Modulation of Pulmonary Defenses in Pathobiology of Chronic Infections

慢性感染病理学中肺防御的调节

基本信息

  • 批准号:
    7931135
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-04-01 至 2014-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Olszewski M.A.: Modulation of Pulmonary Defenses in Pathobiology of Chronic Infections Objectives: Macrophages (M) are crucial for either clearance or persistence of the opportunistic yeast C. neoformans. When properly activated, M generate fungicidal nitric oxide from L-arginine to destroy ingested cryptococci. In unfavorable clinical circumstances, M become alternatively activated and induce Arginase (ARG1), an intracellular enzyme that consumes L-arginine but does not induce nitric oxide. The proposed studies will focus on dysregulation of M function by C. neoformans, and the role of recently defined virulence factor, heat shock protein Ssa1 in this porcess. Our objective is to test the hypothesis that Ssa1, induces the alternative activation of M and in this fashion promotes rapid growth of C. neoformans in the lungs. We plan to determine, if Ssa1-induced effects are mediated through Ssa1-binding to the scavenger receptor A (SRA) on M and through subsequent upregulation of ARG1 in these cells. Research Plan: The proposed research is presented as three interrelated specific aims: 1) To determine if cryptococcal Ssa1 promotes alternative activation of MF. We propose a series of experiments with cultures of isolated murine M to analyze the effects of recombinants Ssa1 protein and the effects of Ssa1 expression by C. neoformans on M activation status. These in vitro studies will be validated by in vivo infections with Ssa1 producing and Ssa1-deleted mutants of C. neoformans in mice and M phenotype analysis. 2) To determine if the mechanism alternative activation of MF by Ssa1 is induced via the SRA signaling. In this aim, we will determine if SRA signaling is required for Ssa1-induced effects and for the changes in M activation status. 3) To determine if the effects of Ssa1 gene expression by C. neoformans on MF function can be reversed by ARG1 inhibition or manipulations with cytokine environment. Our final aim will explore, if preventing the alternative activation of M by gamma- interferon and/or blocking Arginase1 enzyme would prevent the Ssa1-mediated virulence and lead to improved killing of C. neoformans by M. Methods: Models of murine C. neoformans infections and the isolated mouse M cell cultures, which yielded significant insights into the host-pathogen interaction and understanding mechanisms of anticryptococcal protection, will be used. Ssa1 producing wild type strain of C. neoformans: H99; Ssa1 knockout strain derived from H99; and the revertant strain ssa1::SSA1 with restored SSA1 gene will be used in these studies to induce pulmonary infections in mice or to treat the primary M cultures. Cryptococcal recombinant Ssa1 protein will be also used to treat these cells. Biology of M, cell phenotypes and cytokines produced by these cells will be evaluated in vivo and in vitro, utilizing: 6-color flow cytometry, qPCR and ELISA. Production of fungicidal nitric oxide by M will be evaluated using flow-ctometry based DAF-DT assay. We will use the knockout mice with disrupted SRA gene to determine if SRA signaling contributes to alternative activation of M by C. neoformans. Clinical Relevance: Pulmonary infectious diseases are significant source of morbidity in patients with HIV, organ transplant recipients, alcoholics, IV substance abusers and patients with lymphoproliferative malignancies. Treatment of fungal infections with conventional anti-microbial agents in these patients has been disappointing. Our studies reveal how a major opportunistic fungal pathogen C. neoformans may exploit the loopholes in M signaling to establish intracellular parasitism and propose a treatment strategy to prevent its occurrence. PUBLIC HEALTH RELEVANCE: Relevance to the Veterans Health: Pulmonary infectious diseases are a major source of morbidity and mortality in VA patients with compromised immune systems as a result of AIDS, substance abuse, or stemming from treatment of malignancy, auto-immune disease, or organ transplantation. Antibiotic therapy is often inadequate; thus knowledge of pulmonary host defense is of central importance to the development of new therapies Our studies reveal how a major opportunistic fungal pathogen C. neoformans may exploit the loopholes in the immune system defenses to establish intracellular parasitism and propose a treatment strategy to prevent its occurrence. Demonstrating importance of these pathways may become a cornerstone for novel therapeutic strategies for treatment of cryptococcosis in both immunocompromised and immunocompetent patients.
描述(由申请人提供): Olszewski M.A.:慢性感染病理生物学中肺防御的调节目的:巨噬细胞(M)对机会性酵母菌C的清除或持续至关重要。新人类当适当激活时,M从L-精氨酸产生杀真菌的一氧化氮以破坏摄入的隐球菌。在不利的临床情况下,M被交替激活并诱导精氨酸酶(ARG 1),这是一种消耗L-精氨酸但不诱导一氧化氮的细胞内酶。拟开展的研究将集中于C.以及最近定义的毒力因子热休克蛋白Ssa 1在此过程中的作用。我们的目的是检验Ssa 1诱导M的选择性激活并以这种方式促进C的快速生长的假设。肺部有新生儿我们计划确定,如果Ssa 1诱导的影响是通过Ssa 1结合到M上的清道夫受体A(SRA),并通过随后在这些细胞中上调ARG 1介导的。研究计划:本研究的主要目的是:1)确定隐球菌Ssa 1是否促进MF的替代激活。我们提出了一系列的实验与分离的小鼠M的培养物,以分析重组Ssa 1蛋白的影响和Ssa 1表达的影响,由C。M激活状态的新生儿。这些体外研究将通过体内感染产生Ssa 1和缺失Ssa 1的C.小鼠中的新形式和M表型分析。2)确定Ssa 1对MF的替代激活机制是否通过SRA信号传导诱导。在这个目标中,我们将确定是否SRA信号是必需的Ssa 1诱导的效果和M激活状态的变化。3)目的探讨C.新生儿对MF功能的影响可以通过ARG 1抑制或用细胞因子环境进行操作来逆转。我们的最终目的是探索,如果通过γ-干扰素和/或阻断精氨酸酶1来阻止M的交替激活,是否会阻止Ssa 1介导的毒力并导致提高对C的杀伤。neoformans,M.方法:采用小鼠C.将使用新型隐球菌感染和分离的小鼠M细胞培养物,其产生了对宿主-病原体相互作用和理解抗隐球菌保护机制的重要见解。Ssa 1产生菌野生型菌株。新生儿:H99;在这些研究中,将使用来自H99的SSA 1敲除菌株和具有恢复的SSA 1基因的回复突变菌株ssa 1::SSA 1诱导小鼠肺部感染或处理原代M培养物。隐球菌重组Ssa 1蛋白也将用于治疗这些细胞。将利用6色流式细胞术、qPCR和ELISA在体内和体外评价M的生物学、细胞表型和这些细胞产生的细胞因子。将使用基于流式细胞术的DAF-DT测定法评价M产生的杀真菌一氧化氮。我们将使用SRA基因被破坏的敲除小鼠来确定SRA信号是否有助于C对M的替代激活。新人类临床相关性:肺部传染病是艾滋病毒感染者、器官移植受者、酗酒者、静脉药物滥用者和淋巴组织增生性恶性肿瘤患者发病的重要原因。用常规抗微生物剂治疗这些患者的真菌感染令人失望。我们的研究揭示了一种主要的机会致病真菌C。新生儿可能会利用M信号的漏洞建立细胞内寄生,并提出一种治疗策略,以防止其发生。 公共卫生相关性: 与退伍军人健康的相关性:肺部感染性疾病是由于艾滋病、药物滥用或恶性肿瘤、自身免疫性疾病或器官移植治疗导致免疫系统受损的VA患者发病率和死亡率的主要来源。抗生素治疗往往是不够的,因此肺部宿主防御的知识是至关重要的新疗法的发展,我们的研究揭示了一个主要的机会性真菌病原体C。新生儿可能会利用免疫系统防御的漏洞建立细胞内寄生,并提出预防其发生的治疗策略。证明这些途径的重要性可能成为免疫功能低下和免疫功能正常患者隐球菌病治疗新策略的基石。

