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）， EBV相关的B细胞肿瘤和赤道非洲最常见的儿科癌症尚未完全了解。由于原发性EBV感染与反复疟疾感染之间的时间间隔较长，因此需要进行纵向研究，以充分了解疟疾在eBL病因学中对EBV形成T细胞免疫的累积影响。因此，本研究旨在验证我们的中心假设，即疟疾会对EBV特异性T细胞反应的分化和存活产生不利影响，从而导致T细胞失去对EBV的控制，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。目的1。确定儿童中T记忆干细胞（TSCM）的流行是否与EBV控制相关，以及从儿童中分离出的EBV特异性TSCM是否在IL-15和IL-7的指示下具有扩增能力。CD4+和CD8+ T细胞亚群将以记忆标志物（CD45RA/RO、CCR7、CD27、CD127和CD95）的表达和功能(IL-2、TNF-？干扰素- ?在一项针对具有不同疟疾暴露史的儿童的回顾性队列研究中，这些儿童被归类为EBV控制者或非控制者。IL-7和IL-15刺激将用于评估TSCM （CD45RA+, CCR7+, CD27+, CD95+）的扩张潜力。目标2。评估儿童疟疾相关的促炎因子（IL-12、IL-23、IL-31、IL-33）和调节性细胞因子（IL-27、IL-35、IL-37）水平与EBV控制相关的T细胞分化调节因子表达之间的关系。我们假设疟疾引起的细胞因子环境的改变会影响转录因子（IRF4、T-bet、Eomes、Bcl6和TCF1）的表达，从而影响T细胞的存活。目标3。确定原发性EBV感染期间的疟疾合并感染是否会对与病毒控制相关的EBV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会逐渐改变

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.