Macrophage effector functions during respiratory fungal infection

描述（由申请人提供）：尽管患者护理普遍进步，肺囊虫肺炎（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细胞来源的信号对宿主防御PcP至关重要。然而，宿主辅助性T细胞（TH）介导的免疫应答也参与了pcp相关的免疫发病机制。TH细胞介导这些过程的确切下游效应机制尚不清楚，这削弱了我们设计最佳治疗策略的能力。巨噬细胞的表型和效应功能受TH细胞的调控。TH1信号诱导巨噬细胞经典活化表型（CAM），而TH2信号产生替代活化表型（AAM）。然而，这些不同的巨噬细胞激活程序对宿主防御和/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，对PcP的反应可以控制巨噬细胞的表型。例如，对PcP小鼠给予抗炎剂磺胺氮唑导致巨噬细胞具有AAM表型，而不是对照小鼠中所见的CAM表型。重要的是，改变对TH2/AAM途径的反应导致PcP相关免疫发病机制减弱，同时增强巨噬细胞介导的Pc清除。本应用程序的具体目的是确定肺泡巨噬细胞（AM）表型和效应功能的调节如何影响cpp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物，定向调节巨噬细胞极化代表了改善PcP结果的一种新的治疗策略。我们将联合使用药理学、免疫学和基因敲除技术来确定AM极化差异如何控制PcP的发病、炎症和消退/修复阶段，并确定巨噬细胞作用的机制。我们的长期目标是了解调节肺部先天免疫和适应性免疫的机制，以促进合理设计治疗策略，增强宿主防御，同时限制免疫发病机制。为了实现这一目标，我们提出了具体的目标，将：1)确定巨噬细胞活化如何调节对Pc的免疫反应；2)明确CD4+ T细胞对Pc的非依赖性耐药机制；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AMs作为介导免疫发病机制和宿主防御的效应物。这项研究具有重要意义，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.