Host Response to P. carinii in Neonatal Mice

新生小鼠对卡氏疟原虫的宿主反应

• 批准号: 8085894
• 负责人: Beth A Garvy
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8085894
• 关键词: Address; Adoptive Cell Transfers; Adult; Age; Agonist; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Autopsy; Binding; CD 200; CD4 Positive T Lymphocytes; Cell physiology; Child; Cyst; Cytokine Activation; Data; Defect; Environment; Environmental Risk Factor; Epithelial Cells; Funding; Glucans; Goals; HIV; Health; Health Services Accessibility; Immigration; Immune response; Immune system; In Vitro; Incidence; Individual; Infant; Infection; Intrinsic factor; Life; Ligation; Lung; Macrophage-1 Antigen; Mannans; Morbidity - disease rate; Mus; Neonatal; Newly Diagnosed; Pattern recognition receptor; Phagocytosis Induction; Phenotype; Pneumocystis; Pneumocystis carinii; Pneumocystis carinii Pneumonia; Production; Regulatory T-Lymphocyte; Signal Pathway; Signal Transduction; Site; Specificity; Specimen; Stimulus; Sudden infant death syndrome; T-Lymphocyte; TLR2 gene; TNFSF5 gene; Testing; Toll-Like Receptor 2; Transgenic Mice; Up-Regulation; antiretroviral therapy; cytokine; dectin 1; in vivo; macrophage; mannose receptor; mortality; neonate; non-compliance; pup; receptor; response

DESCRIPTION (provided by applicant): Pneumocystis pneumonia PCP) causes significant morbidity and mortality among HIV-infected individuals who are newly diagnosed, failed retroviral therapy, or do not have access to care. Infants are particularly susceptible to pulmonary infections and it has been recently appreciated that not only are individuals exposed to Pneumocystis early in life, but infants appear to carry the infection as evidenced by the high incidence found in autopsy specimens from babies that died of SIDS. HIV-infected infants tend to have a more fulminant course of PCP, likely because of the immature immune system along with depletion of CD4+ cells. In the previous funding period we found that, in contrast to our hypothesis, the delay in clearance of Pneumocystis we observed in neonatal mice was not solely due to elevated anti-inflammatory cytokines in the lungs through the first 3 weeks of life. Instead, we found that alveolar macrophages from neonatal mice are intrinsically unresponsive to Pneumocystis. The goal for this funding period is to differentiate the contribution of environmental factors and intrinsic factors to neonatal alveolar macrophage function in response to Pneumocystis. Specifically, we will test the hypothesis that: neonatal alveolar macrophages fail to respond to Pneumocystis due to a defect in signaling through pattern recognition receptors along with delayed second signals from proinflammatory cytokines or costimulatory molecules on T cells. To address this hypothesis we have proposed two aims. 1. We will determine whether alveolar macrophages from neonatal mice are intrinsically unresponsive to Pneumocystis. In vitro and in vivo experimental strategies will be used to determine whether neonatal alveolar macrophages can respond to stimuli through the dectin-1 ?-glucan receptor, mannose receptor, or TLR2. 2. We will determine whether secondary signals from T cells are required to stimulate neonatal alveolar macrophages. We will use adoptive transfer of cells and treatment with exogenous stimulatory molecules in an attempt to stimulate alveolar macrophages to respond to Pneumocystis. These studies are a logical extension of our previous funding period and will address the mechanisms responsible for neonatal unresponsiveness Pneumocystis. PUBLIC HEALTH RELEVANCE: Pneumocystis pneumonia (PCP) is an AIDs defining illness that is still prevalent in newly diagnosed HIV-infected individuals and those who fail therapy, are non-compliant, or do not have access to antiretroviral therapy. PCP often has a worse course in children due to the immaturity of the immune system. The goal of this project is to understand the function of alveolar macrophages and CD4 T cells and their interactions in infants with PCP.

描述（由申请人提供）：肺炎肺炎肺炎PCP）在被新诊断，逆转录病毒治疗失败或无法获得护理的HIV感染者中引起了显着的发病率和死亡率。婴儿特别容易受到肺部感染的影响，最近人们不仅认为，不仅患有生命早期暴露于肺炎的个体，而且婴儿似乎带有感染，这证明了死于SIDS的婴儿的尸检标本中的高发病率证明。感染HIV的婴儿倾向于更暴发的PCP病程，这可能是由于不成熟的免疫系统以及CD4+细胞的耗竭。在上一个资金期间，我们发现，与我们的假设相比，在新生小鼠中观察到的肺类胸膜清除的延迟并不仅仅是由于肺部肺部前三周的抗炎细胞因子升高所致。取而代之的是，我们发现来自新生小鼠的肺泡巨噬细胞本质上对肺囊肿没有反应。在此资金期间的目标是区分环境因素和内在因素对响应肺类细胞的新生儿肺泡巨噬细胞功能的贡献。具体而言，我们将检验以下假设：由于通过模式识别受体信号传导的缺陷以及促炎细胞因子或T细胞上的cost摄取分子的延迟，新生儿肺泡巨噬细胞无法应对肺炎藻。为了解决这一假设，我们提出了两个目标。 1。我们将确定来自新生小鼠的肺泡巨噬细胞在本质上对肺炎囊肿没有反应。体外和体内实验策略将用于确定新生儿肺泡巨噬细胞是否可以通过Dectin-1？-Glucan受体，甘露糖受体或TLR2对刺激做出反应。 2。我们将确定是否需要来自T细胞的次级信号刺激新生儿肺泡巨噬细胞。我们将使用细胞的继产和外源刺激分子的治疗，以试图刺激肺泡巨噬细胞以应对肺炎。这些研究是我们以前的资金期间的逻辑扩展，它将解决导致新生儿无反应性气囊的机制。公共卫生相关性：肺炎肺炎肺炎（PCP）是一种定义疾病的艾滋病，在新诊断的艾滋病毒感染者中仍然普遍存在，而失败治疗，不合规或无法获得抗逆转录病毒疗法的人。由于免疫系统的不成熟，PCP通常在儿童方面较差。该项目的目的是了解肺泡巨噬细胞和CD4 T细胞的功能及其在PCP婴儿中的相互作用。