Effects of Malaria on EBV Persistence in Children

描述(申请人提供)：地方性Burkitt淋巴瘤(EBL)是赤道非洲最常见的儿童癌症。有两个辅助因素与这一儿童癌症的病因有关：EB病毒(EBV)感染，以及持续和强烈暴露于恶性疟原虫疟疾(全地方性疟疾)。虽然有大量的流行病学数据证实EBV和恶性疟原虫都是EBL出现所必需的共同致癌物，但这些病原体相互作用的机制及其在这种恶性肿瘤的病因学中的独特作用仍不清楚。在这个应用中，我们将检验三个相互关联的假设：1)在初次EBV感染之前感染恶性疟原虫的儿童会有更高的病毒载量，病毒载量的增加会发生在整个婴幼儿和幼儿时期，并且病毒载量的增加与疟疾的暴露频率和强度有关；2)在婴幼儿和幼儿时期反复感染恶性疟原虫会导致丧失一种已有的EBV特异性抗病毒CD8+T细胞反应；3)在婴幼儿和幼儿时期反复感染恶性疟原虫会导致外周B细胞池的扩大，并出现恶性前B细胞表型。我们将在一项对1个月至3岁儿童的纵向研究中，确定恶性疟原虫感染如何调节EBV免疫和持久性，以检验这些假设。为了检验疟疾暴露的影响，将对居住在肯尼亚西部的两组暴露于疟疾的不同(如全流行和散发性)儿童进行比较，以实现本研究的目标，这些目标是：1)确定EBV和恶性疟原虫感染的年龄，并确定反复感染恶性疟原虫对EBV感染的建立和维持的影响；2)确定不同疟疾暴露的儿童的EBV特异性CD8+T细胞反应；3)确定全流行疟疾对儿童B细胞亚群和体内平衡的影响。

DESCRIPTION (provided by applicant): Endemic Burkitt's lymphoma (eBL) is the most common childhood cancer in Equatorial Africa. Two cofactors are linked to the etiology of this pediatric cancer: Epstein-Barr virus (EBV) infection, and sustained and intense exposure to Plasmodium falciparum malaria (holoendemic malaria). While there is a wealth of epidemiologic data establishing both EBV and P. falciparum as co-carcinogens necessary for the emergence of eBL, the mechanisms by which these pathogens interact and their unique roles in the etiology of this malignancy remain unknown. In this application, we will test three inter-related hypotheses: 1) children infected with P. falciparum before primary EBV infection will have a higher viral load and increases in viral load will occur throughout infancy and early childhood and correlate with the frequency and intensity of malaria exposure; 2) repeated P. falciparum infections throughout infancy and early childhood results in the loss of an established EBV-specific anti-viral CD8+ T cell response and 3) repeated P. falciparum infections throughout infancy and early childhood result in the expansion of the peripheral B cell pool and the emergence of a pre-malignant BL B-cell phenotype. We will test these hypotheses by determining how P. falciparum infections modulate EBV immunity and persistence in a longitudinal study of children followed from 1 month through 3 years of age. To examine the effects of malaria exposure, two populations of children with divergent exposures to malaria (e.g. holoendemic and sporadic) living in Western Kenya will be compared to achieve the objectives of this study which are: 1) to identify the age of EBV and P. falciparum infections, and determine the effects of repeated P. falciparum infections on the establishment and maintenance of EBV infection; 2) to determine the EBV-specific CD8+ T cell response of children with divergent malaria exposures and 3) to determine the influence of holoendemic malaria on blood B cell subpopulations and homeostasis in children.