Molecular mechanisms of eastern equine encephalitis virus pathogenesis

东部马脑炎病毒发病的分子机制

• 批准号: 10416025
• 负责人: WILLIAM B KLIMSTRA
• 金额: $ 48.55万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10416025
• 关键词: Acute; Acute Disease; Affect; Alphavirus; American; Animals; Antiviral Agents; Binding; Binding Sites; Category B pathogen; Cells; Centers for Disease Control and Prevention (U.S.); Culicidae; Dendritic Cells; Disease; Disease Outbreaks; Eastern Equine Encephalitis Virus; Encephalitis; Epidemic; Equus caballus; Feeding behaviors; Funding; Growth; Hematopoietic; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Horse Diseases; Human; Immune; In Vitro; Individual; Infection; Innate Immune Response; Interferons; Intervention; Lymphoid Tissue; Mammals; MicroRNAs; Molecular; Mus; Mutation; Myeloid Cells; Neurons; North America; Pharmaceutical Preparations; Phenotype; Predisposition; Process; Production; Proteoglycan; RNA Viruses; Resistance; Role; Severities; Tropism; United States; United States Department of Agriculture; United States National Institutes of Health; Vaccine Design; Vaccines; Variant; Vertebrate Viruses; Viral Genome; Viral Pathogenesis; Virion; Virulent; Virus; Virus Diseases; Virus Replication; Work; aged; antagonist; arthropod-borne; bioweapon; cell type; cytokine; human disease; in vivo; macrophage; mortality; receptor; receptor binding; response; syndecan; targeted treatment; vector mosquito; virus tropism; young adult

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.

摘要 东部马脑炎病毒（NA-EEEV）的北美株是最多的 神经毒性的节肢动物传播的甲病毒和一个最急性毒性 已知的病毒，导致30-70%的有症状的人类病例死亡， 马的死亡率是一致的。此外，NA-EEEV被认为是潜在的 是NIH B类优先病原体和USDA/CDC选择剂。 NA-EEEV的流行范围在美国正在扩大， 最近从蚊子中分离出了这种病毒， 攻击性的人类进食行为，增加了爆发的可能性， 严重脑炎。然而，没有获得许可的疫苗或抗病毒治疗剂， 该病毒的研究仍然严重不足。 人类感染的特点是有限的前驱疾病和快速发病 脑炎的迹象，通常被视为感染的第一个迹象。最近的工作已经 表明病毒的两种表型是EEEV严重性的主要原因 感染：1）避免病毒颗粒进入淋巴组织， 由于硫酸乙酰肝素受体与病毒结合引起的神经元感染;和2）限制 EEEV在骨髓细胞，特别是巨噬细胞和树突状细胞中的复制， 造血细胞特异性microRNA miR 142 - 3 p与病毒基因组的结合。 总之，这些活动基本上阻断了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， 严重的通常致命的脑炎。 在此更新应用程序中，我们寻求提供一个综合的理解， HS结合和miR 142 - 3 p限制的关系，1）特异性的 蛋白多糖受体在EEEV体外感染性和体内嗜性和疾病中的作用; 2） 不同人类和非人类宿主对EEEV复制和疾病的易感性; 和3）在感染期间HS结合和miR 142 - 3 p限制性表型的变异性， 哺乳动物宿主和这种变化对骨髓细胞对 与EEEV的互动。

项目成果

Lower temperatures reduce type I interferon activity and promote alphaviral arthritis.

较低的温度会降低 I 型干扰素活性并促进甲病毒性关节炎。

• DOI: 10.1371/journal.ppat.1006788
• 发表时间: 2017
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Prow,NatalieA;Tang,Bing;Gardner,Joy;Le,ThuyT;Taylor,Adam;Poo,YeeS;Nakayama,Eri;Hirata,ThiagoDC;Nakaya,HelderI;Slonchak,Andrii;Mukhopadhyay,Pamela;Mahalingam,Suresh;Schroder,WayneA;Klimstra,William;Suhrbier,Andreas
• 通讯作者: Suhrbier,Andreas