Enterovirus Pathogenesis

肠道病毒发病机制

• 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
• 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' 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

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，但我们对病毒如何引起疾病的理解是不完整的。目标 其中一项拟议的研究是研究脊髓灰质炎在转基因小鼠中的发病机制， 脊髓灰质炎病毒细胞受体将通过以下具体目标实现这一目标。1.确定 脊髓灰质炎病毒如何在干扰素存在下复制。用IFNa处理的培养细胞中的脊髓灰质炎病毒复制 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IFN α。 抑制宿主细胞翻译。实验旨在提供2Apro蛋白酶是 在IFN α存在下生长所必需的，并确定2Apro是否阻断IFN α的诱导 合成或IFN诱导ISG。我们还发现脊髓灰质炎病毒感染阻断了诱导 的ISG。我们将确定这种效应是否是由病毒蛋白酶2Apro或3Cpro引起的， 受病毒复制影响的先天感应和IFN诱导步骤。确定关系 在小鼠中IFN 0/p应答和脊髓灰质炎病毒发病机制之间。脊髓灰质炎病毒的限制性嗜性 在CD 155 Tg小鼠中，通过IFN 0/β反应确定。CD 155 Tg小鼠的非神经器官似乎 通过诱导强有力的ISG应答而免受脊髓灰质炎病毒感染。相反，大脑和 脊髓不产生ISG应答，且不能免受脊髓灰质炎病毒感染。这些重要 观察结果导致了一些关于脊髓灰质炎病毒发病机制与 和IFNa/p反应，这是在这个目标。为什么小鼠对胰岛素抵抗的ISG反应很差？ 中枢神经系统中的脊髓灰质炎病毒？ISG对小鼠脊髓灰质炎病毒的反应程度如何 肠道，它负责防止该部位的感染吗？萨宾疫苗株 在CD 155 Tg x IFNAR小鼠中的神经毒性？这些菌株在中枢神经系统中的复制减少 系统导致增强ISG反应，限制病毒复制？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。在这方面的实验 设计特定的目标以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TLR 3、TLR 7/8、RIG-I和MDA-5在感受 脊髓灰质炎病毒在小鼠和培养细胞中复制。脊髓灰质炎病毒诱导RIG-I裂解的生物学作用 MDA-5将被确定。由于脊髓灰质炎病毒是一种模式病原体，因此该结果将有助于 控制其他医学相关病毒。