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）-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，最终是致命的。虽然有一个共识，即感染EB病毒（EBV）和反复感染恶性疟原虫疟疾在儿童期（如全地方性疟疾）是BL的病因学的重要组成部分，疟疾和EBV的相互作用，增加地方性BL的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。这项建议的总体目标是继续我们的调查EB病毒和疟疾的相互作用在肯尼亚婴儿的地方性BL的风险。在我们目前的R 01（CA 102667）中，我们随访了一组年龄从2个月到36个月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个月大时感染。重要的是，在生命早期感染的儿童保持了慢性病毒载量。这些研究支持了长期以来的假设，即早期EBV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对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，即婴儿在6个月大时感染EBV的易感性与胎盘疟疾有关。婴儿在生命早期感染，而他们的免疫反应不发达，将有病毒的免疫控制差。免疫控制不良的长期后果是大量潜伏感染的细胞，这最终会耗尽针对EB病毒的免疫反应，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，胎盘型疟疾改变了婴儿控制原发性EBV感染的能力，导致生命早期感染和未能产生有效的EBV免疫力。我们将通过招募在疟疾全流行的肯尼亚基苏穆区Chulaimbo医院产前门诊就诊的孕妇来建立婴儿队列，并前瞻性地随访婴儿从出生到两岁。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;确定了影响6个月龄婴儿对EBV易感性的因素;确定早期EBV感染对EBV特异性免疫应答的发展、非典型耗竭记忆B细胞的频率的影响，以及癌前B细胞的出现。如果我们的模型被证明是有效的，那么BL的预防应该集中在通过关注患有胎盘疟疾的孕妇来延迟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，是一种快速生长的B细胞恶性肿瘤，如果不治疗，最终是致命的。这项研究所获得的知识将提高地方性BL的病因学的理解，这将最终允许旨在预防BL的方案的设计。

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.