Immunopathogenesis of Pulmonary Tularemia and Plague

图拉氏方济氏菌(Francisella Tularensis)具有许多特性，被归类为A类病原菌和潜在的生物武器。它很容易生长，作为一种气雾剂，它在暴露人群中的感染率很高。兔热病疫苗的历史是值得注意的，因为活疫苗株(LVS)在非人类灵长类动物和人类中显示出保护作用，但FDA的批准是有问题的，因为它的衰减的基础和稳定性尚未确定。识别由图拉氏丝虫基因组编码的诱导保护的候选疫苗可能导致亚单位疫苗。我们已经建立了一种原发肺部感染生物群A毒力土拉氏丝虫的小鼠模型，在这种模型中，LVS诱导了对毒力土拉氏丝虫呼吸道攻击的保护性反应。我们打算在小鼠和灵长类动物身上研究图拉氏丝虫获得性反应过程中肺部与病原体的相互作用。我们已经与疫苗候选发现公司MacroGenics和Lovelace呼吸研究所(LRRI)建立了合作伙伴关系。使用表达文库免疫，我们将识别由毒力图拉氏丝虫基因组编码的保护性表位，这将导致疫苗。最后，候选疫苗将在雾化图拉氏丝虫的非人类灵长类模型中进行测试。目的1.确定肺内特异性免疫细胞和炎症介质在图拉尔生物群获得性肺免疫反应中的作用。目的2.利用表达文库免疫技术寻找新的图拉氏肺吸虫亚单位疫苗候选 目的3.在非人类灵长类动物模型中确定肺炎图拉热症的临床表型和宿主反应的特征，为在该模型中对候选疫苗进行有效的测试提供关键的背景数据。

Francisella tularensis (F. tularensis) has many characteristics that warrant its classification as a category A pathogen and potential bioweapon. It is easy to grow and as an aerosol, it has a high rate of infection in exposed populations. The tularemia vaccine history is remarkable in that the Live Vaccine Strain (LVS) demonstrated protection in nonhuman primates and humans but FDA approval was problematic because the basis and stability of its attenuation has not been identified. Identification of vaccine candidates encoded by the F. tularensis genome that induce protection could lead to a subunit vaccine. We have developed a murine model for primary pulmonary infection with Biovar A virulent F. tularensis for which LVS induces a protective response against a respiratory challenge with virulent F. tularensis. We intend to study the lung-pathogen interaction during the acquired responses for F. tularensis in mice and primates. We have partnered with MacroGenics, a vaccine candidate discovery company, and Lovelace Respiratory Research Institute (LRRI). Using expression library immunization, we will identify protective epitopes encoded by the virulent F. tularensis genome that will lead to a vaccine. Finally, the vaccine candidates will be tested in a nonhuman primate model of aerosolized F. tularensis. Aim 1. Determine the role for specific immune cells and inflammatory mediators in the lung during the acquired pulmonary immune response to Biovar A F. tularensis. Aim 2. Identify new subunit vaccine candidates against F. tularensis using expression library immunization Aim 3. Determine the clinical phenotype and characterize the host response to pneumonic tularemia in the non-human primate model, providing critical background data to permit efficient testing of vaccine candidates in the model.