NLR control of antiviral defense in the respiratory mucosa

描述（由申请人提供）：甲型流感是一种主要的人类病原体，每年导致全球500多万人患上严重疾病，被列为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起着重要作用。已知流感病毒感染由两种天然传感器识别，Toll样受体7 （TLR7）和细胞质RNA传感器rig - 1。然而，nod样受体（NLR）的作用是识别流感病毒，炎症小体的激活在流感免疫反应中的后果尚不清楚。在初步研究部分，我们提供了明确的证据，表明炎症小体在呼吸道流感感染期间在体内被激活。更重要的是，我们证明了炎症小体诱导的il -1 β提供了一个关键信号，可以招募各种类型的细胞到肺粘膜，并启动CD4、CD8 T细胞和抗体反应。缺乏炎性小体的小鼠更容易受到病毒复制和死亡的影响。在这个应用中，我们建立在这些观察的基础上，提出通过两个特定的目的来阐明炎症小体介导流感病毒呼吸道感染的适应性免疫反应的机制。在第一个目标中，我们建议检查树突状细胞NLR刺激在其抗原呈递能力中的重要性，以刺激肺部流感感染的na - CD4和CD8 T细胞。在第二个目标中，我们将研究B细胞对NLR炎性小体产生流感抗体反应的内在需求。具体来说，我们将分别研究通过炎症小体激活B细胞在上呼吸道和下呼吸道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。

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.