Hemolytic Complications in Babesia Infections

巴贝虫感染的溶血并发症

• 批准号: 10647738
• 负责人: Cheryl Ann Lobo
• 金额: $ 67万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-20 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647738
• 关键词: Acceleration; Anemia; Autoantibodies; Babesia; Babesiosis; Binding; Biological Assay; Biology; Blood Vessels; Bone Marrow; Cause of Death; Cell membrane; Cell physiology; Cells; Chromatin; Collaborations; Communicable Diseases; Complement; Cytolysis; Data; Defect; Deposition; Developing Countries; Development; 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; Inflammatory; Kinetics; Knockout Mice; Link; Lipids; Macrophage; 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; Phenotype; Physical condensation; Predisposition; Production; Property; Proteins; Reagent; Role; Sickle Cell; Signal Pathway; System; Technology; Testing; Transfusion; Vascular blood supply; combat; common symptom; cytokine; diagnostic tool; experience; extracellular vesicles; fungus; immune activation; in vivo; insight; monocyte; mortality; mouse model; novel strategies; pathogen; pathogenic bacteria; progenitor; response; sample fixation; success; 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.

摘要： SCD表现出对感染的易感性增加，这反过来又导致SCD特异性病理生理学后遗症。 感染是这些患者死亡的主要原因，特别是在血液供应不发达的欠发达国家。 有效筛选。即使在美国，输血传播的病原体也可能是发病的主要威胁， SCD患者的死亡率。EV由病原体和宿主细胞响应于感染而产生，并携带充当 感染宿主中效应分子异化的媒介。溶血和贫血是两种常见的症状， 伴随着许多传染病。特别是针对红细胞的寄生虫病，如疟疾和 然而，这些并发症也见于许多其他感染。虽然目前的建议侧重于婴儿，一个单一的 我们认为，病原体衍生的EV对宿主细胞的影响是许多病原体致病机制中的共同主题， 感染性疾病和这项研究的结果可能对其他感染性疾病引起的溶血并发症有影响。 剂. SCD中的溶血并发症是这些输血中观察到的死亡的主要病理学原因 因此，必须阐明在这些感染患者中观察到的较高程度溶血的原因。 来源于寄生细胞的EV可以改变细胞膜，影响基因表达并调节信号通路， 促进溶血。我们的总体目标是确定感染过程中细胞外囊泡驱动溶血的机制， SCD，使用Babeland作为我们的模型。假设：婴儿贫血在SCD中被夸大，因为EV加速a） 旁观者RBC破坏和B）由于SCD对1） EV介导的改变和旁观者RBC的补体调理作用导致直接/间接溶解2）免疫 3）EV介导的去核抑制 红系祖细胞在SCD BM红细胞生成中的作用。为了深入了解这些分子和细胞过程， 在体内和体外SCD感染模型中，我们将：1）阐明EV摄取介导直接溶血的机制 通过检查EV介导的引起溶血的SCD RBC膜的改变2）阐明EV的机制 通过检查巨噬细胞极化和TLR信号传导途径活化来调节血管外溶血， 评估EV诱导自身抗体的作用和机制，并确定自身抗体的贡献 3）阐明EV摄取的机制， 通过定义EV诱导和感染的潜在分子机制而导致红细胞生成障碍- 诱导SCD骨髓中红系祖细胞的去核缺陷。我们建议的研究将导致一个更好的 了解寄生虫EV在与人类巴贝虫病相关的发病机制中的作用，特别是高 在镰状细胞背景下观察到溶血。我们预计这些研究将导致诊断工具的完善，并提供 对抗人类巴贝斯虫病贫血的新策略。