Role of Polymorphonuclear Phagocytes in Malaria Sepsis

描述（由申请人提供）：全球每年有4亿人感染疟疾，这对发展中国家的政治、社会和经济造成了严重的不稳定。疟疾感染导致产生高水平的热原细胞因子，如TNFa和IFN？它们协调宿主对感染的反应，并引起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）是IL-1受体（以及相关的IL-18r和IL-33r）以及Toll样受体（TLRs）的适配器信号分子，对于启动这种早期炎症反应和啮齿动物疟疾的发病机制至关重要。我们对急性疟疾患者外周血单核细胞的微阵列分析表明，编码TLR信号通路中关键蛋白的基因表达增强。我们假设，在压倒性的疟疾感染时，吞噬细胞中的先天免疫受体负责强烈的细胞分裂血症和随后的发病率和死亡。当然，这个假设既没有创新，也没有风险。但是与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公开数据的缺乏令人惊讶，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完全被忽视了。pmn是最丰富的白细胞，并产生许多炎症介质。此外，PMNs表达TLR2、TLR4和TLR9，它们对疟原虫糖脂和DNA的先天免疫反应至关重要。我们假设pmn在人类急性疟疾发作期间的先天免疫反应中发挥重要作用，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获得的其他吞噬细胞相比，PMNs在体外对免疫刺激疟疾成分作出反应的能力；（ii）疟疾患者经寄生虫治疗化疗前后PMNs的体外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急性恶性疟原虫感染期间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为治疗疟疾提供新的治疗见解。公共卫生相关性：疟疾是世界上最常见的传染病，每年夺去数百万人的生命。美国公民在热带地区旅行或参与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导致疾病的原因，希望能够设计出更好的治疗方法，包括可能预防疟疾的有效疫苗。

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.