Alveolar macrophage and mycobacteria

描述（由申请人提供）：HIV感染受试者中发生的严重免疫抑制通常与分枝杆菌感染并发症有关。结核分枝杆菌是一种世界性的病原体，是正常和免疫抑制受试者发病和死亡的主要原因。非结核分枝杆菌如M.禽流感可以是机会性感染，其感染免疫抑制的个体或具有潜在疾病如肺矽肺病的受试者。无论分枝杆菌是作为病原体还是机会性感染生物体，肺中的分枝杆菌首先感染肺泡巨噬细胞（AM），肺泡腔的常驻炎性细胞。AM必须由细胞因子如IFN-γ或TNF-α引发和激活，以最大限度地响应感染性生物体如分枝杆菌。虽然它是公认的，AM是核心的分枝杆菌疾病的发病机制，有很少的研究，已经检查了AM在体内的作用，在应对分枝杆菌感染。我们已经开发了一种新的方法来“重建”正常和激活的AM到免疫缺陷动物的肺。我们将使用这种新的方法来测试假设防御在AM的响应分枝杆菌，如MAC或M。结核病允许最初的肺部感染和随后在免疫抑制期间的传播;相反，纠正这些AM缺陷将恢复肺泡免疫，控制肺部感染并防止传播。我们将研究AM在体内对分枝杆菌感染的反应的潜在机制，然后使用各种策略激活AM进行重建，以观察肺泡宿主防御是否恢复和感染是否根除。这也将测试是否AM激活的促炎细胞因子，如IFN-γ介导肺泡宿主防御分枝杆菌由AM衍生的TNF-α。这些具体目标包括：1）确定重建到免疫缺陷小鼠肺中的正常AM恢复肺泡宿主防御分枝杆菌并防止传播的机制，2）确定促炎细胞因子如IFN-γ是否对于肺泡宿主防御分枝杆菌和防止传播是必需的，3）确定对重建的巨噬细胞的离体基因治疗是否导致促炎细胞因子如IFN-γ的持续过表达，γ在体内，提高肺泡宿主防御分枝杆菌和防止传播，和4），以确定是否促炎细胞因子，如IFN-？肺泡宿主对分枝杆菌的防御由AM衍生的TNF-α介导。该提案将在体内测试通过其他手段不可能的假设，并将确定是否重建正常或激活的AM是足以恢复肺泡宿主防御分枝杆菌疾病，尽管存在持续的全身免疫抑制。

DESCRIPTION (provided by applicant): Profound immunosuppression as occurs in HIV-infected subjects is frequently associated with complicating mycobacterial infections. Mycobacterium tuberculosis is a worldwide pathogen and is a major cause of morbidity and mortality in both normal and immunosuppressed subjects. Non-tuberculous mycobacteria such as M. avium can be opportunistic infections that infect immunosuppressed individuals or subjects with underlying disorders such as pulmonary silicosis. Regardless of whether mycobacteria are acting as pathogens or opportunistic infectious organisms, mycobacteria in the lung first infect alveolar macrophages (AMs), the resident inflammatory cell of the alveolar spaces. AMs must be primed and activated by cytokines such as IFN-gamma or TNF-alpha to maximally respond to infectious organisms such as mycobacteria. Although it is recognized that AMs are central to the pathogenesis of mycobacterial disease, there are few studies that have examined the role of AMs in vivo in response to mycobacterial infection. We have developed a novel approach to "reconstitute" normal and activated AMs into the lungs of immunodeficient animals. We will use this new approach to test the hypothesis Deficiencies in the response of AMs to mycobacteria such as MAC or M. tuberculosis permit initial lung infection and subsequent dissemination during immunosuppression; conversely, correction of these AM deficiencies will restore alveolar immunity, control lung infection and prevent dissemination. We will examine the underlying mechanisms by which AMs respond in vivo to mycobacterial infection and will then use a variety of strategies to activate AMs for reconstitution to see if alveolar host defense is restored and infection eradicated. This will also test whether AMs activated by pro-inflammatory cytokines such as IFN-gamma mediate alveolar host defense to mycobacteria by AM-derived TNF-alpha. These Specific Aims include: 1) to determine the mechanisms by which normal AMs reconstituted into the lungs of immunodeficient mice restore alveolar host defense to mycobacteria and prevent dissemination, 2) to determine if proinflammatory cytokines such as IFN-gamma are essential for alveolar host defense to mycobacteria and to prevent dissemination, 3) to determine if ex vivo gene therapy to reconstituted macrophages results in persistent overexpression of pro-inflammatory cytokines such as IFN-gamma in vivo and improves alveolar host defenses to mycobacteria and prevents dissemination, and 4) to determine if the effects of pro-inflammatory cytokines such as IFN-? on alveolar host defenses to mycobacteria are mediated by AM-derived TNF-alpha. This proposal will test hypotheses in vivo not possible by other means and will determine whether reconstitution of normal or activated AMs is sufficient to restore alveolar host defense to mycobacterial disease despite the presence of ongoing systemic immunosuppression.