Plasmodium Falciparum Infection and Interference with Effective B Cell Memory

恶性疟原虫感染和对有效 B 细胞记忆的干扰

• 批准号: 8851512
• 负责人: Bryan R Greenhouse
• 金额: $ 19.81万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8851512
• 关键词: Acute; Affinity; Antibodies; Antibody Affinity; Antibody Response; Antigens; Antimalarials; Area; Avidity; B-Lymphocytes; Binding; Blood; Cells; Cessation of life; Chemoprevention; Child; Clinical; Data; Defect; Development; Disease; Exhibits; Exposure to; Falciparum Malaria; Flow Cytometry; Frequencies; HIV; Health; Household; Humoral Immunities; Immune system; Immunity; Immunoglobulin-Secreting Cells; Immunologics; Individual; Infection; Intervention; Label; Laboratories; Lead; Life; Maintenance; Malaria; Measures; Memory; Memory B-Lymphocyte; Methods; Microscopy; Morbidity - disease rate; Outcome; Parasitemia; Parasites; Phenotype; Plasmodium falciparum; Positioning Attribute; Receptors, Antigen, B-Cell; Research Infrastructure; Sampling; Serological; Site; Specificity; Staging; Surface; Testing; Time; Uganda; acquired immunity; base; cohort; density; design; experience; malaria transmission; mortality; pathogen; peripheral blood; premature; prevent; response; transmission process; vaccine-induced immunity

DESCRIPTION (provided by applicant): Naturally acquired immunity is critical in modulating morbidity and mortality from falciparum malaria in endemic areas, where some individuals are infected hundreds of times per year. Humoral responses to Plasmodium falciparum (Pf) are a critical component of this immunity, and Pf-specific memory B cells (MBCs) are likely important in the development and maintenance of an effective response. Unfortunately, protection from clinical disease takes many years to develop, during which time children living in endemic areas experience multiple episodes of symptomatic malaria, resulting in over 1 million deaths annually. Why does antimalarial immunity develop so slowly? One potential explanation is that Pf infection interferes with the development of effective B cell memory. An atypical phenotype of MBC, exhibiting evidence for lower affinity maturation and less capacity for differentiation into antibody secreting cells, has recently been described in the blood of HIV infected subjects. Recent studies have demonstrated that people living in malaria endemic areas have elevated frequencies of similar atypical MBCs, but the relationship between Pf exposure and frequencies of atypical MBCs has not been investigated in detail. Moreover, it is unclear what the consequences of these cells are in malaria infected individuals. We hypothesize that frequent exposure to Pf results in the selective diversion of Pf-specific B cells into an atypical MBC phenotype, delaying the acquisition of protective immunity to Pf. We are in a unique position to test this hypothesis, with access to a well characterized cohort of subjects living in an area of high but heterogeneous malaria transmission intensity and established laboratory infrastructure. Pf transmission intensity at our site in Tororo, Uganda ranks among the highest in the world, and preliminary data from this site suggest that affinity of Pf-specific antibody responses may be compromised in this setting. We will test our hypothesis with the following Specific Aims: 1) To measure the association between Pf exposure and enrichment of atypical memory B cells in children living in a high transmission region of Uganda.; and 2) To measure the association between enrichment of atypical memory B cells and serological and parasitological evidence of protective humoral immunity to malaria. We anticipate this study will show that increased exposure to Pf is associated with increased defects in B cell memory, characterized by higher proportions of Pf-specific MBCs showing an atypical phenotype and evidence of reduced Pf-specific antibody affinity and ability to control blood stage parasites. If so, counter to prevailig notions that malaria control efforts will delay the acquisition of immunity, strategies designed to reduce exposure may have a positive impact on immunity. In addition, methods to characterize Pf-specific B cells developed in this study will have broad application for investigating humoral immunity to Pf.

描述（由申请人提供）：自然获得的免疫力对于调节流行地区恶性疟疾的发病率和死亡率至关重要，那里有些人每年被感染数百次。对恶性疟原虫（PF）的体液反应是这种免疫力的关键组成部分，而PF特异性记忆B细胞（MBC）可能在开发和维持有效反应中很重要。不幸的是，免受临床疾病的保护需要多年的发展，在此期间，生活在地方性地区的儿童经历了多次症状性疟疾，每年导致超过100万人死亡。为什么抗疟疾的免疫力如此缓慢？一种潜在的解释是，PF感染会干扰有效B细胞记忆的发展。最近在HIV感染受试者的血液中描述了MBC的非典型表型，该表型表现出较低的亲和力成熟和较少分化为抗体分泌细胞的能力的证据。最近的研究表明，居住在疟疾地区的人们的频率升高了相似的非典型MBC，但是尚未详细研究PF暴露与非典型MBC的频率之间的关系。此外，尚不清楚这些细胞在受疟疾感染的个体中的后果。我们假设频繁暴露于PF会导致PF特异性B细胞的选择性转移成非典型的MBC表型，从而延迟了对PF的保护性免疫的获取。我们处于检验这一假设的独特位置，访问居住在高但异质的疟疾传播强度和已建立的实验室基础设施领域的受试者的众多受试者中。乌干达的PF传播强度在世界上排名最高，该站点的初步数据表明，在这种情况下，PF特异性抗体反应的亲和力可能会受到损害。我们将以以下特定目的检验我们的假设：1）在乌干达高传播地区的儿童中，PF暴露与非典型记忆B细胞的富集之间的关联。 2）衡量非典型记忆B细胞富集与保护性体液对疟疾的富集之间的关联。我们预计这项研究将表明，对PF的接触增加与B细胞记忆中的缺陷增加有关，其特征是较高比例的PF特异性MBC，表现出非典型表型，以及PF特异性抗体亲和力降低的证据和控制血液阶段寄生虫的能力。如果是这样，请与盛行的观念相反，即疟疾控制努力将延迟获得免疫的获得，旨在的策略 减少暴露可能会对免疫产生积极影响。此外，在本研究中开发的PF特异性B细胞表征的方法将在研究对PF的体液免疫力方面具有广泛的应用。