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

描述(由申请人提供)：对恶性疟原虫(PF)和间日疟原虫(PV)感染引起的高密度寄生虫病和临床疾病的自然获得性免疫(NAI)在儿童时期发展缓慢，在没有血液期感染的周期性增强的情况下逐渐减弱。血清中的免疫球蛋白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久的疟疾特异性记忆B细胞(MBC)的能力受损，以及由此导致的长寿命抗体分泌浆细胞(LLPC)到广泛的疟疾AGS。血液阶段的PF和PV可能会抑制疟疾MBC和LLPC的产生和维持，这是因为它们的高Ag负荷引发了全身性促炎反应，例如升高的肿瘤坏死因子-β、干扰素-γ，这些最终被下调(可能部分解释了为什么流行区许多感染疟疾的儿童没有症状)。在当前的建议中，我们检验了一种假设，即在NAI很少或没有NAI的个人中，例如幼儿和初治疟疾的成年人，反复感染疟疾所引发的炎症环境向上上调了有效的抑制反馈环，从而损害了MBC和LLPC的生成和维持。这里研究的一个中心目标是在疟疾感染的易感性和简单的发病率以及产生和维持疟疾抗原特异性微核细胞的能力之间建立联系。我们将评估和比较这些关系与PF和PV的关系，因为在巴布亚新几内亚(PNG)类似的传播条件下，NAI到PV的发展速度比PF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分歧的人群中普遍存在。虽然免疫调节机制将被广泛地利用已知或可疑反馈环的基因芯片分析来考虑，但通过结合疟疾抗原免疫复合体(IC)来调节B细胞受体(BCR)激活阈值的抑制性Fc？RIIb将被具体评估。我们将在西南太平洋ICEMR批准的IRB协议的支持下，使用在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 MBC生成的关系；(Iii)评估FCGR2B功能多态是否影响NAI和疟疾Ag特异性MBC的发育。

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.