Monocyte-derived dendritic cells in malaria

疟疾中的单核细胞衍生树突状细胞

• 批准号: 9282641
• 负责人: RICARDO TOSTES GAZZINELLI
• 金额: $ 41.45万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282641
• 关键词: Address; Adoptive Transfer; Antigen Presentation; Area; Binding; Brain; CCR5 gene; CD8-Positive T-Lymphocytes; CXCL10 gene; CXCL9 gene; CXCR3 gene; Cell Differentiation process; Cell physiology; Cell surface; Cells; Cellular Immunity; Cerebral Malaria; Cerebrovascular system; Cessation of life; Child; Communicable Diseases; Data; Dendritic Cells; Development; Disease; Effector Cell; Elements; Encephalitis; Erythrocytes; Gene Expression Profiling; Goals; Grant; Host resistance; Human; ITGAM gene; ITGAX gene; Immune; Individual; Infection; Inflammation; Inflammatory; Interferon Type II; Interleukin-12; Kinetics; Lead; Leukocytes; Ligands; Malaria; Mediating; Mediator of activation protein; Microscopy; Military Personnel; Modeling; Morphology; Mus; Names; Neuraxis; Neurocognitive Deficit; Neurologic Symptoms; Nucleic Acids; Pathogenesis; Pathogenicity; Pathology; Patients; Phenotype; Plasmodium; Plasmodium falciparum; Property; Recruitment Activity; Reporter; Reporting; Resistance; Risk; Rodent; Role; Scanning; Shapes; Signs and Symptoms; Source; Spleen; T-Lymphocyte; T-Lymphocyte and Natural Killer Cell; Testing; Therapeutic Intervention; Transcript; Transgenic Mice; Travel; Vaccines; base; cell motility; chemokine; chemokine receptor; cytokine; in vivo; insight; killings; macrophage; migration; monocyte; monocyte chemoattractant protein 1 receptor; mortality; mouse model; neuroinflammation; novel; operation; prevent; reconstitution; response; sensor

Project Summary Cerebral malaria (CM) is a severe neurological manifestation of infection with Plasmodium species. Mortality is high and neurocognitive deficits may persist in recovered patients. Evidences obtained from humans and in a rodent malaria model indicate that sequestration of infected erythrocytes within cerebral blood vessels and neuroinflammation are essential components of CM. Hence, to fulfill the promise of immune-based therapeutic interventions, a better understanding of relevant mechanisms of CM pathogenesis is needed. While a variety of immune cells, primarily CD8+ T cells, are involved, the mechanisms that govern immune cell cooperation leading to this lethal pathology are poorly understood. Using selective depletions recent studies have demonstrated the importance of CD11c+MHC-IIhi dendritic cells (DCs) as well as CD11b+F4/80+Ly6c+CCR2+ inflammatory monocytes (iMOs), both in host resistance to Plasmodium and pathogenesis of CM. Although these cell subsets have overlapping functions, DCs are more specialized in antigen presentation and shaping T cell mediated immunity. However, the main DC subset(s) that mediate CM development has not been defined. We found that infection with P. berghei ANKA (Pba) promotes a massive differentiation of iMOs into splenic monocyte derived dendritic cells (MO- DCs) at 5 days post-infection, and two days later they emerge in the CNS culminating in the development of lethal CM. Thus, our main hypothesis is that MO-DCs are central players in promoting neuroinflammation in PbA infected mice. Our goal is to interrogate what are the endogenous elements that promote differentiation of iMOs into MO-DCs and the mechanism by which MO-DCs promote neuroinflammation in rodent malaria. Our first aim is to fully characterize the malaria-induced splenic MO-DCs based on cell surface markers, morphological properties, and unbiased analysis of gene expression. Our preliminary results indicate that the highly purified MO-DCs (CD11c+MHC-IIhi CD11b+F4/80+DC-SIGN+Ly6c+) express high levels of IFNγ-inducible chemokines, CXCL9 and CXCL10, as well as the chemokine receptor CCR5, thus we named these cells CCR5+CXCL9/10+ MO-DCs. Furthermore, activation of nucleic acid sensing TLRs have been shown to initiate cytokine response by both human and mouse macrophages and DCs exposed to Plasmodium components. Hence, in the second aim we will investigate the importance of TLR activation as well as IFNγ in promoting MO-DCs differentiation and function. Finally, in Aim 3 we will investigate the emergence of MO-DCs in the CNS of PbA infected mice. Our preliminary data also suggest that CCR5 is a key chemokine receptor that mediates MO-DC migration into inflamed brain. We hypothesize that once in the CNS, MO-DCs are important source of CXCL9 and CXCL10, amplifying recruitment and activation of pathogenic CD8+ T lymphocytes. Taken together, these studies will provide novel and significant insights into the mechanisms that DCs mediate the development of neuroinflammation and pathogenesis of malaria.

