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恶性疟疾流行地区的发病率和死亡率至关重要，在这些地区，一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的关键组成部分，而 Pf 特异性记忆 B 细胞 (MBC) 可能在有效反应的形成和维持中发挥重要作用。不幸的是，针对临床疾病的保护需要很多年才能形成，在此期间，生活在流行地区的儿童会经历多次有症状的疟疾发作，每年导致超过 100 万人死亡。为什么抗疟免疫力发展得如此缓慢？一种可能的解释是 Pf 感染会干扰有效 B 细胞记忆的发育。最近在 HIV 感染者的血液中描述了 MBC 的非典型表型，其表现出较低的亲和力成熟和较低的分化为抗体分泌细胞的能力。最近的研究表明，生活在疟疾流行地区的人们出现类似非典型 MBC 的频率较高，但 Pf 暴露与非典型 MBC 频率之间的关系尚未得到详细研究。此外，尚不清楚这些细胞对疟疾感染者有何影响。我们假设频繁接触 Pf 会导致 Pf 特异性 B 细胞选择性转向非典型 MBC 表型，从而延迟获得对 Pf 的保护性免疫。我们处于检验这一假设的独特位置，可以接触到生活在疟疾传播强度高但异质性地区的一组特征明确的受试者，并建立完善的实验室基础设施。我们位于乌干达托罗罗的站点的 Pf 传输强度位居世界最高之列，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。我们将通过以下具体目标来检验我们的假设： 1) 测量生活在乌干达高传播地区的儿童中 Pf 暴露与非典型记忆 B 细胞富集之间的关联。 2) 测量非典型记忆 B 细胞的富集与疟疾保护性体液免疫的血清学和寄生虫学证据之间的关联。我们预计这项研究将表明，增加接触 Pf 与 B 细胞记忆缺陷增加相关，其特征是较高比例的 Pf 特异性 MBC 显示非典型表型，以及 Pf 特异性抗体亲和力和控制血期寄生虫能力降低的证据。如果是这样，与疟疾控制工作将延迟获得免疫力的普遍观念相反，旨在 减少接触可能对免疫力产生积极影响。此外，本研究中开发的表征 Pf 特异性 B 细胞的方法将在研究对 Pf 的体液免疫方面具有广泛的应用。