Macrophage effector functions during respiratory fungal infection

呼吸道真菌感染期间巨噬细胞效应功能

基本信息

批准号：
8837679
负责人：
Terry W Wright
金额：
$ 38.05万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8837679
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

项目摘要

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）：尽管患者护理取得了普遍进步，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与病原体相互作用的生物学，以确定 PcP 的替代治疗策略。 T 细胞衍生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) 介导的免疫反应也有助于 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清楚，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功能受 TH 细胞调节。 TH1 信号诱导经典的巨噬细胞激活表型 (CAM)，而 TH2 信号产生另一种激活表型 (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，控制巨噬细胞表型以响应 PcP 是可能的。例如，给患有 PcP 的小鼠施用抗炎剂柳氮磺吡啶，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，将反应转向 TH2/AAM 途径会导致 PcP 相关免疫发病机制减弱，同时增强巨噬细胞介导的 Pc 清除率。本申请的具体目标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。该提议的总体假设是，AM 是宿主防御和 PcP 相关免疫发病机制的关键效应器，巨噬细胞极化的定向调节代表了一种改善 PcP 结果的新治疗策略。我们将结合药理学、免疫学和敲除技术来确定差异 AM 极化如何控制 PcP 的发病、炎症和消退/修复阶段，并确定巨噬细胞的作用机制。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，以促进合理设计治疗策略，以增强宿主防御，同时限制免疫发病机制。为了实现这一目标，我们提出了具体目标，即：1）确定差异性巨噬细胞激活如何调节对 PC 的免疫反应； 2) 确定CD4+ T细胞独立抵抗PC的机制； 3) 评估调节 AM 表型是否是治疗 PcP 的有效策略。该提案具有创新性，因为它重点关注 AM 作为介导免疫发病机制和宿主防御的效应器。拟议的研究意义重大，因为它将增强我们对 PcP 相关免疫发病机制的理解，并有可能产生新的治疗策略，从而改善患者护理。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The alveolar epithelial cell chemokine response to pneumocystis requires adaptor molecule MyD88 and interleukin-1 receptor but not toll-like receptor 2 or 4.

肺泡上皮细胞趋化因子对肺孢子虫的反应需要接头分子 MyD88 和白细胞介素 1 受体，但不需要 Toll 样受体 2 或 4。

DOI：
发表时间：
2012-11
期刊：
影响因子：
3.1
作者：
Bello;Wang, Jing;Olsen, Keith;Gigliotti, Francis;Wright, Terry W
通讯作者：
Wright, Terry W

Neither classical nor alternative macrophage activation is required for Pneumocystis clearance during immune reconstitution inflammatory syndrome.

在免疫重建炎症综合征期间，肺孢子虫清除不需要经典或替代巨噬细胞激活。

DOI：
发表时间：
2015-12
期刊：
影响因子：
3.1
作者：
Zhang, Zhuo;Wang, Jing;Hoy, Zachary;Keegan, Achsah;Bhagwat, Samir;Gigliotti, Francis;Wright, Terry W
通讯作者：
Wright, Terry W

Pneumocystis: where does it live?

肺孢子虫：它生活在哪里？