NeuroEbola

总结 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%。 取决于疫情的爆发单克隆抗体Zmapp、Mab 114、REGN-EB 3和 使用Remdesivir（病毒RNA合成抑制剂），提高了埃博拉治疗单位的存活率 (ETU)在刚果-金沙萨持续爆发埃博拉病毒病期间。尽管有治疗，34% 的EVD幸存者出现眼部并发症。此外，他们的[平均值（SD）]最小检验 检查（MMSE）评分，即[25（5.5）]相对于对照组[29.9（0.6）]（p < 0.01）;女性表现较差 [24.8（5.90）相对于男性[28.4（3.2）]（p < 0.01）。EVD幸存者抑郁的几率更高[OR： 14.9（95%CI：4.4 - 50.1）]，主要发生在女性[OR：4.4. (95%CI：2.1 - 9.6）]，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，对于一个单位 校正年龄和抑郁状态后，ctXptNP增加; ctXpt降低=病毒载量升高]。EBOV 在急性EVD后的几个月内，在母乳、湿制品和精液中持续存在。我们建议测试 假设EBOV的初始和/或持续性决定了神经眼科后遗症的发生 病毒载量与可辨别的IgG应答，和/或由升高的细胞因子驱动的持续性炎症状态 和免疫细胞活化;通过解决以下具体目标：目标1.对比神经- 在确诊的EVD幸存者中发现的眼科缺陷（范围和程度）与在其 IgG+但无EVD的密切接触者和IgG-对照组（每组N = 90）。在目标1A中，研究参与者将 使用神经认知的纵向（0、6、12、24、36和48个月时间点）评估 注意力变量（听觉和视觉）的计算机化测试，注意力表现测试，以及 非语言认知技能的CogState。在目标1B中，他们将接受视觉敏锐度的心理物理测试， 对比敏感度、色觉和视野;以及光谱域光学相干断层扫描， 阐明视觉通路内疾病的结构生物标志物。目的 差异 水平 过多 2、决定是否组- 在目的1中发现的神经眼科结果是由EBOV病毒载量或持续性介导的， 抗EBOV IgG的改变，循环免疫细胞的水平或活化状态的改变，和/或 促炎细胞因子。目标3将提高神经认知评估的能力， 眼科评估和EVD免疫分析和分子生物学（RT-PCR）。知识差距， 需要填补的问题包括缺乏对（1）EBOV持久性，（2）持久性免疫失调，（3）IgG 无明显EVD症状的阳性，均在EVD治疗后的背景下。拟议的总体目标 工作与NIH的全球健康使命保持一致，同时整合FIC的研究所特定使命， 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.