Enterovirus Pathogenesis

脊髓灰质炎是由脊髓灰质炎病毒引起的一种急性中枢神经系统感染。脊灰病毒是一种 重要的人类病原体，但我们对病毒如何导致疾病的了解还不完整。目标是 其中一项拟议的研究是在合成脊髓灰质炎病毒的转基因小鼠中研究脊髓灰质炎的发病机制。 脊髓灰质炎病毒的细胞受体。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是如何复制的。脊髓灰质炎病毒在IFNA处理的培养细胞中复制 病毒2Apno酶的单一氨基酸变化使病毒对IFNA敏感而不影响 抑制宿主细胞的翻译。实验的目的是提供证据，证明2APro蛋白酶是 在有IFNA存在的情况下对生长至关重要，并确定2Apro是否能阻断干扰素的诱导 合成，或干扰素诱导的ISGs。我们还发现，脊髓灰质炎病毒感染阻断了这种诱导 在ISG中。我们将确定这种影响是由病毒蛋白水解酶、2Apro还是3Cpro引起的，并确定 受病毒复制影响的先天感知和干扰素诱导的步骤。确定关系 在小鼠中IFNo/p应答与脊髓灰质炎病毒致病机制之间的关系。脊髓灰质炎病毒的限制性嗜性 在CD155Tg小鼠中是由IFNo/p反应决定的。CD155Tg小鼠的非神经器官似乎是 通过诱导强有力的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，也不会受到脊髓灰质炎病毒感染的保护。这些都很重要 观察导致了一些关于脊髓灰质炎病毒致病机制之间关系的其他问题。 和IFNA/p反应，这些都是在这一目标中处理的。为什么小鼠的ISG反应很差 中枢神经系统中的脊髓灰质炎病毒？小鼠对脊髓灰质炎病毒的ISG反应有多大 肠道，它是否负责预防该部位的感染？沙宾疫苗毒株 CD155Tg x IFNAR*‘*小鼠的神经毒性？减少这些菌株在中枢神经系统中的复制 系统导致增强的ISG反应，从而限制病毒复制？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接触时触发。在这方面的实验 特定目的是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RIG-I裂解的生物学作用 并测定丙二醛-5的含量。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 控制其他医学上相关的病毒。

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.