Effects of Malaria on EBV Persistence in Children

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，儿童时期感染eb病毒（EBV）和反复感染恶性疟原虫疟疾（如全地方性疟疾）是BL病因学的重要组成部分，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在BL中启动B细胞癌发生的事件。本提案的总体目标是继续我们对肯尼亚有地方性BL风险的婴儿中EBV和疟疾相互作用的研究。在我们当前的R01 （CA102667）中，我们跟踪了一组从2个月到36个月大的不同疟疾暴露儿童的前瞻性队列。我们观察到，出生在疟疾全流行地区的儿童首次感染EBV的年龄明显较早，约35%的儿童在6个月大时感染EBV。重要的是，早期感染的儿童保持着慢性病毒载量。这些研究支持了长期以来的假设，即EBV感染的早期是BL的一个危险因素。然而，我们不知道的是，为什么这些婴儿在生命早期感染，以及早期感染如何限制EBV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，即6个月大的婴儿对EBV感染的易感性与胎盘疟疾有关。在生命早期感染的婴儿免疫反应不发达，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细胞的数量增加，这可能最终耗尽对EBV的免疫反应，并增加从潜伏感染的B细胞中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，导致生命早期感染，无法形成有效的EBV免疫。我们将招募在疟疾全面流行的肯尼亚基苏木区丘兰博医院产前诊所就诊的孕妇，建立一个婴儿队列，并对婴儿从出生到两岁进行前瞻性随访。为了验证我们的假设，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抗原致敏的影响；确定婴儿在6个月前对eb病毒易感性的影响因素；确定早期感染eb病毒对eb病毒特异性免疫反应的发展、非典型耗尽记忆B细胞的频率和恶性前B细胞的出现的影响。如果我们的模型被证明是有效的，这意味着预防乙型肝炎的重点应该放在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。

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.