NLR control of antiviral defense in the respiratory mucosa

描述(申请人提供)：甲型流感是一种主要的人类病原体，每年在全球超过500万人中导致严重疾病，并被归类为NIAID C类优先病原体。先天免疫在快速清除病毒和产生长期保护性免疫方面都发挥着重要作用。已知流感病毒感染由两个先天感受器识别，即Toll样受体7(TLR7)和胞质RNA感应器RIG-I。然而，NOD样受体(NLR)的作用是识别流感病毒，而炎症小体激活在流感免疫反应中的结果尚不清楚。在初步研究部分，我们提供了明确的证据，证明在呼吸道流感感染期间，体内的炎性小体被激活。更重要的是，我们证明了炎症小体诱导的IL-1β提供了一个关键信号，可以将各种类型的细胞招募到肺粘膜，并启动CD4、CD8 T细胞和抗体反应。缺乏炎症体的老鼠更容易受到病毒复制和死亡的影响。在这个应用中，我们在这些观察的基础上，提出通过两个特定的目的来阐明炎性小体通过两个特定的目的来介导呼吸道感染流感病毒的获得性免疫反应的机制。在第一个目的中，我们建议检测刺激树突状细胞中的NLR在其抗原提呈能力中的重要性，以刺激原始的CD4和CD8T细胞对肺部的流感感染。在第二个目标中，我们将研究B细胞在产生流感抗体反应中对NLR炎性小体的内在要求。具体地说，我们将研究通过炎性小体激活B细胞在上呼吸道和下呼吸道的IgA和IgG反应中的重要性。对先天传感器如何协调产生保护性免疫结果的基本了解，将有助于为设计针对流感相关疾病的免疫干预和预防措施奠定重要基础。 相关性：流感病毒是一种主要的公共卫生风险，基因工程的最新进展引起了人们对使用流感作为生物威胁的担忧。这项R21建议的目标是了解通过NOD样受体对流感病毒的天然识别如何使关键免疫细胞类型、树突状细胞和B细胞能够在肺内协调适应性免疫反应和抗病毒保护。

DESCRIPTION (provided by applicant): Influenza A is a major human pathogen that causes severe illnesses in over 5 million people worldwide annually, and is classified as a NIAID Category C Priority Pathogen. Innate immunity plays an important role in both rapid clearance of virus as well as in generating long-term protective immunity. Influenza virus infection is known to be recognized by two innate sensors, the Toll like receptor 7 (TLR7) and cytosolic RNA sensor RIG-I. However, the role of NOD-like receptor (NLR) is recognition of influenza virus, and the consequence of activation of inflammasomes in immune responses to influenza is unknown. In the Preliminary Studies section, we provide clear evidence that inflammasomes are activated in vivo during respiratory influenza infection. More importantly, we demonstrate that inflammasome-induced IL-1beta provides a key signal to recruit variety of cell types to the lung mucosa, and to initiate CD4, CD8 T cell and antibody responses. Mice deficient in inflammasomes are rendered more susceptible to viral replication and death. In this application, we build on these observations to propose to elucidate the mechanisms by which inflammasomes mediate adaptive immune responses to respiratory infection with influenza virus through two specific Aims. In the first Aim, we propose to examine the importance of NLR stimulation in dendritic cells in their antigen presenting capacity to stimulate na¿ve CD4 and CD8 T cells to flu infection in the lung. In the second Aim, we will examine the B cell-intrinsic requirement for NLR inflammasomes in the generation of antibody responses to influenza. Specifically, we will examine the importance of B cell activation through inflammasomes in IgA and IgG responses in the upper and lower respiratory tracts, respectively. Basic understanding of how the innate sensors orchestrate the generation of protective immune outcomes will help establish important foundation with which to design immunological interventions and preventative measures against flu-associated diseases. RELEVANCE: Influenza virus is a major public health risk, and recent advances in genetic engineering have raised concerns about the use of influenza as a biological threat. The goal of this R21 proposal is to understand how innate recognition of influenza virus through the NOD-like receptors enables key immune cell-types, dendritic cells and B cells, to orchestrate adaptive immune responses and antiviral protection in the lung.