Mechanisms of Enterovirus Entry

肠道病毒进入机制

基本信息

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
项目类别：
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

项目摘要

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.

使用高分辨率的冷冻电子显微镜（Cryo EM），我们将研究Coxsackievivirus B3（CVB3）使用的机制，通过与Coxsackievievirus和腺病毒受体（CAR）接合来进入宿主细胞。 CVB3是一种引起心肌炎，胰腺炎的人类病原体，最近与少年糖尿病的发作有关。我们对CVB3进入的拟议研究是持续的先前授予期。先前完成的工作的一部分是与费城儿童医院传染病的杰弗里·伯格森（Jeffery Bergelson）合作，后来已退休。拟议的继续研究肠病毒进入的项目包括与FDA的Konstantin Chumakov合作。 Chumakov将与我们合作探索上一个资金期间最有希望的结果之一，这是发现汽车足迹中的一个在CVB3 Capsid上的区域在其他三种病毒及其受体中保存下来，因此使用三个物种越过四个物种不同的宿主蛋白用于进入。进一步检查表明1）该区域在所有人类肠病毒中都高度保守，包括所有三种脊髓灰质炎病毒菌株。 2）共有四个不同的高度保守区域。先前的工作和我们的初步结果将这些保守的站点与与入口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和作为迫切需要的抗病毒药的目标。我们将使用传统的二十面体平均方法以及不对称的重建方法，其中一些方法最近是由我们开发的。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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

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

A human monoclonal antibody binds within the poliovirus receptor-binding site to neutralize all three serotypes.

DOI：
10.1038/s41467-023-41052-9
发表时间：
2023-10-10
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Charnesky, Andrew J.;Faust, Julia E.;Lee, Hyunwook;Puligedda, Rama Devudu;Goetschius, Daniel J.;Dinunno, Nadia M.;Thapa, Vaskar;Bator, Carol M.;Cho, Sung Hyun (Joseph);Wahid, Rahnuma;Mahmood, Kutub;Dessain, Scott;Chumakov, Konstantin M.;Rosenfeld, Amy;Hafenstein, Susan L.
通讯作者：
Hafenstein, Susan L.