Effects of Malaria on EBV Persistence in Children

疟疾对儿童 EBV 持久性的影响

• 批准号: 7090089
• 负责人: ROSEMARY ROCHFORD
• 金额: $ 29.33万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7090089
• 关键词: Africa; Burkitt' s lymphoma; Epstein Barr virus; Plasmodium falciparum; cancer risk; carcinogenesis; cell population study; clinical research; cytotoxic T lymphocyte; disease /disorder etiology; immune response; infant human (0-1 year); longitudinal human study; malaria; microorganism interaction; pediatric neoplasm /cancer; preschool child (1-5); viral carcinogenesis; virus load

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.

描述（由申请人提供）：地方性伯基特淋巴瘤（eBL）是赤道非洲最常见的儿童癌症。两个辅因子与这种儿科癌症的病因有关：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确立EBV和恶性疟原虫作为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病因学中的独特作用仍然未知。在本申请中，我们将检验三个相互关联的假设：1）在原发性EBV感染之前感染恶性疟原虫的儿童将具有较高的病毒载量，并且病毒载量的增加将在整个婴儿期和幼儿期发生，并且与疟疾暴露的频率和强度相关; 2）在整个婴儿期和幼儿期反复的恶性疟原虫感染导致已建立的EBV特异性抗病毒CD 8 + T细胞应答的丧失，以及3）在整个婴儿期和幼儿期反复的恶性疟原虫感染导致外周B细胞库的扩增和恶变前BL B细胞表型的出现。我们将通过一项对1个月至3岁的儿童进行的纵向研究来确定恶性疟原虫感染如何调节EBV免疫力和持久性，从而验证这些假设。为了研究疟疾暴露的影响，两个疟疾暴露不同的儿童群体，本研究的目的是：1）确定EBV和恶性疟原虫感染的年龄，并确定恶性疟原虫重复感染对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CD 8 + T细胞应答和3）确定全地方性疟疾对儿童血液B细胞亚群和体内平衡的影响。