Role of Polymorphonuclear Phagocytes in Malaria Sepsis

描述(申请人提供)：在世界范围内，每年有4亿人感染疟疾，在发展中国家造成重大的政治、社会和经济不稳定。疟疾感染导致产生高水平的致热细胞因子，如TNFa和干扰素？，这些细胞因子协调宿主对感染的反应，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)是IL-1受体(及其相关的IL-18r和IL-33r)以及Toll样受体(TLRs)的适配信号分子，在启动这种早期炎症反应和啮齿动物疟疾的发病机制中起着关键作用。我们对急性疟疾患者外周血单核细胞的微阵列分析显示，编码蛋白的基因表达增强，这些蛋白在TLR信号通路中至关重要。我们假设，在疟疾感染压倒性的情况下，吞噬细胞中的先天免疫受体是导致严重的细胞分裂素血症和随后的发病率和死亡的原因。当然，这种假设既没有创新性，也没有风险。但与疟疾相关的细胞分裂素血症的最基本细节尚未确定。虽然关于单核细胞和树突状细胞的已发表数据的稀少令人惊讶，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被完全忽视。中性粒细胞是最丰富的白细胞，能产生多种炎症介质。此外，中性粒细胞表达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，因此是新的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，体外对免疫刺激性疟疾成分的反应的能力；以及(Ii)体外细胞因子的产生和基因表达，从疟疾患者通过化疗寄生虫治疗前后获得的PMN。最终，我们希望确定先天免疫受体在恶性疟原虫急性感染期间的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疟疾的治疗提供新的治疗见解。与公共卫生相关：疟疾是世界上最常见的传染病，每年导致数百万人死亡。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致病的原因，希望能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.