Dissecting the role of EBV and P. falciparum in endemic Burkitt lymphoma pathogenesis

剖析 EBV 和恶性疟原虫在地方性伯基特淋巴瘤发病机制中的作用

• 批准号: 10459337
• 负责人: Micah A. Luftig
• 金额: $ 64.04万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-14 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459337
• 关键词: Affect; Affinity; Africa; African Burkitt' s lymphoma; Antigens; Area; Automobile Driving; B Cell Proliferation; B-Cell Activation; B-Cell Antigen Receptor; B-Cell Development; B-Cell Lymphomas; B-Lymphocytes; C-Myc Translocation; CD8-Positive T-Lymphocytes; Cell Line; Cell Survival; Cell surface; Cells; Characteristics; Child; Child Support; Chromatin; Chronic; Clinical; Coupled; Data; EBNA2 protein; Epidemiology; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Event; Exposure to; Gene Expression; Generations; Genes; Genetic Transcription; Goals; Heavy-Chain Immunoglobulins; Human Herpesvirus 4; IGH@ gene cluster; Immune; Immune response; Immune system; Immunity; Immunologic Surveillance; Immunosuppression; In Vitro; Individual; Infection; Large-Cell Immunoblastic Lymphoma; Literature; Lymphoma cell; Lymphomagenesis; MYC gene; Maintenance; Malaria; Malignant Childhood Neoplasm; Mediating; Molecular; Oncogenes; Parasites; Pathogenesis; Pattern; Plasmodium falciparum; Publishing; Receptor Signaling; Regulation; Risk; Role; Signal Transduction; Specificity; Surface; Surface Immunoglobulins; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tumor Immunity; Viral; Viral Genome; Virus; Work; activation-induced cytidine deaminase; c-myc Genes; cell transformation; co-infection; human pathogen; humanized mouse; in vivo; infected B cell; interest; mouse model; neoantigens; neoplastic cell; novel; pathogen; post-transplant; pressure; screening; tumor; tumorigenesis

Our long-term goal is to understand how the development of B-cell lymphomas is influenced by infection and the antigen specificity of their surface-bound B-cell receptors (BCR). The objective in this proposal is to understand how Pf and EBV cooperate to promote and maintain eBL. It is our central hypothesis that Pf infection promotes EBV-mediated B-cell proliferation, Pf antigens are recognized by the EBV-infected BCR promoting the BL-characteristic IgH/c-Myc translocation, and that eBL tumor maintenance is supported by EBV regulation of tumor cell survival and Pf alteration of T-cell immunity. Our central hypothesis is premised on strong rationale from the literature and our preliminary data characterizing the interplay between EBV and Pf in eBL. First, EBV is clonally present in eBL cells suggesting both an early role in tumorigenesis and a requirement in tumor maintenance. Second, malaria holoendemic areas are known hotspots for eBL where rates are as much as 100- fold higher than in low/no malarial regions. Third, EBV infection of B cells potently activates expression of activation-induced cytidine deaminase (AID), which is critical for BL-characteristic Ig/c-Myc translocations. While the EBV latent protein EBNA2 opens B-cell chromatin upstream of the c-Myc gene promoting expression, it also suppresses IgH transcription. Since IgH transcription is required for AID to gain access to the IgH locus and is required for the IgH/c-Myc translocation, an additional factor must be affecting EBV-infected cells allowing this translocation to occur. We hypothesize that Pf provides this factor in the form of antigen recognized by the EBV- infected B-cell surface Ig. We propose that Pf infections provide both mitogenic signals to promote B-cell proliferation as well as critical antigens driving AID-mediated BCR affinity maturation, which aberrantly leads to the IgH/c-Myc translocation. Following the translocation, eBL tumors must withstand strong pressure from the immune system against both the virus and tumor neoantigens. Our recent work indicates a strong suppressive influence of Pf infection in vivo on CD8 T-cell recognition of EBV and eBL that we propose supports tumor maintenance. The rationale for this proposal is that understanding the molecular mechanisms of eBL initiation and pathogenesis vis-à-vis viral and parasite co-infection will provide us with a platform for understanding the role of BCR specificity in B lymphomagenesis as well as how Pf infection influences immune surveillance to support tumor maintenance. We plan to test our central hypothesis by pursuing the following three specific aims: 1) to determine the role of P. falciparum in collaborating with EBV to induce B-cell proliferation and tumorigenesis, 2) to determine the role of P. falciparum antigens as the critical trigger of the IgH/c-Myc translocation in eBL, and 3) to determine the interplay between EBV and P. falciparum immune alterations in eBL tumor maintenance.

我们的长期目标是了解b细胞淋巴瘤的发展如何受到感染的影响