Role of Polymorphonuclear Phagocytes in Malaria Sepsis

多形核吞噬细胞在疟疾败血症中的作用

• 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
• 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

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（申请人提供）：全球每年有4亿人感染疟疾，导致发展中国家的政治、社会和经济严重不稳定。疟疾感染导致产生高水平的致热性细胞因子，如TNF α和IFN？，其协调宿主对感染的反应以及引起在疾病期间观察到的症状。我们的研究表明，髓样分化因子88（MyD 88），IL-1受体（和相关的IL-18 r和IL-33 r）以及Toll样受体（TLR）的衔接子信号传导分子，对于啮齿动物疟疾的这种早期炎症反应和发病机制的起始是至关重要的。我们对急性疟疾患者外周血单核细胞的微阵列分析表明，TLR信号通路中关键蛋白质编码基因的表达增强。我们推测，在压倒性的疟疾感染，先天免疫受体的吞噬细胞是负责激烈的细胞因子血症和随后的发病率和死亡。当然，这个假设既不创新也不冒险。但是疟疾相关的细胞因子血症的最基本细节还有待研究。虽然关于单核细胞和树突状细胞的已发表数据的缺乏是令人惊讶的，但多形核白细胞（PMN）作为细胞因子和其他介质的来源的作用已被完全忽视。中性粒细胞是最丰富的白细胞，并产生许多炎症介质。此外，PMNs表达TLR 2、TLR 4和TLR 9，它们对于针对疟原虫糖脂和DNA的先天免疫应答至关重要。我们假设中性粒细胞在人类急性疟疾发作期间的先天免疫应答中起重要作用，因此是新型免疫疗法的潜在靶点。因此，我们打算评估：（i）与从健康和疟疾患者中获得的其他吞噬细胞相比，PMN在体外对免疫刺激性疟疾组分作出反应的能力;以及（ii）在通过化疗进行寄生虫学治愈之前和之后从疟疾患者中获得的PMN中的离体细胞因子产生和基因表达。最终，我们希望确定先天免疫受体在恶性疟原虫急性感染过程中中性粒细胞反应和全身炎症中的作用。这些知识可能有助于对疟疾的治疗提出新的见解。公共卫生相关性：疟疾是世界上最常见的传染病，每年造成数百万人死亡。美国公民在热带地区旅行或参加军事行动时有感染疟疾的风险。这笔赠款的目的是更好地了解疟疾为什么会引起疾病，希望能够设计出更好的疗法，包括可能预防疟疾的有效疫苗。

项目成果

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