Plasmodium Falciparum Infection and Interference with Effective B Cell Memory

描述（由申请人提供）：在疟疾流行地区，自然获得性免疫对于调节恶性疟疾的发病率和死亡率至关重要，在这些地区，有些人每年感染数百次。对恶性疟原虫（Pf）的体液应答是这种免疫的关键组成部分，而Pf特异性记忆B细胞（MBCs）可能在形成和维持有效应答中发挥重要作用。不幸的是，预防临床疾病需要多年时间才能形成，在此期间，生活在流行地区的儿童会多次出现有症状的疟疾，每年造成100多万人死亡。为什么抗疟疾免疫的发展如此缓慢？一种可能的解释是，Pf感染干扰了有效B细胞记忆的发展。最近在HIV感染者的血液中描述了MBC的非典型表型，显示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出现类似非典型结核杆菌的频率较高，但尚未详细调查Pf暴露与非典型结核杆菌频率之间的关系。此外，目前还不清楚这些细胞对疟疾感染者的影响。我们假设，频繁暴露于Pf会导致Pf特异性B细胞选择性转向非典型MBC表型，延迟对Pf的保护性免疫的获得。我们处于一个独特的位置来验证这一假设，我们获得了一个生活在高但异质性疟疾传播强度地区的具有良好特征的受试者队列，并建立了实验室基础设施。我们在乌干达Tororo的站点的Pf传播强度是世界上最高的，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细胞富集之间的关系；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系。我们预计这项研究将表明，暴露于Pf的增加与B细胞记忆缺陷的增加有关，其特征是Pf特异性MBCs的比例更高，表现出非典型表型，并且有证据表明Pf特异性抗体亲和力降低，控制血期寄生虫的能力降低。如果是这样，与疟疾控制努力将推迟获得免疫的普遍观念相反，旨在

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.