Molecular mechanisms of eastern equine encephalitis virus pathogenesis

东部马脑炎病毒发病的分子机制

基本信息

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
项目类别：
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

项目摘要

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.

抽象的东部马脑炎病毒 (NA-EEEV) 的北美毒株是最常见的节肢动物传播的甲病毒具有神经毒性，也是毒性最强的病毒之一已知的病毒，导致 30-70% 有症状的人类病例死亡，几乎马科动物的死亡率一致。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 的流行范围正在美国扩大，人类病例数正在增加，并且最近已从蚊子物种中分离出该病毒人类的攻击性进食行为，增加了爆发更多疾病的可能性严重脑炎。然而，目前还没有获得许可的疫苗或抗病毒疗法该病毒的研究仍然严重不足。人类感染的特点是前驱性疾病有限且发病迅速脑炎症状，通常作为感染的第一个迹象。最近的工作有研究表明，该病毒的两种表型在很大程度上导致了 EEEV 的严重性感染：1）避免病毒颗粒进入淋巴组织并加剧病毒与硫酸乙酰肝素受体结合导致神经元感染； 2) 限制 EEEV 在骨髓细胞，特别是巨噬细胞和树突状细胞中复制的影响造血细胞特异性 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，极大地抑制了淋巴组织的复制。抑制先天免疫反应并直接促进神经元感染，导致严重且常常致命的脑炎。在此续订申请中，我们力求提供对以下方面的综合理解： HS 结合和 miR142-3p 限制的关系，1) 特异性的作用蛋白聚糖受体与 EEEV 体外感染性以及体内向性和疾病的关系； 2）不同人类和非人类宿主对 EEEV 复制和疾病的易感性； 3) 感染过程中 HS 结合和 miR142-3p 限制性表型的变异性哺乳动物宿主以及这种变异对骨髓细胞反应的影响与 EEEV 的相互作用。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Encephalitic Alphaviruses Exploit Caveola-Mediated Transcytosis at the Blood-Brain Barrier for Central Nervous System Entry.

脑炎甲病毒利用小凹介导的血脑屏障转胞吞作用进入中枢神经系统。

DOI：
发表时间：
2020
期刊：
影响因子：
6.4
作者：
Salimi, Hamid;Cain, Matthew D;Jiang, Xiaoping;Roth, Robyn A;Beatty, Wandy L;Sun, Chengqun;Klimstra, William B;Hou, Jianghui;Klein, Robyn S
通讯作者：
Klein, Robyn S

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：
发表时间：
2017-12
期刊：
影响因子：
6.7
作者：
Prow, Natalie A;Tang, Bing;Gardner, Joy;Le, Thuy T;Taylor, Adam;Poo, Yee S;Nakayama, Eri;Hirata, Thiago D C;Nakaya, Helder I;Slonchak, Andrii;Mukhopadhyay, Pamela;Mahalingam, Suresh;Schroder, Wayne A;Klimstra, William;Suhrbier, Andreas
通讯作者：
Suhrbier, Andreas

Macromolecular Synthesis Shutoff Resistance by Myeloid Cells Is Critical to IRF7-Dependent Systemic Interferon Alpha/Beta Induction after Alphavirus Infection.

骨髓细胞的大分子合成阻断抵抗对于甲病毒感染后 IRF7 依赖性系统干扰素 α/β 诱导至关重要。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Bhalla, Nishank;Gardner, Christina L;Downs, Sierra N;Dunn, Matthew;Sun, Chengqun;Klimstra, William B
通讯作者：
Klimstra, William B

Antibody Preparations from Human Transchromosomic Cows Exhibit Prophylactic and Therapeutic Efficacy against Venezuelan Equine Encephalitis Virus.

来自人转染色体牛的抗体制剂对委内瑞拉马脑炎病毒具有预防和治疗功效。

DOI：
发表时间：
2017-07-15
期刊：
影响因子：
0
作者：
Gardner, Christina L;Sun, Chengqun;Luke, Thomas;Raviprakash, Kanakatte;Wu, Hua;Jiao, Jin;Sullivan, Eddie;Reed, Douglas S;Ryman, Kate D;Klimstra, William B
通讯作者：
Klimstra, William B

Electrocardiography Abnormalities in Macaques after Infection with Encephalitic Alphaviruses.

感染脑炎甲病毒后猕猴心电图异常。