Molecular mechanisms of eastern equine encephalitis virus pathogenesis

摘要 北美东部马脑炎病毒株(NA-EEEV)最多 节肢动物传播的甲型病毒的神经毒力，也是毒性最强的病毒之一 已知的病毒，导致30%-70%的有症状的人类病例死亡，几乎 马匹的统一死亡率。此外，NA-EEEV被认为是一种潜在的 生物武器，是NIH B类优先病原体和USDA/CDC选择剂。 NA-EEEV在美国的流行范围正在扩大，人类病例的数量 该病毒正在增加，最近从蚊子物种中分离出这种病毒 攻击性的人类进食行为，增加了暴发的可能性 严重的脑炎。然而，没有获得许可的疫苗或抗病毒疗法，而且 对该病毒的研究仍然严重不足。 人类感染的特征是一种有限的前驱疾病和快速发病 脑炎的症状，通常被认为是感染的第一个迹象。最近的工作有 表明病毒的两种表型在很大程度上导致了EEEV的严重程度 感染：1)避免病毒颗粒接触淋巴组织和加重 与病毒结合的硫酸乙酰肝素受体引起的神经元感染；2)限制 在髓系细胞，特别是巨噬细胞和树突状细胞中复制EEEV，通过 造血细胞特异性microRNA miR142-3p与病毒基因组的结合。 总之，这些活动基本上阻止了EEEV的淋巴组织复制， 抑制先天免疫反应并直接促进神经元感染导致 严重的，通常是致命的脑炎。 在此续期申请中，我们寻求提供对以下方面的综合了解 HS结合与miR142-3p限制的关系，与1)特异性 蛋白多糖受体在EEEV体外感染性和体内嗜性与疾病；2) 不同人类和非人类宿主对EEEV复制和疾病的易感性； 3)Hs结合和miR142-3p限制表型在感染过程中的变化 哺乳动物宿主及其变异对髓系细胞免疫应答的影响 与EEEV的交互。

ABSTRACT North American strains of eastern equine encephalitis virus (NA-EEEV) are the most neurovirulent of the arthropod-borne alphaviruses and one of the most acutely virulent viruses known, causing mortality in 30-70% of symptomatic human cases and almost uniform mortality in equines. Furthermore, NA-EEEV is considered a potential bioweapon and is an NIH Category B priority pathogen and USDA/CDC Select Agent. The endemic range of NA-EEEV is expanding within the US, numbers of human cases are increasing and the virus has recently been isolated from mosquito species with aggressive human feeding behavior, raising the potential for increased outbreaks of severe encephalitis. Yet, no licensed vaccines or antiviral therapeutics are available and the virus remains critically understudied. Human infections are characterized by a limited prodromal disease and rapid onset of encephalitis signs, often observed as the first indication of infection. Recent work has shown that two phenotypes of the virus are largely responsible for the severity of EEEV infection: 1) avoidance of virus particle access to lymphoid tissues and exacerbation of neuron infection due to heparan sulfate receptor binding by the virus; and 2) restriction of EEEV replication in myeloid cells, particularly macrophages and dendritic cells, by binding of the hematopoietic cell-specific microRNA, miR142-3p, to the virus genome. Together, these activities essentially block lymphoid tissue replication by EEEV, greatly suppress innate immune responses and directly promote neuron infection leading to severe and often fatal encephalitis. In this renewal application, we seek to provide an integrated understanding of relationship of HS binding and miR142-3p restriction, to 1) the role of specific proteoglycan receptors in EEEV infectivity in vitro and tropism and disease in vivo; 2) susceptibility of different human and non-human hosts to EEEV replication and disease; and 3) variability of HS binding and miR142-3p restriction phenotypes during infection of mammalian hosts and the effects of this variation on responses of myeloid cells to interactions with EEEV.