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

基本信息

  • 批准号:
    10459337
  • 负责人:
  • 金额:
    $ 64.04万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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细胞淋巴瘤的发展是如何受到感染的影响 和其表面结合B细胞受体(BCR)的抗原特异性。本提案的目标是 了解Pf和EBV如何合作促进和维持eBL。我们的中心假设是, 促进EBV介导的B细胞增殖,Pf抗原被EBV感染的BCR识别,促进B细胞增殖。 BL-特征性IgH/c-Myc易位,并且eBL肿瘤维持受到EBV调节的支持, 肿瘤细胞存活和T细胞免疫的Pf改变。我们的中心假设是建立在强有力的理论基础上的 从文献和我们的初步数据表征EBV和Pf之间的相互作用在eBL。首先,EBV 克隆性存在于eBL细胞中,表明在肿瘤发生中的早期作用和肿瘤发生中的需要 上维护其次,疟疾全流行区是已知的eBL热点,其发病率高达100- 比低疟疾/无疟疾地区高一倍。第三,B细胞的EBV感染有效地激活了 活化诱导的胞苷脱氨酶(AID),其对于BL-特征性IG/c-Myc易位至关重要。而 EBV潜伏蛋白EBNA 2打开c-Myc基因上游的B细胞染色质,促进表达,它还 抑制IgH转录。由于AID需要IgH转录才能进入IgH基因座, IgH/c-Myc易位所需的,一个额外的因素必须影响EBV感染的细胞,使这一点 translocation发生。我们假设Pf以EBV识别的抗原形式提供该因子, 感染B细胞表面IG。我们认为,Pf感染提供了促有丝分裂信号,促进B细胞增殖, 增殖以及驱动艾滋病介导的BCR亲和力成熟的关键抗原,这异常地导致 IgH/c-Myc易位。易位后,eBL肿瘤必须承受来自肿瘤细胞的强大压力。 免疫系统抵抗病毒和肿瘤新抗原。我们最近的研究表明 体内Pf感染对CD 8 T细胞识别EB病毒和eBL的影响,我们认为这支持肿瘤 上维护这一建议的基本原理是,了解eBL启动的分子机制, 以及病毒和寄生虫共感染的发病机制将为我们提供一个了解 BCR特异性在B淋巴瘤发生中的作用以及Pf感染如何影响免疫监视, 支持肿瘤维持。我们计划通过追求以下三个具体目标来检验我们的中心假设: 1)为了确定恶性疟原虫在与EBV协同诱导B细胞增殖和肿瘤发生中的作用, 2)确定恶性疟原虫抗原作为eBL中IgH/c-Myc易位的关键触发物的作用,和 3)以确定EBV和恶性疟原虫免疫改变在eBL肿瘤维持中的相互作用。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Micah A. Luftig其他文献

Comparison of nanopore with illumina whole genome assemblies of the Epstein-Barr virus in Burkitt lymphoma
  • DOI:
    10.1038/s41598-025-94737-0
  • 发表时间:
    2025-03-31
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Isaac E. Kim;Abebe A. Fola;Enrique Puig;Titus Kipkemboi Maina;Sin Ting Hui;Hongyu Ma;Kaleb Zuckerman;Eddy O. Agwati;Alec Leonetti;Rebecca Crudale;Micah A. Luftig;Ann M. Moormann;Cliff Oduor;Jeffrey A. Bailey
  • 通讯作者:
    Jeffrey A. Bailey
Author Correction: Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation
  • DOI:
    10.1186/s13059-021-02405-z
  • 发表时间:
    2021-06-17
  • 期刊:
  • 影响因子:
    9.400
  • 作者:
    Nisha Padmanabhan;Huang Kie Kyon;Arnoud Boot;Kevin Lim;Supriya Srivastava;Shuwen Chen;Zhiyuan Wu;Hyung-Ok Lee;Vineeth T. Mukundan;Charlene Chan;Yarn Kit Chan;Ong Xuewen;Jason J. Pitt;Zul Fazreen Adam Isa;Manjie Xing;Ming Hui Lee;Angie Lay Keng Tan;Shamaine Ho Wei Ting;Micah A. Luftig;Dennis Kappei;Warren D. Kruger;Jinsong Bian;Ying Swan Ho;Ming Teh;Steve George Rozen;Patrick Tan
  • 通讯作者:
    Patrick Tan
Epstein-Barr virus induces germinal center light zone chromatin architecture and promotes survival through enhancer looping at the emBCL2A1/em locus
爱泼斯坦-巴尔病毒诱导生发中心亮区染色质结构,并通过 emBCL2A1/em 位点的增强子环化促进存活
  • DOI:
    10.1128/mbio.02444-23
  • 发表时间:
    2023-12-11
  • 期刊:
  • 影响因子:
    4.700
  • 作者:
    Joanne Dai;Elliott D. SoRelle;Emma Heckenberg;Lingyun Song;Jana M. Cable;Gregory E. Crawford;Micah A. Luftig;Alan N. Engelman
  • 通讯作者:
    Alan N. Engelman

