Hemolytic Complications in Babesia Infections

巴贝虫感染的溶血并发症

基本信息

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
项目类别：
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

项目摘要

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 表现出对感染的易感性增加，进而导致 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，尤其是在血液供应不足的欠发达国家。有效筛选。即使在美国，输血传播的病原体也可能是发病率和死亡率的主要威胁。 SCD 接受者的死亡率。 EV 由病原体和宿主细胞响应感染而产生，并作为载体受感染宿主中效应分子异化的载体。溶血和贫血是两种常见症状伴随许多传染病。对于针对红细胞的寄生虫病尤其如此，例如疟疾和巴贝斯虫，这些并发症也见于许多其他感染。虽然目前的提案重点关注巴贝斯虫，但单一病原体，我们认为病原体衍生的 EV 对宿主细胞的影响是许多疾病发病机制中的一个共同主题传染病和这项研究的结果可能对其他传染病引起的溶血并发症有影响代理。 SCD 的溶血并发症是导致这些输血死亡的主要原因传播，因此必须阐明这些感染患者中出现较高程度溶血的原因。来自寄生细胞的 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的溶血机制 SCD，使用巴贝虫作为我们的模型。假设：巴贝虫贫血在 SCD 中被夸大，因为 EV 加速 a) 旁观者红细胞破坏和 b) 由于 SCD 易感性增加而加剧无效红细胞生成 1) EV 介导的旁观者红细胞的改变和补体调理作用导致直接/间接裂解 2) 免疫 EV 激活导致吞噬作用增加并诱导自身抗体 3) EV 介导的去核抑制 SCD BM 红细胞生成中红系祖细胞的影响。为了深入了解这些分子和细胞过程，使用体内和体外 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 EV 介导的 SCD RBC 膜改变导致溶血 2) 阐明 EV 机制通过检查巨噬细胞极化和 TLR 信号通路激活来调节血管外溶血，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旁观者红细胞清除中的调理作用和/或补体固定 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，有助于红细胞生成障碍 - 诱导 SCD 骨髓中红系祖细胞的去核缺陷。我们提出的研究将带来更好的结果了解寄生虫 EV 在人类巴贝虫病（特别是超巴贝虫病）相关发病机制中的作用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虫病贫血的新策略。