项目成果

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Michal A Olszewski其他文献

Michal A Olszewski的其他文献

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{{ truncateString('Michal A Olszewski', 18)}}的其他基金

BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10593999
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10471518
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Request for BD FACSAria Fusion Cell Sorter ShEEP Application
请求 BD FACSAria 融合细胞分选仪 SheEEP 申请
  • 批准号:
    9905139
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
BLR&D Research Career Scientist Award Application
BLR
  • 批准号:
    10046729
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Immunoregulatory Mechanisms to Combat CNS Pathology During Infection
感染期间对抗中枢神经系统病理的免疫调节机制
  • 批准号:
    10485452
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Modulation of Pulmonary Defenses in Pathobiology of Chronic Infections
慢性感染病理学中肺防御的调节
  • 批准号:
    8259074
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Modulation of Immune Defenses in Pathobiology of CNS Infection
中枢神经系统感染病理学中免疫防御的调节
  • 批准号:
    10084210
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Modulation of Pulmonary Defenses in Pathobiology of Chronic Infections
慢性感染病理学中肺防御的调节
  • 批准号:
    8195410
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Modulation of Pulmonary Defenses in Pathobiology of Chronic Infections
慢性感染病理学中肺防御的调节
  • 批准号:
    8397547
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Modulation of Immune Defenses in Pathobiology of Chronic Infections
慢性感染病理学中免疫防御的调节
  • 批准号:
    9281605
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:

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