Role of plasmacytoid dendritic cells in human metapneumo virus infection

描述（由申请方提供）：人偏肺病毒（hMPV）是副粘病毒科的一种新成员，可引起幼儿、老年人和免疫功能低下患者的严重下呼吸道感染。针对hMPV的疫苗的开发进展缓慢，目前尚无特异性治疗方法。hMPV介导的肺部病理和临床疾病的机制尚未完全了解，但实验证据表明，T细胞，特别是CD 4+隔室，在hMPV感染的免疫发病机制中发挥核心作用。基于我们小组的初步数据，我们将检验肺浆细胞样树突状细胞（pDC），介导抗病毒反应的关键免疫细胞，在控制hMPV诱导的肺部炎症中起主要作用的假设。来自R 03的资金将用于生成支持以下假设的关键数据：pDC通过诱导调节性T细胞和IL-12 p40产生来调节hMPV感染中的肺部炎症。我们在这项资助中提出的工作包括在一个完善的hMPV感染实验小鼠模型中进行研究。所提出的目标的实现将为我将通过NIH R 01申请进行的其他机制研究奠定基础，其中总体目标将集中于定义pDC调节hMPV感染中肺发病机制的细胞和分子机制。了解调节hMPV诱导的肺部炎症的机制对于开发hMPV感染的新治疗策略或新疫苗在临床上是重要的。 公共卫生相关性：人偏肺病毒（Human metapneumovirus，hMPV）是副粘病毒科新发现的一种病毒，是婴幼儿下呼吸道感染的主要病原体之一。我们已经表明，浆细胞样树突状细胞（pDC）调节肺部炎症的小鼠模型中的hMPV感染。在这项试点资助提案中，我们将研究肺pDC控制hMPV感染期间炎症反应的机制，长期目标是开发新的策略，以增强抗病毒免疫力和对hMPV和其他呼吸道病毒病原体的持久保护，这些病原体会导致显著的气道发病率。

DESCRIPTION (provided by applicant): Human metapneumovirus (hMPV), a newly-recognized member of the Paramyxoviridae family, causes serious lower respiratory tract infections in young children, the elderly and immunocompromised patients. Development of a vaccine against hMPV has progressed slowly and no specific therapy is currently available. The mechanisms of hMPV-mediated lung pathology and clinical disease are not fully understood, but experimental evidence suggests that T cells, particularly the CD4+ compartment, play a central role in the immunopathogenesis of hMPV infections. Based on preliminary data from our group, we will test the hypothesis that lung plasmacytoid dendritic cells (pDC), critical immune cells in mediating antiviral response, play a major role in controlling hMPV-induced lung inflammation. Funding from this R03 grant will be used to generate critical data in support of the hypotheses that pDC regulate pulmonary inflammation in hMPV infection by the induction of regulatory T cells and IL-12p40 production. The work that we propose in this grant includes investigations in a well established experimental mouse model of hMPV infection. Accomplishment of the proposed aims will generate the base for additional mechanistic studies that I will pursue through an NIH R01 application where overall objective will be focused on defining the cellular and molecular mechanisms by which pDC regulate lung pathogenesis in hMPV infection. Understanding the mechanisms that regulate hMPV- induced inflammation in the lung is important clinically for the development of new treatment strategies or novel vaccines for hMPV infection. PUBLIC HEALTH RELEVANCE: Human metapneumovirus (hMPV), a newly-recognized member of the Paramyxoviridae family, is one of the major etiologic agents of lower respiratory tract infections in infants and young children. We have shown that plasmacytoid dendritic cells (pDC) regulate pulmonary inflammation in a mouse model of hMPV infection. In this pilot grant proposal we will investigate the mechanisms by which lung pDC control inflammatory responses during hMPV infection with the long long-term goal of developing new strategies to boost antiviral immunity and long-lasting protection against hMPV and other respiratory viral pathogens that cause significant airway morbidity.