Effects of Malaria on EBV Persistence in Children

疟疾对儿童 EBV 持久性的影响

• 批准号: 7986999
• 负责人: ROSEMARY ROCHFORD
• 金额: $ 31.17万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7986999
• 关键词: Address; Affect; Africa; African Burkitt' s lymphoma; Age; Age-Months; B lymphoid malignancy; B-Lymphocytes; Birth; Burkitt Lymphoma; Cells; Child; Childhood; Chronic; Clinic; Clinical; Consensus; Data; Development; Employee Strikes; Enrollment; Epstein-Barr Virus Infections; Etiology; Event; Failure; Falciparum Malaria; Fetus; Frequencies; Goals; Hospitals; Human Herpesvirus 4; Immune response; Immunity; Immunoglobulin G; Immunologics; Infant; Infection; Investigation; Kenya; Knowledge; Life; Link; Malaria; Malignant - descriptor; Malignant Childhood Neoplasm; Maternal and Child Health; Maternal antibody; Memory B-Lymphocyte; Modeling; Pattern; Population; Predisposing Factor; Predisposition; Pregnant Women; Premalignant; Prevention; Prevention program; Research; Risk; Risk Factors; Testing; Viral Antigens; Viral Load result; Virus; adaptive immunity; base; cohort; design; exhaust; improved; in utero; infancy; infected B cell; neutralizing antibody; programs; prospective; public health relevance; transmission process; tumorigenesis

DESCRIPTION (provided by applicant): Endemic Burkitt's lymphoma (BL)-the most prevalent childhood cancer in Equatorial Africa-is a rapidly growing B-cell malignancy that is ultimately fatal if untreated. While there is a consensus that infection with Epstein-Barr virus (EBV) and repeated infections with Plasmodium falciparum malaria in childhood (e.g. holoendemic malaria) are essential components in the etiology of BL, the mechanisms of malaria and EBV interactions that increase the risk for endemic BL remain to be elucidated. The long-term goal of our research is to identify the events that initiate B cell oncogenesis in BL. The overall objective of this proposal is to continue our investigations of EBV and malaria interactions in Kenyan infants at risk for endemic BL. In our current R01 (CA102667), we followed a prospective cohort of children with divergent malaria exposures from 2 months through 36 months of age. We observed that children born in the malaria holoendemic region had a significantly earlier age of primary infection with EBV, with ~35% infected by 6 months of age. Importantly, children infected early in life maintained a chronic viral load. These studies support the long-held hypothesis that early age of EBV infection is a risk factor for BL. What we do not know however, is why these infants are infected early in life and how early age of infection limits control of EBV. Based on our data and the data of others, we propose a model whereby susceptibility of infants to infection with EBV by 6 months of age is linked to placental malaria. Infants infected early in life while they have under-developed immune responses will have poor immunologic control of the virus. The long term consequences of poor immunologic control is a greater number of latently infected cells which can ultimately exhaust the immune response against EBV and increase the risk for a malignant clone to emerge from the latently infected B cell. Our central hypothesis is that placental malaria alters an infants ability to control primary EBV infection resulting in infection earlier in life and failure to develop effective EBV immunity. We will establish an infant cohort by enrolling pregnant women attending an antenatal clinic at Chulaimbo Hospital in Kisumu District, Kenya where malaria is holoendemic, and follow infants prospectively from birth to their second birthday. To test our hypothesis, we determine the effects of placental malaria on transfer of maternal EBV-specific neutralizing antibodies and in utero sensitization to EBV antigens; determine the factors influencing susceptibility of infants to EBV by 6 months of age; determine the effects of early age of EBV infection on the development of EBV-specific immune responses, the frequency of atypical exhausted memory B cells, and the emergence of pre-malignant B cells. If our model proves valid, the implications are that prevention of BL should focus on delaying the age of EBV infection by focusing on pregnant women with placental malaria, or on blocking transmission to infants. PUBLIC HEALTH RELEVANCE: Endemic Burkitt's lymphoma (BL), the most prevalent childhood cancer in Equatorial Africa, is a rapidly growing B-cell malignancy that is ultimately fatal if untreated. The knowledge gained by this study will improve the understanding of the etiology of endemic BL which will ultimately allow for the design of programs aimed at the prevention of BL.

描述（由申请人提供）：地方性伯基特淋巴瘤（BL）是赤道非洲最常见的儿童癌症，是一种快速生长的 B 细胞恶性肿瘤，如果不治疗，最终会致命。虽然人们一致认为，儿童期感染 Epstein-Barr 病毒 (EBV) 和反复感染恶性疟原虫疟疾（例如全地方性疟疾）是 BL 病因的重要组成部分，但疟疾和 EBV 相互作用增加地方性 BL 风险的机制仍有待阐明。我们研究的长期目标是确定 BL 中启动 B 细胞肿瘤发生的事件。该提案的总体目标是继续调查有地方性 BL 风险的肯尼亚婴儿中 EB 病毒和疟疾的相互作用。在我们当前的 R01 (CA102667) 中，我们对一组 2 个月至 36 个月期间接触过不同疟疾的儿童进行了前瞻性队列研究。我们观察到，出生在疟疾肆虐地区的儿童初次感染 EBV 的年龄明显较早，约 35% 的儿童在 6 个月大时就被感染。重要的是，生命早期感染的儿童维持着慢性病毒载量。这些研究支持了长期以来的假设，即早期 EB 病毒感染是 BL 的危险因素。然而，我们不知道的是为什么这些婴儿在生命早期就被感染，以及早期感染如何限制 EB 病毒的控制。根据我们的数据和其他人的数据，我们提出了一个模型，根据该模型，6 个月大的婴儿对 EBV 感染的易感性与胎盘疟疾相关。婴儿在生命早期被感染，而他们的免疫反应尚未发育成熟，因此对病毒的免疫控制能力较差。免疫控制不良的长期后果是潜伏感染的细胞数量增多，最终会耗尽针对 EBV 的免疫反应，并增加潜伏感染的 B 细胞出现恶性克隆的风险。我们的中心假设是胎盘疟疾改变了婴儿控制原发性 EBV 感染的能力，导致婴儿早期感染并无法形成有效的 EBV 免疫力。我们将招募在疟疾肆虐的肯尼亚基苏木区楚莱姆博医院产前诊所就诊的孕妇建立婴儿队列，并对婴儿从出生到两岁生日进行前瞻性跟踪。为了检验我们的假设，我们确定了胎盘疟疾对母体 EBV 特异性中和抗体转移和子宫内对 EBV 抗原敏感的影响；确定影响 6 个月大婴儿对 EBV 易感性的因素；确定早期 EBV 感染对 EBV 特异性免疫反应的发展、非典型耗竭记忆 B 细胞的频率以及癌前 B 细胞出现的影响。如果我们的模型被证明是有效的，那么这意味着 BL 的预防应该集中于通过关注患有胎盘疟疾的孕妇来推迟 EBV 感染的年龄，或者阻止传播给婴儿。 公共卫生相关性：地方性伯基特淋巴瘤 (BL) 是赤道非洲最常见的儿童癌症，是一种快速增长的 B 细胞恶性肿瘤，如果不治疗，最终会致命。本研究获得的知识将增进对地方性 BL 病因学的了解，最终有助于设计旨在预防 BL 的计划。