨卡病毒（ZIKV）是一种新出现的蚊子传播的黄病毒，由于其能够引起全球公共卫生问题，在孕妇感染期间引起严重的先天性畸形2，以及脑膜脑炎，或感染后自身免疫性脱髓鞘在感染，非妊娠成人。宿主与病毒的相互作用 ZIKV感染和传播的特征仍然很差，对脑的感染后影响也是如此分别在先天性和成人感染中的发育和功能。我们已经发展出先天性的和ZIKV感染的成人模型，这些模型有助于定义ZIKV的许多致病特征感染在初步研究中，淋巴细胞（Rag 1-/-）、B细胞（μMT-/-）或T细胞缺陷的小鼠功能（TCR-/-）显示出不同的清除病毒的能力，这取决于暴露的方式。因此，μMT-/- 小鼠在ZIKV感染的先天性模型中表现出增加的发病机制，而Rag 1-/-和TCR-/-成年小鼠在ZIKV感染的先天性模型中表现出增加的发病机制。小鼠在颅内感染ZIKV后表现出存活率降低。我们假设抗原特异性T 细胞是从成年小鼠的大脑中消除ZIKV所必需的，而体液免疫起着重要的作用。在先天性感染期间ZIKV的清除中起主导作用。目标1我们将定义在CNS的先天性和成人ZIKV感染期间免疫介导的清除。虽然30%的先天性感染胎儿通过超声表现出形态异常（例如，小头畸形或脑钙化）12，大多数先天性感染的人没有表现出形态学或结构异常认知障碍和神经发育异常可能发生在先天性ZIKV感染可能对神经发育有重要影响，但也可能对子宫内感染后的神经发育有重要影响。此外，从急性ZIKV感染中恢复的成年人的记忆障碍最近已经被证实。在文献中报道。一种可能的机制涉及ZIKV感染神经干细胞和早期细胞凋亡。神经细胞类型的祖细胞。然而，在ZIKV恢复的成年小鼠的初步研究中，我们观察到，持续的小胶质细胞激活，减少SGZ神经发生和严重的空间学习缺陷，后者其通过缺乏经由干扰素-γ受体（IFNγR）的信号传导而得到改善。这些研究表明，免疫机制也可能导致从ZIKV脑炎恢复的成年人的记忆功能障碍。我们假设ZIKV的先天性感染由于直接作用于神经系统而导致认知改变。神经元祖细胞和放射状胶质细胞功能的间接破坏，导致功能异常，连通性。我们进一步假设CD 8 +IFNγ+ T细胞在成年ZIKV-1的CNS内的持续存在。恢复的动物促进小胶质细胞活化，这改变了学习和记忆的神经相关性，突触可塑性和成人神经发生。目标2和3将定义空间记忆的机制在成人和先天性ZIKV感染期间的功能障碍，并确定先天性ZIKV感染的影响。使用光学神经成像的ZIKV感染对脑功能连接的影响