Hemolytic Complications in Babesia Infections

巴贝虫感染的溶血并发症

• 批准号: 10023591
• 负责人: Cheryl Ann Lobo
• 金额: $ 65.22万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10023591
• 关键词: Anemia; Autoantibodies; Babesia; Babesiosis; Binding; Biological Assay; Biology; Bone Marrow; Cause of Death; Cell membrane; Cell physiology; Cells; Chromatin; Collaborations; Communicable Diseases; Complement; Cytolysis; Data; Defect; Deposition; Developing Countries; Development; Diagnostic; Erythroblasts; Erythrocytes; Erythroid; Erythroid Progenitor Cells; Erythrophagocytosis; Erythropoiesis; Event; Exhibits; Fatty Acids; Gene Expression; Generations; Goals; Hemolysis; Human; Immune; Impairment; In Vitro; Infection; Infectious Agent; Kinetics; Knockout Mice; Link; Lipids; Malaria; Mechanics; Mediating; Membrane; Membrane Microdomains; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Mus; Osmotic Fragility test; Parasites; Parasitic Diseases; Pathogenesis; Pathology; Pathway interactions; Patients; Phagocytes; Phagocytosis Induction; Phenotype; Physical condensation; Predisposition; Production; Property; Proteins; Reagent; Role; Sickle Cell; Signal Pathway; Suggestion; System; Technology; Testing; Transfusion; Vascular blood supply; combat; common symptom; cytokine; experience; extracellular vesicles; fungus; immune activation; in vivo; insight; macrophage; monocyte; mortality; mouse model; novel strategies; pathogen; pathogenic bacteria; progenitor; response; sample fixation; success; tool; transmission process; uptake

ABSTRACT: SCD exhibits increased susceptibility to infection which in turn leads to SCD-specific pathophysiological sequelae. Infection is the leading cause of death in these patients especially in less developed countries where the blood supply is not efficiently screened. Even in the US, transfusion transmitted pathogens can represent a major threat of morbidity and mortality to SCD recipients. EVs are produced by pathogens and host cells in response to infection and carry serve as vehicles for dissimilation of effector molecules in the infected host. Hemolysis and anemia are two common symptoms that accompany many infectious diseases. While particularly true of parasitic diseases that target red cells, like malaria and babesia, these complications are also seen in many other infections. While the current proposal focuses on babesia, a single pathogen, we believe that the impact of pathogen derived EVs on host cells is a common theme in the pathogenesis of many infectious diseases and results from this study can have implications for hemolytic complications caused by other infectious agents. Hemolytic complications in SCD are the major contributing pathology to fatalities seen in these transfusion transmissions, making it imperative to elucidate the reason for the higher degree of hemolysis seen in these infected patients. EVs derived from parasitized cells can alter cell membranes, impact gene expression and modulate signaling pathways to promote hemolysis. Our overall goal is to define mechanisms of extracellular vesicle driven hemolysis during infection in SCD, using Babesia as our model. Hypothesis: Babesia anemia is exaggerated in SCD because EVs accelerate a) bystander RBC destruction and b) exacerbate ineffective erythropoiesis due to the increased susceptibility of SCD to 1) EV-mediated alterations and complement opsonization of bystander RBCs resulting in direct /indirect lysis 2) immune activation by EVs resulting in increased phagocytosis and induction of autoAbs 3) EV mediated inhibition of enucleation of erythroid progenitors in SCD BM erythropoiesis. To gain insight into these molecular and cellular processes, using in vivo and in vitro SCD infection models, we will: 1) Elucidate mechanisms by which EV Uptake mediates direct hemolysis by examining EV mediated alterations in membranes of SCD RBCs that cause hemolysis 2) Elucidate mechanisms of EV modulation of extravascular hemolysis by examining macrophage polarization and TLR signaling pathway activation, assessing the role and mechanism of autoAb induction by EVs and determining the contribution of autoantibody opsonization and/or complement fixation in bystander RBC clearance 3) Elucidate mechanisms by which EV Uptake contributes to dyserythropoiesis by defining the underlying molecular mechanisms for both EV-induced and infection- induced enucleation defects in erythroid progenitor cells in SCD bone marrow. Our proposed studies will result in a better understanding of the role of parasite EVs in the pathogenesis associated with human babesiosis especially the hyper- hemolysis seen in the sickle cell context. We anticipate these studies will lead to the refinement of diagnostic tools and offer novel strategies to combat anemia in human babesiosis.

抽象的： SCD表现出增加对感染的敏感性，进而导致SCD特异性病理生理后遗症。 感染是这些患者的主要死亡原因 有效筛选。即使在美国，输血传播的病原体也可以代表发病率的主要威胁和 SCD接收者的死亡率。电动汽车是由病原体和宿主细胞响应感染而产生的，并携带为 在受感染宿主中分散效应分子的车辆。溶血和贫血是两个常见症状 伴随着许多传染病。尤其是针对红细胞的寄生疾病，例如疟疾和 巴比西亚，在许多其他感染中也可以看到这些并发症。当前的提议重点是巴贝西亚 病原体，我们认为病原体衍生的电动汽车对宿主细胞的影响是许多人的发病机理的常见主题 传染病和这项研究的结果可能对其他感染性引起的溶血并发症有影响 代理商。 SCD中的溶血并发症是对这些输血中死亡的主要病理 传播，因此必须阐明这些感染患者的溶血程度更高的原因。 源自寄生细胞的电动汽车可以改变细胞膜，影响基因表达并调节信号传导途径 促进溶血。我们的总体目标是确定在感染期间感染期间细胞囊泡驱动的溶血的机制 SCD，使用Babesia作为我们的模型。假设：在SCD中，贝贝西亚贫血被夸大了，因为电动汽车加速了a） 旁观者RBC破坏和b）由于SCD的易感性增加到1）而加剧无效的红细胞生成 EV介导的变化和补充旁观者RBC的调子化导致直接 /间接裂解2）免疫 电动汽车的激活导致吞噬作用增加并诱导自动ab 3）EV介导的摘除抑制作用 SCD BM红细胞生成中的红细胞祖细胞。使用In In In中的这些分子和细胞过程深入了解这些分子和细胞过程 体内和体外SCD感染模型，我们将：1）阐明EV摄取介导直接溶血的机制 通过检查引起溶血的SCD RBC膜的EV介导的变化2）阐明EV的机制 通过检查巨噬细胞极化和TLR信号通路激活，调节血管外溶血的调节， 通过电动汽车评估自动启动诱导的作用和机制，并确定自身抗体的贡献 旁观者RBC间隙中的调子化和/或补体固定3）阐明了EV吸收的机制 通过定义EV诱导和感染的潜在分子机制来促进孕育促性疾病 SCD骨髓中的红细胞祖细胞中诱导的插核缺陷。我们提出的研究将使更好 了解寄生虫电动汽车在与人类Babesiosis相关的发病机理中的作用，特别是 在镰状细胞环境中看到的溶血。我们预计这些研究将导致诊断工具的完善并提供 在人类babesios中打击贫血的新型策略。