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

疟疾对伯基特淋巴瘤病因中 EBV 免疫力的影响

• 批准号: 8767080
• 负责人: ANN M MOORMANN
• 金额: $ 57.57万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8767080
• 关键词: 3 year old; 5 year old; 9 year old; Africa; African Burkitt' s lymphoma; Age; Antigens; Area; B lymphoid malignancy; B-Cell Neoplasm; Burkitt Lymphoma; CD8B1 gene; Cell Lineage; Cell Survival; Cells; Child; Childhood; Cohort Studies; Defect; Detection; Development; Diagnosis; Environment; Epstein-Barr Virus Infections; Etiology; Event; Falciparum Malaria; Frequencies; Functional disorder; Gene Expression; Human; Human Herpesvirus 4; IL2RB gene; IL7R gene; IRF4 gene; Immune; Immune response; Immunity; Immunologic Monitoring; Immunologics; Immunosuppression; In Vitro; Incidence; Individual; Infant; Infection; Inflammatory; Interferon Type II; Interferons; Interleukin-12; Interleukin-15; Interleukin-2; Interleukin-7; Intervention; Kenya; Knowledge; Life; Longitudinal Studies; Lymphomagenesis; Lytic; Maintenance; Malaria; Malignant Childhood Neoplasm; Memory; Nuclear Antigens; Peptides; Phenotype; Prevalence; Preventive; Recording of previous events; Reporting; Risk; Sampling; Seminal; Severities; Shapes; Specificity; Staging; Stem cells; T cell differentiation; T cell regulation; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Epitopes; T-Lymphocyte Subsets; TNF gene; TNFRSF6 gene; Testing; Therapeutic; Viral; Viral Antigens; Viral load measurement; cytokine; early childhood; experience; improved; insight; interleukin-23; novel; peripheral blood; prevent; prospective; public health relevance; research study; response; transcription factor

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.

描述（由申请人提供）：恶性疟原虫疟疾和 Epstein-Barr 病毒 (EBV) 之间的联合流行病相互作用，使儿童易患地方性伯基特淋巴瘤 (eBL)，这是一种与 EBV 相关的 B 细胞肿瘤，也是赤道非洲最常见的儿童癌症。没有完全理解。由于原发 EBV 感染之间的时间间隔较长，再加上反复的疟疾感染，与儿童期后期出现 eBL 之间的时间间隔较长，因此需要进行纵向研究，以充分了解疟疾对 EBV 的 T 细胞免疫的累积影响。电子BL。因此，本提案旨在检验我们的中心假设，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，导致 T 细胞失去对 EBV 的控制，从而为淋巴瘤的发生奠定基础。该假设将通过以下具体目标进行检验。目标 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 在 IL-15 和 IL-7 的指导下是否具有扩增能力。在一项回顾性队列研究中，CD4+ 和 CD8+ T 细胞亚群的特征是记忆标记物（CD45RA/RO、CCR7、CD27、CD127 和 CD95）的表达和功能（IL-2、TNF-α、IFN-α、CD107a）具有不同疟疾暴露史的儿童被归类为 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+）的扩展潜力。目标 2. 评估疟疾相关促炎细胞因子（IL-12、IL-23、IL-31、IL-33）和调节细胞因子（IL-27、IL-35、IL-37）水平与表达之间的关系调节与儿童 EBV 控制相关的 T 细胞分化的转录因子。我们假设疟疾诱导的细胞因子环境变化将影响转录因子（IRF4、T-bet、Eomes、Bcl6 和 TCF1）的表达，从而影响 T 细胞存活。目标 3. 确定原发性 EBV 感染期间的疟疾合并感染是否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疟疾后是否逐渐改变 感染。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会改变细胞因子环境，从而影响 EBV 特异性 T 细胞的质量和存活。通过研究儿童 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 细胞调节和生存复杂性的了解，使同时感染 EBV 和疟疾的儿童患 eBL 的风险增加，这将有助于制定针对这种常见儿童癌症的预防和治疗策略。