Receptor tyrosine kinase signaling and influenza viral RNA synthesis

描述(申请人提供)：流感病毒感染肺部导致一种传染性急性呼吸道疾病，可能导致严重的并发症，如肺炎。尽管有积极的疫苗计划，流感病毒仍然是一种主要的全球人类病原体，导致每年的流行病和偶尔的大流行，具有发病率和死亡率。在流感病毒分离株中已经发现对所有可用的抗流感药物的耐药性，这突显了开发新的抗流感疗法的必要性和紧迫性。参与流感生命周期的宿主信号通路和宿主因子是潜在的抗病毒靶点，但对其在病毒复制中的功能和机制缺乏了解是开发适当干预措施的主要障碍。我们有初步的数据表明，宿主神经生长因子受体TrkA信号在流感病毒复制中的病毒RNA合成阶段发挥着重要作用。TrkA是神经营养素受体酪氨酸激酶的成员，也包括TrkB和TrkC。已有研究表明，神经营养因子和Trk受体在包括人肺在内的许多非神经性组织中都有表达，但它们在肺组织中的病理生理作用尚不清楚，其在呼吸道病毒病原体复制中的潜在功能也从未被研究过。我们假设宿主TrkA信号被流感病毒感染激活，在正反馈环中，通过增强病毒RNA合成促进流感病毒复制。我们建议通过确定TrkA、B和C在流感病毒复制和RNA合成中的特定作用(目标1)以及TrkA信号参与流感病毒RNA合成的机制(目标2)来验证这一新假说。这项探索性研究将评估宿主TrkA信号在流感病毒感染中的重要性的全新概念，为后续全面研究宿主信号在流感病毒RNA合成中的机制特征提供概念和事实基础，并可能导致开发新的抗病毒疗法来治疗这种传染性肺部疾病。从更广泛的意义上讲，它将为肺部Trk信号如何影响呼吸道病原体复制的未知领域带来重要见解，这可能导致针对一类传染性呼吸道疾病的新的广谱治疗措施。

DESCRIPTION (provided by applicant): Influenza virus infection of the lungs causes a contagious acute respiratory disease that may result in severe complications such as pneumonia. Despite the active vaccine program, influenza virus remains a major global human pathogen causing annual epidemic and occasional pandemics with morbidity and mortality. Resistance to all available anti-flu drugs has been identified in influenza virus isolates, highlighting the need and urgency to develop novel anti-flu therapeutics. Host signaling pathways and host factors that are involved in the flu life cycle represent potential anti-viral targets, but the poor understanding of their functions and mechanisms in viral replication is a major barrier for the development of appropriate interventions. We have preliminary data to suggest that host nerve growth factor (NGF) receptor TrkA signaling plays important roles in the influenza viral replication at the step of viral RNA synthesis. TrkA is a member of neurotrophin receptor tyrosine kinases that also include TrkB and TrkC. It has been shown that neurotrophins and Trk receptors are expressed in many non-neuronal tissues including human lungs, but their pathophysiological roles in lungs remain largely unknown and their potential functions in the replication of respiratory viral pathogens have never been investigated. We hypothesize that host TrkA signaling is activated by influenza viral infection and, in a positive feedback loop, facilitates influenza viral replication by enhancing viral RNA synthesis. We propose to validate this novel hypothesis by determining the specific role of TrkA, B, and C in flu viral replication and RNA synthesis (Aim 1) and the mechanism of TrkA signaling involved in flu viral RNA synthesis (Aim 2). This exploratory study will evaluate a complete novel concept on the importance of host TrkA signaling in the influenza virus infection, provide the conceptual and factual basis for a subsequent full scale research effort on the mechanistic characterization of host signaling in the flu viral RNA synthesis, and potentially lead to the development of novel anti-viral therapeutics to treat this infectious lung disease. In a broader sense, it will shed important insights into an unknown area of how the Trk signaling in the lungs affect the replication of respiratory pathogens that may lead to novel broad-spectrum therapeutic measures against a class of infectious respiratory diseases.