NeuroEbola

摘要 埃博拉病毒(EBOV)是人类已知的最致命的病原体之一，病死率为25%-90% 根据疫情的不同。首次用单抗ZMapp、Mab114、REGN-EB3和 使用了雷米西韦(病毒RNA合成的抑制剂)，提高了埃博拉治疗单位的存活率 (ETU)在刚果-金沙萨持续爆发的埃博拉病毒病(EVD)期间。尽管接受了治疗，34%的人 的EVD幸存者出现了眼部并发症。此外，他们有较低的[均值(SD)]最小测验 考试(MMSE)分数，即[25(5.5)]相对于对照组[29.9(0.6)](p&lt；0.01)；女性表现很差 [24.8(5.90)相对于男性[28.4(3.2)](p&lt；0.01)。EVD幸存者患抑郁症的几率更高[OR： 14.9(95%CI：4.4-50.1)]，女性居多[OR：4.4。(95%CI：2.1-9.6)]而且，有趣的是， 女性与较高的初始EBOV病毒载量相关[OR：0.84(95%CI：0.73-0.98，p=0.03，一个单位 在对年龄和抑郁状态进行调整后，ctXptNP增加；ctXpt较低=病毒载量较高]。EBOV 在急性EVD后，坚持母乳、湿准备和精液几个月。我们建议测试一下 假设神经性眼科后遗症的发生是由EBOV的初始和/或持续性决定的 病毒载量，具有可识别的免疫球蛋白反应，和/或由升高的细胞因子驱动的持续炎症状态 和免疫细胞激活；通过解决以下具体目标：目的1.对比神经细胞和 在确诊的EVD幸存者中发现的眼科缺陷(光谱和程度)与他们的 免疫球蛋白阳性但无EVD密切接触者和免疫球蛋白阴性对照(每组90例)。在目标1A中，研究参与者将 使用以下工具对神经认知进行纵向(0、6、12、24、36和48个月时间点)评估 注意力变量的计算机化测试(听觉和视觉)，注意表现的测试，以及 用于非语言认知技能的CogState。在目标1B中，他们将接受视力的心理物理测试， 对比敏感度、色觉和视野；以及光谱域-光学相干层析成像 阐明视觉通路中疾病的结构生物标志物。目标 差异 水准仪 过多 2将决定小组是否- 在AIM 1中发现的神经眼科结果是由EBOV病毒载量或持久性介导的， 抗EBOV免疫球蛋白，循环免疫细胞水平或激活状态的变化，和/或 致炎细胞因子。目标3将增强神经认知评估的能力， 眼科评估和EVD免疫分析及分子生物学(RT-PCR)。知识的差距 包括对(1)EBOV持久性，(2)长期免疫失调，(3)免疫球蛋白缺乏了解 阳性，没有明显的EVD症状，都是在EVD治疗后的情况下。建议的总体目标是 工作与NIH的全球卫生使命相一致，同时整合FIC特定于研究所的使命， NEI、NIAID、NINDS和疾病预防办公室。

SUMMARY Ebolaviruses (EBOV) are among the deadliest pathogens known to man, with a case fatality rate of 25–90% depending on the outbreak. For the first time, monoclonal antibodies Zmapp, Mab114, REGN-EB3 and Remdesivir (inhibitor of viral RNA synthesis) were used, improving survival rates in Ebola treatment units (ETU) during the ongoing outbreak of Ebola virus disease (EVD) in Congo-Kinshasa. Despite treatments, 34% of EVD survivors experienced eye complications. In addition, they had lower [mean (SD)] minimental test examination (MMSE) scores i.e. [25 (5.5)] relative to controls [29.9 (0.6)] (p < 0.01); and women perform poorly [24.8 (5.90] relative to men [28.4 (3.2)](p < 0.01). The odds of depression were higher in EVD survivors [OR: 14.9 (95%CI: 4.4 – 50.1)], mostly in women [OR: 4.4. (95%CI: 2.1 – 9.6)] and, intriguingly, MMSE deficit in women was associated with higher initial EBOV viral load [OR: 0.84 (95%CI: 0.73 – 0.98, p = 0.03, for one-unit increase in ctXptNP; lower ctXpt = higher viral load] after adjustment for age and depression status. EBOV persisted in breastmilk, wet preps, and semen for several months after acute EVD. We propose to test the hypothesis that occurrence of neuroophthalmologic sequalae is dictated by initial and/or persistence of EBOV viral load with discernable IgG responses, and/or a persistent inflammatory state driven by elevated cytokines and immune cell activation; by addressing the following specific aims: Aim 1. To contrast neuro- ophthalmologic deficits (spectrum & extent) found in confirmed EVD survivors to relevant profiles seen in their IgG+ but EVD-free close contacts, and IgG- controls (N = 90 per group). In Aim 1A, study participants will have longitudinal (0, 6, 12, 24, 36, and 48 month-time-points) assessments of neurocognition using the computerized Test of Variables of Attention (auditory and visual), the Test of Attentional Performance, and CogState for nonverbal cognitive skills. In Aim 1B, they will undergo psychophysical tests for visual acuity, contrast sensitivity, color vision, and visual field; as well as spectral domain-optical coherence tomography to elucidate structural biomarkers of disease within visual pathways. Aim differences levels overabundance 2 will determine whether group- on neuroophthalmologic outcomes found in Aim 1 are mediated by EBOV viral load or persistence, of anti-EBOV IgG, alterations in levels or activation status of circulating immune cells, and/or of proinflammatory cytokines. Aim 3 will enhance capacity in neurocognitive assessments, ophthalmologic evaluations and EVD immunoprofiling and molecular biology (RT-PCR). Gaps of knowledge to be filled include lack of understanding of (1) EBOV persistence, (2) long-lasting immune dysregulation, (3) IgG positivity with no overt EVD symptoms, all in contexts of post-EVD treatment. The overall goal of the proposed work aligns with the global health mission of the NIH while integrating the institute-specific missions of FIC, NEI, NIAID, NINDS, and the Office of Disease Prevention.