Kruppel-Like Factor 2 Counters Vascular and Immunologic Dysfunction in Child Cerebral Malaria

Kruppel 样因子 2 可对抗儿童脑型疟疾的血管和免疫功能障碍

• 批准号: 10084256
• 负责人: James Walter Kazura
• 金额: $ 57.65万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084256
• 关键词: Adhesions; Africa; Anti-Inflammatory Agents; Antigen-Antibody Complex; Area; Binding; Binding Proteins; Blood Vessels; Bortezomib; Brain; Cell Line; Cell Lineage; Cell physiology; Cerebral Malaria; Cerebrum; Child; Clinical; Coagulation Process; Complex; Cysteine; Data; Development; Disease; Endothelial Cells; Endothelium; Enrollment; Erythrocyte Membrane; Erythrocytes; Exposure to; Falciparum Malaria; Family; Fever; Flow Cytometry; Functional disorder; Gene Expression; Genetic Transcription; Goals; Head; Health; Histones; Human; Immune; Immune System Diseases; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Laboratories; Life; Ligand Binding; Link; Malaria; Mediating; Membrane Proteins; Messenger RNA; Myelogenous; Myeloid Cells; Nodal; Observational Study; Parasitemia; Parasites; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Permeability; Persons; Phenotype; Plasmodium falciparum; Plasmodium falciparum erythrocyte membrane protein 1; Property; Proteasome Inhibitor; Protein C; Protein Export Pathway; Proteins; Recombinant Proteins; Regulation; Research; Rheumatoid Arthritis; Role; Structure; Surface; Symptoms; TLR2 gene; Tertiary Protein Structure; Testing; Thromboplastin; Up-Regulation; Vascular Diseases; Vascular Endothelium; Virulence; activated Protein C; brain endothelial cell; cytokine; experience; extracellular; knock-down; member; monocyte; mortality; overexpression; prospective; systemic inflammatory response; vascular inflammation

Plasmodium falciparum (Pf) infected erythrocytes can activate endothelial and other myeloid cells, culminating in systemic inflammation and vascular dysfunction that underlie the pathogenesis of cerebral malaria. A subset of the polymorphic Pf Erythrocyte Membrane Protein 1 (PfEMP1) family, a virulence protein exported from the intracellular parasite to the infected erythrocyte surface, is overrepresented in persons with cerebral malaria, who also have elevated levels of circulating immune complexes that can modify endothelial and monocyte function. Members of the Kruppel-like family of factors (KLF) are nodal regulators of endothelial and immune cell function. KLF2 confers an anti-inflammatory, anti-thrombotic, and anti- permeable phenotype to endothelial and myeloid cells by a common mechanism centered on inhibition of NFκB, a key transcriptional inducer of pro-inflammatory activation. However, a causal link between malaria pathogenesis and KLF2 regulation, brain endothelial cell and monocyte function, and malaria elicited immune complexes has not been established. Our central hypothesis is that regulation of KLF2 levels in endothelial and myeloid cells is critical for the pathogenesis of vascular and monocyte dysfunction in cerebral malaria, and that this myeloid cell dysfunction results from interactions with infected erythrocytes expressing specific PfEMP1s and Pf elicited immune complexes. To test this hypothesis, we will enroll Kenyan children presenting with cerebral and uncomplicated malaria and follow them for 6 months. We will examine 1) the impact of PfEMP1 and patient parasite isolates on endothelial KLF2 and NFκB expression, 2) patient monocyte phenotype, function, KLF2 expression, and in vitro monocyte function impacted by PfEMP1 and patient parasite isolates, and 3) the role of immune complexes in vascular endothelial and monocyte dysfunction isolated from children with cerebral and uncomplicated malaria. Research proposed here will inform the rational development of adjunct therapies aimed at reducing vascular dysfunction, mortality and long- term clinical sequela of cerebral malaria by enhancing endogenous cytoprotective pathways of endothelial/myeloid lineage cells.

恶性疟原虫（Pf）感染的红细胞可激活内皮细胞和其他髓系细胞， 细胞，最终导致全身炎症和血管功能障碍， 脑型疟疾的发病机制。多态性Pf红细胞膜蛋白亚类 1（PfEMP 1）家族，一种从细胞内寄生虫输出到感染的 红细胞表面，在脑型疟疾患者中比例过高， 循环免疫复合物水平升高，可改变内皮细胞和单核细胞 功能Kruppel样因子家族（KLF）成员是内皮细胞生长因子的节点调节因子， 和免疫细胞功能。KLF 2具有抗炎、抗血栓形成和抗肿瘤作用。 内皮细胞和髓样细胞的渗透表型，其共同机制集中于 抑制NFκB，一种促炎活化的关键转录诱导物。但 疟疾发病机制与KLF 2调节、脑内皮细胞和 单核细胞功能和疟疾引起的免疫复合物尚未建立。我们 中心假设是内皮细胞和髓样细胞中KLF 2水平的调节对于 脑型疟疾中血管和单核细胞功能障碍的发病机制， 骨髓细胞功能障碍是由于与表达特异性 PfEMP 1 s和Pf引起免疫复合物。为了验证这一假设，我们将招募肯尼亚 患有脑型和无并发症疟疾的儿童，并对他们进行6个月的随访。我们 将检查1）PfEMP 1和患者寄生虫分离株对内皮KLF 2的影响， NFκB表达，2）患者单核细胞表型、功能、KLF 2表达和体外 单核细胞功能受PfEMP 1和患者寄生虫分离株的影响，以及3）免疫调节剂的作用 血管内皮细胞和单核细胞功能障碍的复合物， 脑型和单纯型疟疾。这里提出的研究将告知理性的 开发辅助疗法，旨在减少血管功能障碍、死亡率和长期 通过增强内源性细胞保护途径治疗脑型疟疾的远期临床后遗症 内皮/髓系细胞。

项目成果

Adaptive interventions for optimizing malaria control: an implementation study protocol for a block-cluster randomized, sequential multiple assignment trial.

优化疟疾控制的适应性干预措施：分组随机、序贯多重分配试验的实施研究方案。

• DOI: 10.1186/s13063-020-04573-y
• 发表时间: 2020
• 期刊: Trials
• 影响因子: 2.5
• 作者: Zhou,Guofa;Lee,Ming-Chieh;Atieli,HarrysoneE;Githure,JohnI;Githeko,AndrewK;Kazura,JamesW;Yan,Guiyun
• 通讯作者: Yan,Guiyun

Spatial-temporal heterogeneity in malaria receptivity is best estimated by vector biting rates in areas nearing elimination.

• DOI: 10.1186/s13071-018-3201-1
• 发表时间: 2018-11-27
• 期刊: Parasites & vectors
• 影响因子: 3.2
• 作者: Burkot TR;Bugoro H;Apairamo A;Cooper RD;Echeverry DF;Odabasi D;Beebe NW;Makuru V;Xiao H;Davidson JR;Deason NA;Reuben H;Kazura JW;Collins FH;Lobo NF;Russell TL
• 通讯作者: Russell TL

Increased investment in gametocytes in asymptomatic Plasmodium falciparum infections in the wet season.

• DOI: 10.1186/s12879-020-05761-6
• 发表时间: 2021-01-09
• 期刊: BMC infectious diseases
• 影响因子: 3.7
• 作者: Oduma CO;Ogolla S;Atieli H;Ondigo BN;Lee MC;Githeko AK;Dent AE;Kazura JW;Yan G;Koepfli C
• 通讯作者: Koepfli C