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）：流行的伯基特淋巴瘤（BL） - 赤道非洲最普遍的儿童癌症 - 是一种快速增长的B细胞恶性肿瘤，最终是致命的，即使没有治疗。尽管在儿童期在儿童期感染了爱泼斯坦 - 巴尔病毒（EBV）并反复感染了疟疾疟疾疟原虫（例如全肺疟疾）是BL的病因中的必不可少的组成部分，但在疟疾和EBV相互作用的机理中，会增加疟疾相互作用的风险，这是幼年的必要成分。我们研究的长期目标是确定在BL中引发B细胞肿瘤发生的事件。该提案的总体目的是继续我们对肯尼亚婴儿的EBV和疟疾相互作用的调查。在我们目前的R01（CA102667）中，我们跟踪了从2个月到36个月大的疟疾暴露不足的儿童。我们观察到，在疟疾疟疾地区出生的儿童患有EBV的原发性感染年龄较早，约35％感染了6个月大。重要的是，在生命早期感染的儿童维持了慢性病毒负荷。这些研究支持了以下长期的假设：EBV感染的早期是BL的危险因素。但是，我们不知道的是，为什么这些婴儿在生命的早期就被感染以及感染的早期限制EBV的控制。根据我们的数据和他人的数据，我们提出了一个模型，该模型将婴儿在6个月大时对EBV感染的敏感性与胎盘疟疾有关。婴儿在生命早期感染了免疫反应较低的婴儿对病毒的免疫控制不良。不良免疫控制的长期后果是更多的潜在感染细胞，这些细胞最终会耗尽针对EBV的免疫反应，并增加恶性克隆从潜在受感染的B细胞中出现的风险。我们的核心假设是，胎盘疟疾改变了婴儿控制原发性EBV感染的能力，从而导致生命早期感染和未能发展有效的EBV免疫力。我们将通过在肯尼亚Kisumu区的Chulaimbo医院参加产前诊所的孕妇来建立一个婴儿队列，那里的疟疾是全神病学的，从出生到第二天生日，前瞻性地跟随婴儿。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的影响以及对EBV抗原的子宫敏化；确定影响婴儿在6个月大的EBV敏感性的因素；确定EBV感染的幼年对EBV特异性免疫反应的发展，非典型耗尽的记忆B细胞的频率以及预防性B细胞的出现。如果我们的模型被证明有效，则意味着预防BL应该专注于通过专注于胎盘疟疾的孕妇或阻止对婴儿的传播来延迟EBV感染的年龄。 公共卫生相关性：流行的伯基特淋巴瘤（BL）是赤道非洲最普遍的儿童癌症，是一种迅速增长的B细胞恶性肿瘤，如果未经治疗，最终将致命。这项研究获得的知识将提高人们对流行BL的病因的理解，这最终将允许设计旨在预防BL的程序。