项目摘要 脑型疟疾(CM)是一种严重的神经系统表现，感染疟原虫物种。 死亡率很高，康复患者可能会持续存在神经认知缺陷。从以下方面获得的证据 人类和啮齿动物疟疾模型表明感染的红细胞在大脑中隔离 血管和神经炎症是CM的重要组成部分。因此，要实现……的承诺 以免疫为基础的治疗干预，更好地了解CM的相关机制 发病机制是必要的。虽然涉及多种免疫细胞，主要是CD8+T细胞，但 管理免疫细胞合作导致这种致命病理的机制还知之甚少。 使用选择性耗竭最近的研究表明CD11c+MHC-IIHI树突状细胞的重要性 细胞(DC)和CD11b+F4/80+Ly6c+CCR2+炎性单核细胞(IMOS)均参与宿主抵抗 对疟原虫和CM的致病作用。尽管这些细胞亚集具有重叠的功能，但DC 更擅长抗原呈递和塑造T细胞介导的免疫。然而，主要的DC 调解CM开发的子集(S)尚未定义。我们发现伯氏肺孢子虫感染 血管紧张素转换酶(Anka，PBA)促进IMOS向脾单核细胞来源的树突状细胞(MO- 在感染后5天)，两天后它们出现在中枢神经系统，最终发展为 致命的CM。因此，我们的主要假设是，MO-DC是促进神经炎症的核心角色。 PBA感染小鼠。我们的目标是询问促进分化的内生因素是什么 将IMOS导入MO-DC，以及MO-DC促进啮齿动物疟疾神经炎症的机制。 我们的第一个目标是基于细胞表面标志物对疟疾诱导的脾MO-DC进行全面的表征。 形态特征和基因表达的无偏分析。我们的初步结果表明 高纯度的MO-DC(CD11c+MHC-IIhi CD11b+F4/80+DC-Sign+Ly6c+)高表达 干扰素γ诱导的趋化因子CXCL9和CXCL10，以及趋化因子受体CCR5，因此我们将其命名为 这些细胞是CCR5+CXCL9/10+MO-DC。此外，核酸感应TLRs的激活已经被 人和小鼠巨噬细胞和DC均可启动细胞因子反应 疟原虫成分。因此，在第二个目标中，我们将研究TLR激活的重要性，因为 干扰素γ促进MO-DC的分化和功能。最后，在目标3中，我们将调查 PBA感染小鼠中枢神经系统内可见MO-DC。我们的初步数据还表明，CCR5是一个 关键的趋化因子受体，介导MO-DC迁移到发炎的大脑。我们假设一旦进入 CNS、MO-DC是CXCL9和CXCL10的重要来源，放大了CXCL9和CXCL10的募集和激活 致病CD8+T淋巴细胞。综上所述，这些研究将提供新的和重要的见解 探讨树突状细胞在神经炎症和疟疾发病机制中的作用。