Modeling host susceptibility factors in Acute Flaccid Myelitis

项目摘要/摘要 急性弛缓性脊髓炎宿主易感因素的建模 急性弛缓性脊髓炎(AFM)是一种儿童脊髓灰质炎样神经感染性疾病，其患病率为 近年来急剧增加，至少自2014年以来在美国每两年爆发一次。 原子力显微镜的后果通常是严重的、使人虚弱的终生瘫痪，可能还包括呼吸系统。 失败了。尽管它与脊髓灰质炎有着惊人的相似之处，但人们对疾病的发病机制知之甚少，也很少有有效的方法。 治疗方案是有的。AFM与嗜神经的非脊髓灰质炎肠道病毒有关，尤其是 肠道病毒D68(EV68)。然而，绝大多数EV68感染病例会引起轻微的非特异性病毒 症状或呼吸综合征，而只有一小部分患者因 脊髓运动神经元感染。这一观察表明，AFM的发展需要 允许神经发病的病毒感染和宿主因素的交集。因此，我们将 从AFM患者先前捐赠的组织中产生诱导多能干细胞(IPS)系，并使用 这些都是为了在体外模拟EV68感染导致的AFM。在这个范围内的初步实验 应用将集中在脊髓运动神经元，因为运动神经元死亡是直接原因 AFM患者瘫痪的证据，以及EV68直接运动神经元感染的证据。我们将描述 AFM患者来源和对照分化为脊髓运动的iPS系的组成和重复性 并确定神经元对各种细胞应激源的基线敏感度。这些 研究将为未来感染EV68感染患者来源的iPS运动神经元的实验奠定基础 更好地了解允许病毒感染、运动神经元死亡和功能障碍的宿主因素。 这项工作的结果将是原子力显微镜的模型系统，忠实地再现受影响的细胞类型，在 人类细胞，以及已被证明对疾病易感性的遗传背景。IPS线也将是 未来能够对其他与疾病相关的细胞类型进行建模。这些细胞系将代表一种独特的 为原子力显微镜研究界提供宝贵的资源。

Project Summary/Abstract Modeling host susceptibility factors in Acute Flaccid Myelitis Acute flaccid myelitis (AFM) is a poliomyelitis-like neuroinfectious illness of children whose prevalence has increased dramatically in recent years, occurring in biennial outbreaks in the Unites States since at least 2014. The consequences of AFM are often severe and debilitating lifelong paralysis that may also include respiratory failure. Despite its striking similarity to polio, little is known about disease pathogenesis and few effective treatment options exist. AFM has been connected to neurotropic non-polio enteroviruses, especially Enterovirus D68 (EV68). However, the vast majority of cases of EV68 infections cause mild non-specific viral symptoms or a respiratory syndrome, while only a small minority of patients become paralyzed as a result of spinal motor neuron infection. This observation suggests that the development of AFM requires the intersection of viral infection and host factors that are permissive to neuropathogenesis. We will therefore generate induced pluripotent stem cell (iPS) lines from tissues previously donated by AFM patients, and use these to model AFM resulting from EV68 infection in vitro. The initial experiments within the scope of this application will focus on spinal motor neurons, due to the fact that motor neuron death is the proximate cause of paralysis in AFM patients, and evidence for direct motor neuron infection by EV68. We will characterize the composition and reproducibility of AFM patient derived and control iPS lines differentiated into spinal motor neurons, and determine the baseline susceptibility of the neurons to a variety of cellular stressors. These studies will set the stage for future experiments of EV68 infection of patient-derived iPS motor neurons to better understand host factors that are permissive of viral infection and motor neuron death and dysfunction. The result of this work will be a model system for AFM that faithfully reproduces the affected cell type, in human cells, and on a genetic background with proven susceptibility to disease. The iPS lines will also be capable of modeling other disease-relevant cell types in the future. These cell lines will represent a unique and valuable resource to the AFM research community.