Impact of malaria on shaping immunity to EBV in the etiology of Burkitt lymphoma

描述（由申请人提供）：恶性疟原虫疟疾和EB病毒（EBV）之间的综合征相互作用使儿童易患地方性伯基特淋巴瘤（eBL），这是一种EBV相关的B细胞肿瘤，也是赤道非洲最流行的儿科癌症，目前尚不完全清楚。由于原发性EBV感染，反复疟疾感染，并在儿童后期的eBL的介绍之间的时间延长，纵向研究是必要的，以充分了解的累积影响，疟疾对形成T细胞免疫EBV的病因学eBL。因此，该建议旨在测试我们的中心假设，即疟疾对EBV特异性T细胞应答的分化和存活产生不利影响，导致T细胞对EBV的控制丧失，从而为淋巴瘤形成奠定基础。这一假设将通过以下具体目标进行检验。目标1。确定T记忆干细胞（TSCM）的流行是否与儿童中的EBV控制相关，以及从儿童中分离的EBV特异性TSCM是否具有在IL-15和IL-7的指示下扩增的能力。将通过记忆标志物（CD 45 RA/RO、CCR 7、CD 27、CD 127和CD 95）和功能性（IL-2、TNF-？、IFN-？，CD 107 a）在一项回顾性队列研究中，对被归类为EBV控制者或非控制者的具有不同疟疾暴露史的儿童进行了研究。IL-7和IL-15刺激将用于评价TSCM（CD 45 RA+、CCR 7+、CD 27+、CD 95+）的扩增潜力。目标2.评估疟疾相关促炎（IL-12、IL-23、IL-31、IL-33）和调节（IL-27、IL-35、IL-37）细胞因子水平与调节T细胞分化的转录因子表达之间的关系，这些转录因子与儿童EBV控制相关。我们假设疟疾引起的细胞因子环境的变化会影响转录因子（IRF 4，T-bet，Eomes，Bcl 6和TCF 1）的表达，从而影响T细胞的存活。目标3.确定原发性EB病毒感染期间的疟疾合并感染是否对与病毒控制相关的EB病毒特异性T细胞的发育产生负面影响，以及这种表型在反复感染疟疾后是否发生逐渐改变 感染.一项新建立的前瞻性婴儿队列研究将使我们能够捕获原发性EBV感染期间的关键事件，以确定并发和/或累积的疟疾合并感染是否改变细胞因子环境，从而影响EBV特异性T细胞的质量和存活。从研究儿童T细胞记忆和控制T细胞命运的免疫调节微环境中获得的信息将为疟疾何时以及如何改变EBV免疫监视提供新的机制见解。提高对T细胞调节和存活的复杂性的理解，使儿童同时感染EBV和疟疾的风险增加，这将促进这种常见的儿童癌症的预防和治疗策略的发展。

DESCRIPTION (provided by applicant): The syndemic interaction between Plasmodium falciparum malaria and Epstein-Barr virus (EBV) that predispose children to endemic Burkitt lymphoma (eBL), an EBV-associate B cell tumor and the most prevalent pediatric cancer in Equatorial Africa is not completely understood. Due to the prolonged period between primary EBV infection, compounded by repeated malaria infections, and the presentation of eBL later in childhood, longitudinal studies are required in order to fully understand the cumulative impact of malaria on shaping T cell immunity to EBV in the etiology of eBL. Therefore, this proposal aims to test our central hypothesis that malaria adversely influences the differentiation and survival o EBV-specific T cell responses which results in the loss of T cell control over EBV, thereby setting the stage for lymphomagenesis. This hypothesis will be tested by the following Specific Aims. Aim 1. Determine if the prevalence of T memory stem cells (TSCM) correlates with EBV control in children and if EBV-specific TSCM isolated from children have the capacity to expand when instructed by IL-15 and IL-7. CD4+ and CD8+ T cell subsets will be characterized by expression of memory markers (CD45RA/RO, CCR7, CD27, CD127, and CD95) and functionality (IL-2, TNF-?, IFN-?, CD107a) in a retrospective cohort study of children with divergent malaria exposure histories who have been categorized as EBV controllers or non-controllers. IL-7 and IL-15 stimulation will be used to evaluate the expansion potential of TSCM (CD45RA+, CCR7+, CD27+, CD95+). Aim 2. Evaluate the relationship between malaria-associated pro-inflammatory (IL-12, IL-23, IL-31, IL-33) and regulatory (IL-27, IL-35, IL-37) cytokine levels and the expression of transcription factors regulating T cell differentiation that correlate with EBV control in children. We hypothesize that malaria-induced changes in the cytokine environment will influence expression of transcription factors (IRF4, T-bet, Eomes, Bcl6 and TCF1) and thus influence T cell survival. Aim 3. Determine if malaria co-infection during primary EBV infection has a negative impact on the development of EBV-specific T cells associated with viral control and if this phenotype is progressively altered after repeated malaria infections. A newly established prospective infant cohort study will allow us to capture pivotal events during primary EBV infection to determine whether concurrent and/or cumulative malaria co-infections alter the cytokine milieu and thereby influence the quality and survival of EBV- specific T cells. Information gained from studying T cell memory in children and the immune regulatory microenvironment governing T cell fate will provide novel mechanistic insights into when and how malaria alters EBV immunosurveillance. Improved understanding of the complexity of T cell regulation and survival that renders children co-infected with EBV and malaria at increased risk for eBL will facilitate the development of preventive and therapeutic strategies for this common childhood cancer.