Role of plasmacytoid dendritic cells in human metapneumo virus infection

描述（由申请人提供）：人偏肺病毒（hMPV）是副粘病毒科新发现的成员，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。hMPV疫苗的研制进展缓慢，目前尚无专门的治疗方法。hMPV介导的肺部病理和临床疾病的机制尚不完全清楚，但实验证据表明，T细胞，特别是CD4+细胞室，在hMPV感染的免疫发病机制中起着核心作用。基于我们小组的初步数据，我们将验证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诱导的肺部炎症中发挥主要作用的假设。来自R03拨款的资金将用于生成关键数据，以支持pDC通过诱导调节性T细胞和IL-12p40的产生来调节hMPV感染中的肺部炎症的假设。我们在这项拨款中提出的工作包括在一个建立良好的hMPV感染实验小鼠模型中进行研究。完成所提出的目标将为我将通过NIH R01申请进行的额外机制研究奠定基础，其总体目标将集中在定义pDC调节hMPV感染肺部发病机制的细胞和分子机制。了解hMPV诱导的肺部炎症的调节机制对于开发新的治疗策略或新型hMPV感染疫苗具有重要的临床意义。

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.