Macrophage effector functions during respiratory fungal infection

描述（由申请人提供）：尽管患者护理取得了普遍进展，但肺孢子虫肺炎（PcP）相关死亡率仍然高得令人无法接受。因此，我们需要更好地了解宿主-病原体相互作用的生物学，以确定PcP的替代治疗策略。T细胞来源的信号对于宿主防御PcP至关重要。然而，宿主的T辅助细胞（TH）介导的免疫应答也有助于PcP相关的免疫发病机制。TH细胞介导这些过程的精确下游效应机制尚不明确，这削弱了我们设计最佳治疗策略的能力。巨噬细胞表型和效应子功能由TH细胞调节。TH 1信号诱导经典的巨噬细胞活化表型（CAM），而TH 2信号产生替代活化表型（AAM）。然而，这些不同的巨噬细胞活化程序对宿主防御和/或免疫发病机制的相对贡献尚未确定。我们的初步研究表明，它是可能的控制巨噬细胞表型响应PcP。例如，向患有PcP的小鼠施用抗炎剂柳氮磺胺吡啶导致具有AAM表型的巨噬细胞，而不是在媒介物处理的对照小鼠中看到的CAM表型。重要的是，转移到TH 2/AAM途径的反应导致减弱PcP相关的免疫发病机制，同时增强巨噬细胞介导的Pc清除。本申请的具体目的是确定肺泡巨噬细胞（AM）表型和效应器功能的调节如何影响PcP相关的免疫发病机制和宿主防御。该建议的总体假设是AM是宿主防御和PcP相关免疫发病机制的关键效应子，并且巨噬细胞极化的定向调节代表了改善PcP结果的新治疗策略。我们将使用药理学，免疫学和基因敲除技术的组合，以确定如何差分AM极化控制PcP的发病，炎症和分辨率/修复阶段，并定义巨噬细胞的作用机制。我们的长期目标是了解肺中调节先天性和适应性免疫的机制，以促进合理设计治疗策略，从而在限制免疫发病机制的同时增强宿主防御。为了实现这一目标，我们提出了具体目标，将：1）确定差异巨噬细胞活化如何调节对Pc的免疫应答; 2）确定CD 4 + T细胞对Pc的非依赖性抗性的机制; 3）评估调节AM表型是否是治疗PcP的有效策略。这一建议是创新的，因为它侧重于AM作为介导免疫发病机制和宿主防御的效应器。这项研究意义重大，因为它将增强我们对PcP相关免疫发病机制的理解，并有可能导致新的治疗策略，可以转化为改善患者护理。

DESCRIPTION (provided by applicant): Despite general advances in patient care, Pneumocystis pneumonia (PcP)-related mortality remains unacceptably high. Therefore, we need better understanding of the biology of the host-pathogen interaction to identify alternative treatment strategies for PcP. T cell-derived signals are critical for host defense against PcP. However, the host's T helper (TH)-mediated immune response also contributes to PcP-related immunopathogenesis. The precise downstream effector mechanisms by which TH cells mediate these processes are undefined, impairing our ability to design optimal therapeutic strategies. Macrophage phenotype and effector functions are regulated by TH cells. TH1 signals induce a classical macrophage activation phenotype (CAM), while TH2 signals produce an alternative activation phenotype (AAM). However, the relative contributions of these distinct macrophage activation programs to host defense and/or immunopathogenesis have not been determined. Our Preliminary Studies demonstrate that it is possible to control macrophage phenotype in response to PcP. For example, administering the anti-inflammatory agent sulfasalazine to mice with PcP resulted in macrophages with an AAM phenotype rather than the CAM phenotype seen in vehicle- treated control mice. Importantly, shifting the response to the TH2/AAM pathway resulted in attenuated PcP- related immunopathogenesis while at the same time enhancing macrophage-mediated Pc clearance. The specific objective of this application is to determine how modulation of alveolar macrophage (AM) phenotype and effector function influences both PcP-related immunopathogenesis and host defense. The overarching hypothesis of this proposal is that AMs are key effectors of both host defense and PcP-related immunopathogenesis, and that directed modulation of macrophage polarization represents a novel therapeutic strategy to improve the outcome of PcP. We will use a combination of pharmacological, immunological, and knockout technologies to determine how differential AM polarization controls the onset, inflammatory, and resolution/repair phases of PcP, and to define the mechanisms of macrophage action. Our long-term goal is to understand the mechanisms regulating innate and adaptive immunity in the lung to facilitate the rational design of therapeuti strategies to enhance host defense while limiting immunopathogenesis. To accomplish this goal we propose Specific Aims that will: 1) determine how differential macrophage activation regulates the immune response to Pc; 2) identify mechanisms of CD4+ T cell independent resistance to Pc; and 3) evaluate whether modulating AM phenotype is an effective strategy for the treatment of PcP. This proposal is innovative because it focuses on AMs as effectors mediating both immunopathogenesis and host defense. The proposed research is significant because it will enhance our understanding of PcP-related immunopathogenesis, and has the potential to lead to novel therapeutic strategies that can be translated to improve patient care.