Role of Polymorphonuclear Phagocytes in Malaria Sepsis

多形核吞噬细胞在疟疾败血症中的作用

基本信息

批准号：
7894695
负责人：
RICARDO TOSTES GAZZINELLI
金额：
$ 20.56万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-18 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7894695
关键词：
Acute Aftercare Antimalarials Apoptosis Area Biological Assay Biological Response Modifiers Blood Blood Circulation Brazil CD14 gene Cell Density Cells Centrifugation Cessation of life Clinic Color Communicable Diseases Custom DNA Data Dendritic Cells Developing Countries Disease Economics Endotoxins Enzyme-Linked Immunosorbent Assay Erythrocytes Exposure to Fever Gene Expression Genes Glycolipids Goals Grant Granulocyte-Macrophage Colony-Stimulating Factor Harvest Hour Human IL8 gene Immune Immune response Immune system Immunologic Receptors Immunotherapy In Vitro Incubated Individual Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Insecticide Resistance Interferons Interleukin-1 Receptors Interleukin-12 Journals Knowledge Leukocytes Ligands Lymphocyte Macrophage Colony-Stimulating Factor Malaria Measures Mediating Mediator of activation protein Microarray Analysis Microfluidics Military Personnel Molecular Mono-S Morbidity - disease rate Myelogenous Nature Oligonucleotides Outcome Parasitemia Parasites Pathogenesis Patients Peer Review Peripheral Peripheral Blood Mononuclear Cell Phagocytes Pharmaceutical Preparations Plasmodium Plasmodium falciparum Play Population Preparation Process Production Proteins Publishing Receptor Gene Receptor Signaling Recording of previous events Relative (related person)Reporting Research Review Literature Risk Rodent Role Rupture Sepsis Severity of illness Signal Pathway Signal Transduction Signaling Molecule Source Surface Symptoms TLR2 gene TLR4 gene Testing Time Time Study Toll-Like Receptor Pathway Toll-like receptors Travel Vaccines Visit Work base cell type chemotherapy cytokine defined contribution disorder prevention experience hemozoin immune activation in vivo innovation insight interest killings monocyte neutrophil novel novel therapeutics operation prevent prophylactic public health relevance purge receptor receptor expression receptor-mediated signaling response sensor social volunteer

项目摘要

DESCRIPTION (provided by applicant): Worldwide, 400 million people acquire malaria each year, contributing to significant political, social and economic instability in the developing countries. Malaria infection leads to production of high levels of pyrogenic cytokines, such as TNFa and IFN?, which orchestrate the host response to infection as well as cause the symptoms observed during disease. Our studies suggest that the Myeloid Differentiation Factor 88 (MyD88), an adaptor-signaling molecule for the IL-1 receptor (and the related IL-18r and IL-33r) as well as Toll- like receptors (TLRs), is critical for initiation of this early inflammatory response and pathogenesis of rodent malaria. Our microarray analysis of peripheral blood mononuclear cells from patients with acute malaria demonstrate enhanced expression of genes encoding proteins that are critical in the TLR signaling pathway. We hypothesize that upon overwhelming malaria infection, innate immune receptors in phagocytes are responsible for the intense cytokinemia and subsequent morbidity and death. This hypothesis, of course, is neither innovative nor risky. But the most basic details of malaria-related cytokinemia are yet to be worked out. While the paucity of published data concerning monocytes and dendritic cells is surprising, the role of polymorphonuclear leukocytes (PMN) as a source of cytokines and other mediators has been entirely overlooked. PMNs are the most abundant leukocytes and produce many mediators of inflammation. Furthermore, PMNs express TLR2, TLR4, and TLR9 that are critical for the innate immune response to Plasmodium glycolipids and DNA. We hypothesize that PMNs play an important role in the innate immune response during human acute malaria episodes and hence are potential targets for novel immune therapies. Thus, we intend to evaluate: (i) the ability of PMNs in comparison to other phagocytes obtained from healthy and malaria patients to respond in vitro to immunostimulatory malaria components; and (ii) ex vivo cytokine production and gene expression in PMNs, obtained from malaria patients before and after parasitological cure by chemotherapy. Ultimately, we hope to define the contribution of innate immune receptors in neutrophil responses and systemic inflammation during acute infection with P. falciparum. Such knowledge may contribute to new therapeutic insights to the treatment of malaria. PUBLIC HEALTH RELEVANCE: Malaria is the world's most common infectious disease, and kills millions of individuals annually. US citizens risk obtaining malaria when they travel or are engaged in military operations in tropical areas. The purpose of this grant is to gain a better understanding of why malaria causes disease in the hopes that better therapies can be devised, including an effective vaccine that might prevent malaria.

描述（由申请人提供）：全球，每年有4亿人患疟疾，导致发展中国家的重大政治，社会和经济动荡。疟疾感染导致产生高水平的热原细胞因子，例如TNFA和IFN？，哪个策划了宿主对感染的反应，并导致疾病期间观察到的症状。我们的研究表明，髓样分化因子88（MyD88），一种适用于IL-1受体（以及相关IL-18R和IL-33R）的适应器信号分子以及TOLL-LIKE受体（TLR），对于对开始这种早期炎症反应和啮齿动物疟疾发病机理。我们对急性疟疾患者外周血单核细胞的微阵列分析表明，在TLR信号通路中至关重要的蛋白质的基因表达增强。我们假设在压倒性疟疾感染后，吞噬细胞中的先天免疫受体负责严重的细胞因子血症以及随后的发病率和死亡。当然，这个假设既不是创新的也不是风险。但是，与疟疾相关的细胞因子血症的最基本细节尚未解决。虽然关于单核细胞和树突状细胞的已发表数据的匮乏令人惊讶，但多形核白细胞（PMN）作为细胞因子和其他介体的来源的作用被完全忽略了。 PMN是最丰富的白细胞，产生许多炎症介质。此外，PMNS表达TLR2，TLR4和TLR9对于先天性免疫反应至关重要，对疟原虫的糖脂和DNA至关重要。我们假设PMN在人类急性疟疾发作期间的先天免疫反应中起重要作用，因此是新型免疫疗法的潜在靶标。因此，我们打算评估：（i）与从健康和疟疾患者获得的其他吞噬细胞相比，PMN的能力在体外对免疫刺激性疟疾成分做出反应；（ii）通过化学疗法治愈寄生虫治疗前后从疟疾患者获得的PMN中的体内细胞因子的产生和基因表达。最终，我们希望在恶性疟原虫急性感染期间定义先天免疫受体在中性粒细胞反应和全身炎症中的贡献。这种知识可能有助于疟疾治疗的新治疗见解。公共卫生相关性：疟疾是世界上最常见的传染病，每年杀死数百万人。美国公民在旅行或从事热带地区的军事行动时冒着获取疟疾的风险。这笔赠款的目的是更好地了解为什么疟疾会导致疾病，希望可以设计出更好的疗法，包括可能预防疟疾的有效疫苗。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neutrophil paralysis in Plasmodium vivax malaria.

DOI：
10.1371/journal.pntd.0001710
发表时间：
2012
期刊：
PLoS neglected tropical diseases
影响因子：
3.8
作者：
Leoratti FM;Trevelin SC;Cunha FQ;Rocha BC;Costa PA;Gravina HD;Tada MS;Pereira DB;Golenbock DT;Antonelli LR;Gazzinelli RT
通讯作者：
Gazzinelli RT