Effects of Malaria on EBV Persistence in Children

描述(申请人提供)：地方性Burkitt淋巴瘤(BL)-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，最终将是致命的。虽然目前已达成共识，儿童时期感染EB病毒(EBV)和反复感染恶性疟原虫(如全地方性疟疾)是BL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细胞肿瘤发生的事件。这项建议的总体目标是继续我们对EB病毒和疟疾相互作用的调查，这些婴儿有患地方性白血病的风险。在我们目前的R01(CA102667)中，我们跟踪了从2个月到36个月大的不同疟疾暴露儿童的预期队列。我们观察到，出生在疟疾全流行区的儿童首次感染EBV的年龄明显较早，约35%的儿童在6个月大时感染。重要的是，早期感染的儿童保持着长期的病毒载量。这些研究支持了长期以来的假设，即EBV感染的早期年龄是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被感染，以及感染早期如何限制EBV的控制。基于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个月大时对EBV感染的易感性与胎盘性疟疾有关。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。免疫控制不佳的长期后果是更多的潜伏感染细胞，这些细胞最终会耗尽对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性疟疾改变了婴儿控制原发EBV感染的能力，导致婴儿在生命早期感染，并无法形成有效的EBV免疫。我们将建立一个婴儿队列，招募到肯尼亚基苏木区Chulaimbo医院产前诊所就诊的孕妇，并前瞻性跟踪婴儿从出生到两岁的情况。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对EBV抗原的宫内致敏的影响；确定了6个月大婴儿对EBV易感性的影响因素；确定了EBV感染早期对EBV特异性免疫反应发展的影响；非典型耗尽记忆B细胞的频率，以及癌前B细胞的出现。如果我们的模型被证明是有效的，其含义是，预防BL应该专注于通过关注患有胎盘性疟疾的孕妇来推迟EBV感染的年龄，或者阻止向婴儿的传播。 公共卫生相关性：地方性Burkitt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，最终将是致命的。通过这项研究获得的知识将提高对地方性白血病病因学的理解，最终将允许设计旨在预防白血病的方案。

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.