Mechanisms of Enterovirus Entry

肠道病毒进入机制

• 批准号: 10913891
• 负责人: Susan Hafenstein
• 金额: $ 38.72万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10913891
• 关键词: Acute; Acute Disease; Antiviral Agents; Area; Aseptic Meningitis; Binding; Binding Sites; Biochemical; Biological; CAR receptor; Capsid; Cells; Classification; Collaborations; Communicable Diseases; Complement; Coxsackie B Viruses; Coxsackie Viruses; Cryoelectron Microscopy; Data Collection; Drug Design; Drug Targeting; Encephalitis; Enterovirus; Epitopes; Event; Family; Family Picornaviridae; Funding; Genome; Goals; Grant; Growth; Hour; Human; Human poliovirus; Hydrophobicity; In Situ; Insulin-Dependent Diabetes Mellitus; Link; Lipids; Maps; Modeling; Molecular; Molecular Conformation; Motion; Mutation; Myocarditis; Pancreatitis; Paralysed; Pathogenicity; Pediatric Hospitals; Peptides; Philadelphia; Preparation; Process; Productivity; Proline; Proteins; Protocols documentation; RNA; RNA Viruses; Resolution; Sampling; Sequence Alignment; Site; Specificity; Structure; Test Result; Testing; Viral Genome; Virus; Work; acute infection; adenovirus receptor; cross reactivity; endosome membrane; human pathogen; innovation; insulin dependent diabetes mellitus onset; live cell imaging; nanodisk; particle; receptor; receptor binding; reconstruction; respiratory; tomography

Using high resolution cryo electron microscopy (Cryo EM) we will investigate the mechanisms used by coxsackievirus B3 (CVB3) to enter host cells by engaging the coxsackievirus and adenovirus receptor (CAR). CVB3 is a human pathogen that causes myocarditis, pancreatitis, and has recently been linked to the onset of juvenile diabetes mellitus. Our proposed studies of CVB3 entry are a continuation of a productive previous granting period. Part of the previous work done was in collaboration with Dr. Jeffery Bergelson, Division of Infectious Diseases at Children's Hospital at Philadelphia, who has since retired. The proposed projects to continue studies of enterovirus entry include a collaboration with Konstantin Chumakov, FDA. Chumakov will work with us to explore one of the most promising results from the previous funding period, which was the discovery that a region in the CAR footprint onto the CVB3 capsid is conserved among three other viruses and their receptors, thus crossing four species using three different host proteins for entry. Further examination showed 1) the region is highly conserved among all human enteroviruses, including all three strains of poliovirus. 2) there are in total four different highly conserved regions. Previous work and our preliminary results link these conserved sites to functions linked to entry. Our structure/function studies will include testing each region for function and as targets for antivirals that are desperately needed. We will use both traditional icosahedrally averaged approaches along with asymmetric reconstruction approaches, some of which have been recently developed by us.

利用高分辨率冷冻电子显微镜(Cryo EM)，我们将研究柯萨奇病毒B3(CVB3)通过与柯萨奇病毒和腺病毒受体(CAR)结合进入宿主细胞的机制。CVB3是一种引起心肌炎、胰腺炎的人类病原体，最近被认为与青少年糖尿病的发病有关。我们提出的关于CVB3进入的研究是对先前富有成效的授权期的延续。之前的部分工作是与费城儿童医院传染病科杰弗里·伯格尔森博士合作完成的，伯格森博士现已退休。继续研究肠道病毒进入的拟议项目包括与FDA康斯坦丁·楚马科夫合作。Chumakov将与我们合作探索前一个资助期最有希望的结果之一，即发现CVB3衣壳上的汽车足迹区域在其他三种病毒及其受体中是保守的，从而使用三种不同的宿主蛋白进入四个物种。进一步检查表明，1)该区域在所有人类肠道病毒中高度保守，包括所有三种脊髓灰质炎病毒株。2)共有四个不同的高度保守区。以前的工作和我们的初步结果将这些保守的站点与与条目相关的功能联系起来。我们的结构/功能研究将包括测试每个区域的功能，并将其作为迫切需要的抗病毒药物的靶标。我们将使用传统的二十面体平均方法以及不对称重建方法，其中一些方法是我们最近开发的。

项目成果

Enterovirus 71 Virus Propagation and Purification.

肠道病毒 71 病毒的繁殖和纯化。

• DOI: 10.21769/bioprotoc.1117
• 发表时间: 2014
• 期刊: Bio-protocol
• 影响因子: 0.8
• 作者: Shingler,KristinL;Organtini,LindseyJ;Hafenstein,Susan
• 通讯作者: Hafenstein,Susan

Identification of a pocket factor that is critical to Zika virus assembly.

• DOI: 10.1038/s41467-020-18747-4
• 发表时间: 2020-10-02
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: DiNunno NM;Goetschius DJ;Narayanan A;Majowicz SA;Moustafa I;Bator CM;Hafenstein SL;Jose J
• 通讯作者: Jose J

Cryo-EM maps reveal five-fold channel structures and their modification by gatekeeper mutations in the parvovirus minute virus of mice (MVM) capsid.

冷冻电镜图揭示了小鼠细小病毒 (MVM) 衣壳中的五重通道结构及其看门突变的修饰。

• DOI: 10.1016/j.virol.2017.07.015
• 发表时间: 2017
• 期刊: Virology
• 影响因子: 3.7
• 作者: Subramanian,Suriyasri;Organtini,LindseyJ;Grossman,Alec;Domeier,PhillipP;Cifuente,JavierO;Makhov,AlexanderM;Conway,JamesF;D'AbramoJr,Anthony;Cotmore,SusanF;Tattersall,Peter;Hafenstein,Susan
• 通讯作者: Hafenstein,Susan

Structural comparison of four different antibodies interacting with human papillomavirus 16 and mechanisms of neutralization.

• DOI: 10.1016/j.virol.2015.04.016
• 发表时间: 2015-09
• 期刊: Virology
• 影响因子: 3.7
• 作者: Guan J;Bywaters SM;Brendle SA;Lee H;Ashley RE;Makhov AM;Conway JF;Christensen ND;Hafenstein S
• 通讯作者: Hafenstein S

Molecular determinants of disease in coxsackievirus B1 murine infection.

• DOI: 10.1002/jmv.22133
• 发表时间: 2011-09
• 期刊: JOURNAL OF MEDICAL VIROLOGY
• 影响因子: 12.7
• 作者: Cifuente, Javier O.;Ferrer, Maria F.;Jaquenod de Giusti, Carolina;Song, Wen-Chao;Romanowski, Victor;Hafenstein, Susan L.;Gomez, Ricardo M.
• 通讯作者: Gomez, Ricardo M.