Airway Inflammation

这个项目的总体目标是确定参与激活先天免疫对空气传播感染的分子途径 与革兰氏阴性细菌，是潜在的生物武器，包括鼠疫（耶尔森氏鼠疫菌），兔热病， （土拉热弗朗西斯菌）和类鼻疽（多氏伯克霍尔德氏菌）。我们将使用气溶胶挑战模型在转基因 研究Toll样受体（TLR）和细胞群在介导肝脏炎症和免疫反应中的作用。 细菌和选择的细菌配体。中心假设是TLR介导的信号传导对于先天性免疫缺陷的激活是必不可少的。 免疫Y。鼠疫菌和其他革兰氏阴性菌。具体目标是： 具体目标1。确定MyD 88在介导对雾化Y的先天免疫中的作用。pestis，F.土拉热菌（tularensis）和B. 假鼻疽这一目标将检验MyDgS缺陷动物将无法激活常驻和招募防御的假设， 与野生型对照相比，导致肺中细菌复制加速和感染早期传播。 还将测试半胱天冬酶1缺陷动物以评估IL-1和IL-18介导的活化途径的作用，所述活化途径被信号转导。 通过MyD 88独立于TLR。 具体目标2。确定TLR 4和TLR 2在介导对雾化Y的先天免疫中的作用。鼠疫的第一部分 这一目的将检验Y.鼠疫菌LPS是由TLR 4介导的，TLR 4在激活宿主LPS中起作用， 对活鼠疫菌的抗性;在37 ℃下生长的鼠疫杆菌在体内很难被人MD 2/TLR 4识别; 人TLR 4/MD 2对LPS的识别缺陷导致对气溶胶化鼠疫杆菌的先天免疫应答减弱。第二 本研究的目的之一是验证Y.鼠疫菌诱导TLR-2- 抑制先天性免疫并允许加速细菌复制和传播的体内IL-10依赖性应答。 具体目标3。确定骨髓源性细胞和呼吸道上皮细胞在先天性 免疫应答鼠疫该目的将使用MyD 88缺陷型和野生型小鼠的骨髓嵌合体和转基因小鼠。 在表面活性蛋白C启动子下表达显性阴性IkB的小鼠，以检验骨髓来源的 实质细胞参与了先天性抗Y细胞的激活。肺里的鼠疫

The overall goal of this project is to define molecular pathways involved in the activation of innate immunity to airborne infection with gram negative bacteria that are potential biological weapons, including the agents of plague (Yersinia pestis), tularemia (Francisella tularensis) and melioidosis (Burkholderiapseudomallei). We will use aerosol challenge models in genetically modified mice to explore the roles of Toll-like receptors (TLRs) and cell populations in mediating inflammatory and immune responses to live bacteria and selected bacterial ligands. The central hypothesis is that TLR-mediated signaling is essential for the activation of innate immunity to Y. pestis and other Gram negative bacteria in the lungs. The specific aims are: Specific Aim 1. Determine the role of MyD88 in mediating innate immunity to aerosolized Y. pestis, F. tularensis, and B. pseudomallei. This aim will test the hypothesis that MyDgS-deficient animals will fail to activate resident and recruited defenses, leading to accelerated bacterial replication in the lungs and early dissemination of infection in comparison with wild-type controls. Caspase 1 deficient animals also will be tested to evaluate the role of IL-1- and IL-18-mediated activation pathways that are signaled via MyD88 independently of TLRs. Specific Aim 2. Determine the role of TLR4 and TLR2 in mediating innate immunity to aerosolizcd Y. pestis. The first part of this aim will test the hypotheses that recognition of Y. pestis LPS is mediated by TLR4; that TLR4 has a role in activating host resistance to live Y pestis; that the LPS of Y. pestis grown at 37¿C is poorly recognized by human MD2/TLR4 in vivo; and that defective LPS recognition by human TLR4/MD2 contributes to blunted innate immune responses to aerosolized E pestis. The second part of this aim will test the hypotheses that the low calcium response virulence antigen (LcrV) of Y. pestis induces a TLR-2- dependent IL-10 response in vivo that suppresses innate immunity and permits accelerated bacterial replication and dissemination. Specific Aim 3. Determine the role of bone marrow-derived cells and respiratory epithelial cells in the activation of innate immune responses to Y. pestis. This aim will use bone marrow chimeras of MyD88-deficient and wild type mice and transgenic mice expressing a dominant negative IkB under the surfactant protein C promoter to test the hypothesis that both marrow-derived and parenchymal cells are involved in the activation of innate resistance to Y. pestis in the lungs.