Alveolar macrophage and mycobacteria

描述（由申请人提供）：在hiv感染者中发生的深度免疫抑制通常与并发分枝杆菌感染有关。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。非结核分枝杆菌如鸟分枝杆菌可能是机会性感染，感染免疫抑制的个体或有肺矽肺病等潜在疾病的受试者。无论分枝杆菌是作为病原体还是作为机会性感染生物，肺中的分枝杆菌首先感染肺泡巨噬细胞（AMs），即肺泡间隙的常驻炎症细胞。AMs必须由ifn - γ或tnf - α等细胞因子引发和激活，才能最大限度地对分枝杆菌等感染性生物作出反应。虽然人们认识到AMs是分枝杆菌疾病发病机制的核心，但很少有研究检测AMs在体内对分枝杆菌感染的反应中的作用。我们已经开发了一种新的方法来“重建”正常和激活的AMs进入免疫缺陷动物的肺部。我们将使用这种新方法来验证以下假设：AMs对分枝杆菌（如MAC或结核分枝杆菌）的反应缺陷允许在免疫抑制期间初始肺部感染和随后的传播；相反，纠正这些AM缺陷将恢复肺泡免疫力，控制肺部感染并防止传播。我们将研究AMs在体内对分枝杆菌感染作出反应的潜在机制，然后使用各种策略激活AMs进行重建，以观察肺泡宿主防御是否恢复并根除感染。这也将测试由促炎细胞因子如ifn - γ激活的AMs是否通过am衍生的tnf - α介导肺泡宿主对分枝杆菌的防御。这些具体目标包括：1)确定在免疫缺陷小鼠肺中重组的正常AMs恢复肺泡宿主对分枝杆菌的防御并阻止其传播的机制；2)确定ifn - γ等促炎细胞因子是否对肺泡宿主对分枝杆菌的防御和阻止其传播至关重要。3)确定体外基因治疗重组巨噬细胞是否导致促炎细胞因子如IFN- γ在体内持续过表达，提高肺泡宿主对分枝杆菌的防御能力并阻止传播；4)确定促炎细胞因子如IFN-？am衍生的tnf - α介导了肺泡宿主对分枝杆菌的防御。本研究将在体内验证其他方法无法实现的假设，并确定在存在持续的全身免疫抑制的情况下，重建正常或活化的am是否足以恢复肺泡宿主对分枝杆菌疾病的防御。

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.