Micah A. Luftig的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Micah A. Luftig', 18)}}的其他基金

Defining and exploiting EBV-infected cell heterogeneity in non-Hodgkin lymphomas
定义和利用非霍奇金淋巴瘤中 EBV 感染细胞的异质性
  • 批准号:
    10706553
  • 财政年份:
    2022
  • 资助金额:
    $ 64.04万
  • 项目类别:
Defining and exploiting EBV-infected cell heterogeneity in non-Hodgkin lymphomas
定义和利用非霍奇金淋巴瘤中 EBV 感染细胞的异质性
  • 批准号:
    10541348
  • 财政年份:
    2022
  • 资助金额:
    $ 64.04万
  • 项目类别:
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:
    10204966
  • 财政年份:
    2019
  • 资助金额:
    $ 64.04万
  • 项目类别:
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:
    10671667
  • 财政年份:
    2019
  • 资助金额:
    $ 64.04万
  • 项目类别:
Defining the Mechanisms of Epstein-Barr Virus Persistence and Recurrence
定义 Epstein-Barr 病毒持续存在和复发的机制
  • 批准号:
    10437789
  • 财政年份:
    2016
  • 资助金额:
    $ 64.04万
  • 项目类别:
Targeting Apoptosis and Immune Control of Epstein-Barr Virus Infected Tonsillar B Cells
针对 Epstein-Barr 病毒感染的扁桃体 B 细胞的凋亡和免疫控制
  • 批准号:
    9237256
  • 财政年份:
    2016
  • 资助金额:
    $ 64.04万
  • 项目类别:
Defining the Mechanisms of Epstein-Barr Virus Persistence and Recurrence
定义 Epstein-Barr 病毒持续存在和复发的机制
  • 批准号:
    10599350
  • 财政年份:
    2016
  • 资助金额:
    $ 64.04万
  • 项目类别:
Host pathways regulating Epstein-Barr virus-mediated B cell growth transformation
调节 Epstein-Barr 病毒介导的 B 细胞生长转化的宿主途径
  • 批准号:
    10663313
  • 财政年份:
    2011
  • 资助金额:
    $ 64.04万
  • 项目类别:
Host pathways regulating Epstein-Barr virus-mediated B cell growth transformation
调节 Epstein-Barr 病毒介导的 B 细胞生长转化的宿主途径
  • 批准号:
    8187400
  • 财政年份:
    2011
  • 资助金额:
    $ 64.04万
  • 项目类别:
Host pathways regulating Epstein-Barr virus-mediated B cell growth transformation
调节 Epstein-Barr 病毒介导的 B 细胞生长转化的宿主途径
  • 批准号:
    8843606
  • 财政年份:
    2011
  • 资助金额:
    $ 64.04万
  • 项目类别:

相似海外基金

Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
  • 批准号:
    23H01982
  • 财政年份:
    2023
  • 资助金额:
    $ 64.04万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
  • 批准号:
    23KJ0116
  • 财政年份:
    2023
  • 资助金额:
    $ 64.04万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
  • 批准号:
    10682794
  • 财政年份:
    2023
  • 资助金额:
    $ 64.04万
  • 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
  • 批准号:
    10598276
  • 财政年份:
    2023
  • 资助金额:
    $ 64.04万
  • 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
  • 批准号:
    2233343
  • 财政年份:
    2023
  • 资助金额:
    $ 64.04万
  • 项目类别:
    Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
  • 批准号:
    2233342
  • 财政年份:
    2023
  • 资助金额:
    $ 64.04万
  • 项目类别:
    Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
  • 批准号:
    479363
  • 财政年份:
    2023
  • 资助金额:
    $ 64.04万
  • 项目类别:
    Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
  • 批准号:
    10681989
  • 财政年份:
    2023
  • 资助金额:
    $ 64.04万
  • 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
  • 批准号:
    2237240
  • 财政年份:
    2023
  • 资助金额:
    $ 64.04万
  • 项目类别:
    Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
  • 批准号:
    2305592
  • 财政年份:
    2023
  • 资助金额:
    $ 64.04万
  • 项目类别:
    Continuing Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了