Research to Control and Eliminate Malaria in SE Asia and SW Pacific U19AI089686

描述（由申请人提供）：对高密度寄生虫血症和恶性疟原虫（Pf）和间日疟原虫（Pv）感染的临床疾病的自然获得性免疫（NAI）在儿童时期发展缓慢，在缺乏血液期感染的周期性增强时减弱。血清IgG抗体对这种获得性免疫的发展至关重要。NAI的缓慢获得部分是由于产生持续的疟疾特异性记忆B细胞（MBC）的能力受损，从而导致长寿命的Ab分泌浆细胞（LLPC）产生广泛的疟疾Ags。血分期Pf和Pv可能抑制疟疾MBC和LLPC的产生和维持，因为它们的高银负荷会引发系统性的促炎反应，例如TNF-¿和IFN-y的增加，这些反应最终会下调（可能部分解释了为什么流行地区的许多疟疾感染儿童没有症状）。在目前的提案中，我们研究了这样一种假设，即在很少或没有NAI的个体中，如幼儿和患有疟疾的成年人，反复感染疟疾引起的炎症环境上调了抑制反馈回路，从而损害了MBC和LLPC的产生和维持。这方面研究的一个中心目标是在疟疾感染易感性和简单发病率与产生和维持疟疾ag特异性MBC的能力之间建立联系。我们将评估和比较这些关于Pf和Pv的关系，因为在巴布亚新几内亚（PNG）的类似传播条件下，NAI对Pv的发展比对Pf的发展更快。这些研究将与来自西非和美国国立卫生研究院的合作者一起进行，以确定NAI的这些特征是否在遗传和流行病学上存在差异的人群中普遍存在。虽然免疫调节机制将广泛考虑使用基因微阵列分析已知或可疑的反馈回路，抑制Fc？通过结合疟疾Ag免疫复合物（IC）调节B细胞受体（BCR）激活阈值的RIIB将被特异性评估。我们将在西南太平洋ICEMR批准的IRB协议的支持下，使用巴布亚新几内亚暴露于Pv和Pf的儿童和成人的生物样本和临床/寄生虫数据。该项目的具体目标是：i)将NAI的程度与疟疾ag特异性MBC的频率、广度和持久性相关联；ii)确定急性疟疾引发的免疫调节网络及其与Pf型MBC的关系；（iii）评估FCGR2B功能多态性是否影响NAI和疟疾ag特异性MBC的发展。

DESCRIPTION (provided by applicant): Naturally acquired immunity (NAI) to high-density parasitemia and clinical illness from P. falciparum (Pf) and P. vivax (Pv) infection develops slowly during childhood and wanes in the absence of periodic boosting from blood stage infection. Serum IgG antibodies are critical for development of this acquired immunity. The slow acquisition of NAI arises, in part, from an impaired ability to generate persisting malaria-specifi memory B cells (MBC) and resulting long-lived Ab secreting plasma cells (LLPC) to a broad repertoire malaria Ags. Blood stage Pf and Pv may suppress generation and maintenance of malaria MBC and LLPC by virtue of their high Ag loads that elicit systemic pro-inflammatory responses, e.g. increased TNF-¿, IFN-y which are eventually down-regulated (possibly explaining, in part, why many malaria infected children in endemic areas are asymptomatic). In the current proposal, we examine the hypothesis that the inflammatory milieu elicited by repeated malaria infections among individuals with little or no NAI, e.g. young children and malaria na¿ve adults, upregulates potent inhibitory feedback loops that impair generation and maintenance of MBC and LLPC. A central goal of research here is to establish a link between susceptibility to malaria infection and uncomplicated morbidity and the ability to generate and sustain malaria Ag-specific MBC. We will evaluate and compare these relationships with respect Pf and Pv since NAI to Pv develops more rapidly than to Pf under conditions of similar transmission in Papua New Guinea (PNG). The studies will be performed with collaborators from West Africa and NIH in order to determine whether these features of NAI are generalized across populations that diverge genetically and epidemiologically. While immune regulatory mechanisms will be considered broadly using gene microarray analysis of known or suspected feedback loops, inhibitory Fc?RIIB that regulates the B cell receptor (BCR) activation threshold by binding malaria Ag immune complexes (IC) will be evaluated specifically. We will use biological samples and clinical/parasite data from children and adults exposed to Pv and Pf in PNG under the auspices of approved IRB protocols of the SW Pacific ICEMR. The specific objective of the project are: i) Correlate the degree of NAI with malaria Ag-specific MBC frequency, breadth and durability; ii) Determine the immunoregulatory networks elicited by acute malaria and their relation to generation Pf MBC; (iii) Assess whether FCGR2B functional polymorphisms impact NAI and malaria Ag-specific MBC development.