Enterovirus Pathogenesis

肠道病毒发病机制

基本信息

批准号：
7380955
负责人：
VINCENT R RACANIELLO
金额：
$ 36.23万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7380955
关键词：
3&apos Untranslated Regions Acute Address Affect Amino Acids Animal Model Animal Viruses Animals Antiviral Agents Biological Brain Cells Central Nervous System Infections Cultured Cells DNA Disease Endopeptidases Enterovirus Genome Goals Growth Human Human poliovirus IFNAR1 gene Infection Infection prevention Interferon-alpha Interferons Intestines Laboratories Lead Life Lytic Mediating Modeling Molecular Mus Neuraxis Numbers Oral Poliovirus Vaccine Organ Pathogenesis Pattern Recognition Peptide Hydrolases Phenotype Poliomyelitis Polioviruses Proteins Receptor Cell Research Role Signal Transduction Site Spinal Cord TLR3 gene Transgenic Mice Translations Tropism Variant Viral Virulence Virus Virus Diseases attenuation base cytokine design macromolecule neurotropic virus pathogen poliovirus receptor programs receptor relating to nervous system research study response

项目摘要

Poliomyelitis is an acute infection of the central nervous system cause by poliovirus. Poliovirus is an important human pathogen, yet our understanding of how the virus causes disease is incomplete. The goal of the proposed studies is to study the pathogenesis of poliomyelitis in transgenic mice that synthesize the cell receptor for poliovirus, PVR. This goal will be pursued through the following specific aims. 1. Determine how poliovirus replicates in the presence of IFN. Poliovirus replicates in cultured cells treated with IFNa A single amino acid change in the viral 2Apno proteinase renders the virus sensitive to IFNa without affecting inhibition of host cell translation. Experiments are designed to provide evidence that 2Apro proteinase is essential for growth in the presence of IFNa, and to determine whether 2Apro blocks induction of IFN synthesis, or the induction of ISGs by IFN. We have also found that poliovirus infection blocks the induction of ISGs. We will determine whether this effect is caused by viral proteinase, 2Apro or 3Cpro, and identify the steps in innate sensing and IFN induction that are affected by viral replication.2. Determine the relationship between the IFNo/p response and poliovirus pathogenesis in mice. The restricted tropism of poliovirus in CD155Tg mice is determined by the IFNo/p response. Non-neural organs of CD155Tg mice appear to be protected from poliovirus infection by the induction of a vigorous ISG response. In contrast, the brain and spinal cord do not mount an ISG response and are not protected from poliovirus infection. These important observations lead to a number of other questions about the relationship between poliovirus pathogenesis and the IFNa/p response, which are addressed in this aim. Why do mice mount a poor ISG response to poliovirus in the central nervous system? What is the extent of the ISG response to poliovirus in the mouse intestine, and is it responsible for preventing infection at that site? Are the Sabin vaccine strains neurovirulent in CD155Tg x IFNAR*'* mice? Does reduced replication of these strains in the central nervous system lead to an enhanced ISG response that limits viral replication? 3. Determine the role of pattern recognition molecules in poliovirus replication and pathogenesis. Innate responses to viral infection are triggered when cellular pattern recognition molecules engage viral macromolecules. Experiments in this specific aim are designed to determine the role of specific pattern recognition molecules in poliovirus replication and pathogenesis. We will determine the roles of TLR3, TLR7/8, RIG-I, and MDA-5 in sensing poliovirus replication in mice and in cultured cells. The biological role of poliovirus-induced cleavage of RIG-I and MDA-5 will be determined. Because poliovirus is a model pathogen, the results will contribute to the control of other medically relevant viruses.

脊髓灰质炎是由脊髓灰质炎病毒引起的中枢神经系统的急性感染。脊髓灰质炎病毒是一种重要的人类病原体，但我们对该病毒如何引起疾病的了解并不完整。目标拟议的研究之一是研究转基因小鼠脊髓灰质炎的发病机制，该小鼠合成了脊髓灰质炎病毒（PVR）的细胞受体。这一目标将通过以下具体目标来实现。 1. 确定脊髓灰质炎病毒在干扰素存在下如何复制。脊髓灰质炎病毒在经 IFNa 处理的培养细胞中复制病毒 2Apno 蛋白酶中的单个氨基酸变化使病毒对 IFNa 敏感而不影响抑制宿主细胞翻译。实验旨在提供 2Apro 蛋白酶是在存在 IFNa 的情况下对于生长至关重要，并确定 2Apro 是否会阻断 IFN 的诱导合成，或通过 IFN 诱导 ISG。我们还发现脊髓灰质炎病毒感染会阻碍诱导 ISG 的数量。我们将确定这种效应是否是由病毒蛋白酶、2Apro 或 3Cpro 引起的，并确定受病毒复制影响的先天感应和干扰素诱导步骤。2．确定关系小鼠体内 IFNo/p 反应与脊髓灰质炎病毒发病机制之间的关系。脊髓灰质炎病毒的限制性取向 CD155Tg 小鼠中的 IFNo/p 反应决定。 CD155Tg 小鼠的非神经器官似乎通过诱导强烈的 ISG 反应来保护免受脊髓灰质炎病毒感染。相比之下，大脑和脊髓不会产生 ISG 反应，也无法免受脊髓灰质炎病毒感染。这些重要的观察结果引发了有关脊髓灰质炎病毒发病机制之间关系的许多其他问题以及 IFNa/p 反应，这些都是本目标所解决的。为什么小鼠对 ISG 的反应较差脊髓灰质炎病毒在中枢神经系统中？小鼠中 ISG 对脊髓灰质炎病毒的反应程度如何肠，它是否负责预防该部位的感染？是萨宾疫苗株吗 CD155Tg x IFNAR*'* 小鼠具有神经毒性吗？这些菌株在中枢神经中的复制是否减少系统会导致增强的 ISG 反应从而限制病毒复制吗？ 3.确定模式的作用脊髓灰质炎病毒复制和发病机制中的识别分子。对病毒感染的先天反应是当细胞模式识别分子与病毒大分子结合时触发。这方面的实验具体目标旨在确定特定模式识别分子在脊髓灰质炎病毒中的作用复制和发病机制。我们将确定 TLR3、TLR7/8、RIG-I 和 MDA-5 在传感中的作用脊髓灰质炎病毒在小鼠和培养细胞中的复制。脊髓灰质炎病毒诱导的 RIG-I 裂解的生物学作用并测定MDA-5。由于脊髓灰质炎病毒是一种模式病原体，因此研究结果将有助于控制其他医学相关病毒。