Macrophage effector functions during respiratory fungal infection

呼吸道真菌感染期间巨噬细胞效应功能

• 批准号: 8463611
• 负责人: Terry W Wright
• 金额: $ 36.77万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463611
• 关键词: Address; Adopted; Affect; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Basic Science; Biology; CD4 Positive T Lymphocytes; Data; Disease; Effector Cell; Equilibrium; Exhibits; Failure; Goals; Health; Helper-Inducer T-Lymphocyte; Host Defense; Image; Immune; Immune response; Immunity; Inbred Strains Mice; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intervention; Knock-out; Knockout Mice; Lead; Lung; Macrophage Activation; Mediating; Mediator of activation protein; Methods; Mission; Monoclonal Antibodies; Mouse Strains; Mus; Mycoses; Natural Immunity; Outcome; Pathway interactions; Patient Care; Patients; Phagocytosis; Phase; Phenotype; Pneumocystis; Pneumocystis Infections; Pneumocystis carinii Pneumonia; Process; Reagent; Relative (related person); Research; Research Design; Resistance; Resolution; Role; Signal Transduction; Sulfasalazine; T-Lymphocyte; Technology; Therapeutic; Time; Tissues; Translating; United States National Institutes of Health; adaptive immunity; alternative treatment; base; cytokine; design; improved; in vivo; innovation; killings; lung injury; macrophage; mortality; mouse model; new therapeutic target; novel; novel therapeutics; pathogen; programs; repaired; respiratory; response; tool; translational study; treatment strategy

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.

描述（由申请人提供）：尽管患者护理方面的一般进步，但肺炎囊肿（PCP）相关的死亡率仍然不可接受。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助手（TH）介导的免疫反应也有助于PCP相关的免疫发病。 TH细胞介导这些过程的精确下游效应器机制是不确定的，从而损害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受到TH细胞的调节。 TH1信号诱导经典的巨噬细胞激活表型（CAM），而Th2信号产生了替代激活表型（AAM）。但是，尚未确定这些独特的巨噬细胞激活程序对托管防御和/或免疫发病发生的相对贡献。我们的初步研究表明，可以响应PCP来控制巨噬细胞表型。例如，用PCP给小鼠施用抗炎剂磺胺嘧啶会导致巨噬细胞具有AAM表型，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，转移对TH2/AAM途径的反应会导致PCP相关的免疫病变，同时增强了巨噬细胞介导的PC清除率。该应用的具体目标是确定肺泡巨噬细胞（AM）表型和效应子功能的调节如何影响PCP相关的免疫发病和宿主防御。该提议的总体假设是AMS是宿主防御和与PCP相关的免疫发病发生的关键效应因子，而巨噬细胞极化的定向调节代表了一种改善PCP结果的新型治疗策略。我们将使用药理，免疫和敲除技术的组合来确定差异极化如何控制PCP的发作，炎症和分辨率/修复阶段，并定义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性和适应性免疫的机制，以促进治疗策略的合理设计，以增强宿主防御，同时限制免疫病毒。为了实现这一目标，我们提出的是：1）确定差异巨噬细胞激活如何调节对PC的免疫反应； 2）确定CD4+ T细胞独立于PC的机制； 3）评估调节AM表型是否是治疗PCP的有效策略。该提议具有创新性，因为它专注于AMS，作为介导免疫发育和宿主防御的效应子。拟议的研究很重要，因为它将增强我们对PCP相关的免疫发育的理解，并有可能导致新型的治疗策略，以改善患者护理。