NEUROPATHOGENESIS OF ZIKA VIRUS INFECTIONS

摘要 寨卡病毒(Zika Virus，ZIKV)是一种新出现的蚊媒黄病毒，因其具有 在孕妇感染期间导致严重的先天异常2，以及脑膜脑炎或 感染后自身免疫性脱髓鞘感染后，未怀孕的成年人。宿主-病毒相互作用控制 ZIKV的感染和传播特征仍然很差，感染后对大脑的影响也是如此 先天性感染和成人感染的发育和功能。我们已经发展出先天的 ZIKV感染的成人模型在确定ZIKV的许多致病特征方面发挥了重要作用 感染。在初步研究中，淋巴细胞(RAG1-/-)、B细胞(μMT-/-)或T细胞缺陷的小鼠 功能(TCR-/-)清除病毒的能力因暴露方式的不同而不同。因此，μMT-/- 在先天性ZIKV感染模型中，小鼠表现出更高的致病能力，而Rag1-/-和TCR-/-成体 小鼠在颅内感染ZIKV后存活率下降。我们假设抗原特异性T细胞 细胞需要清除成年小鼠大脑中的ZIKV，而体液免疫起着 先天感染中ZIKV清除的主导作用。目标1我们将定义 先天性和成人ZIKV感染中枢神经系统时的免疫介导清除。 虽然30%的先天性感染胎儿通过超声波表现出形态异常(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或 结构异常。认知障碍和神经发育异常很可能发生在 先天性ZIKV感染，但宫内感染后可能对神经发育也有重要影响。 此外，从急性寨卡病毒感染中恢复的成年人的记忆障碍最近被 在文献中有报道。一种可能的机制涉及ZIKV感染神经干细胞和早期 神经细胞型祖细胞。然而，在对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，SGZ神经发生减少和严重的空间学习障碍，后者 这是改善缺乏信号通过干扰素-γ受体(干扰素γR)。这些研究表明自适应 免疫机制也可能导致ZIKV脑炎恢复期成年人的记忆功能障碍。 我们假设先天性感染ZIKV会导致认知改变，这是由于对 神经前体细胞和间接破坏放射状神经胶质功能，导致功能异常 连通性。我们进一步假设，CD8+干扰素γ+T细胞在成虫中枢神经系统内的持久性- 恢复的动物促进了小胶质细胞的激活，从而改变了学习和记忆的神经关联，如 作为突触可塑性和成人神经发生。目标2和目标3将定义空间记忆的机制 成人和先天性感染ZIKV时的功能障碍及其对先天性感染的影响 应用光学神经成像技术研究ZIKV感染对脑功能连通性的影响。

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.