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。有两个辅助因素与这种儿童癌症的病因有关：EB 病毒 (EBV) 感染和持续、强烈接触恶性疟原虫疟疾（全地方性疟疾）。虽然有大量流行病学数据证实 EBV 和恶性疟原虫是 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病因学中的独特作用仍然未知。在此应用中，我们将测试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发生在整个婴儿期和幼儿期，并且与疟疾暴露的频率和强度相关； 2) 整个婴儿期和幼儿期重复的恶性疟原虫感染导致已建立的 EBV 特异性抗病毒 CD8+ T 细胞反应丧失，3) 整个婴儿期和幼儿期重复的恶性疟原虫感染导致外周 B 细胞池扩张和出现癌前 BL B 细胞表型。我们将通过对 1 个月至 3 岁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，从而检验这些假设。为了检查疟疾暴露的影响，将对居住在肯尼亚西部的两个不同疟疾暴露（例如全流行和散发）儿童群体进行比较，以实现本研究的目标：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 感染建立和维持的影响； 2) 确定不同疟疾暴露儿童的 EBV 特异性 CD8+ T 细胞反应，以及 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。