African trypanosome parasites: a new tool to unveil potential immunological strategies to target CLL

非洲锥虫寄生虫：揭示针对 CLL 的潜在免疫策略的新工具

• 批准号: 10188324
• 负责人: Carl De Trez
• 金额: $ 36.09万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-03 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188324
• 关键词: Affinity; African; Agammaglobulinaemia tyrosine kinase; Agonist; Antigens; Apoptosis; Apoptotic; Autoimmune; B-Cell Development; B-Lymphocytes; C57BL/6 Mouse; CD4 Positive T Lymphocytes; CD8B1 gene; Candidate Disease Gene; Cells; Cellular biology; Cessation of life; Chronic Lymphocytic Leukemia; Cyclic GMP; Development; Emu species; FDA approved; Functional disorder; Gene Expression Profiling; Genetic; Goals; Immune Evasion; Immunity; Immunologics; Immunotherapeutic agent; In Vitro; Infection; Inflammation; Inflammatory; Intervention; Lead; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Memory; Memory B-Lymphocyte; Modeling; Molecular; Multiple Myeloma; Mus; National Cancer Institute; Natural Killer Cells; Outcome; Parasites; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Plasma Cells; Play; Process; Production; Property; Publications; Publishing; Research Proposals; Rheumatoid Arthritis; Role; Series; Signal Transduction; Signaling Molecule; Source; Specificity; T-Lymphocyte Subsets; Testing; Transgenic Mice; Transplantation; Trypanosoma; Trypanosoma brucei brucei; United States; Up-Regulation; Validation; adult leukemia; cancer cell; chemotherapeutic agent; chronic infection; chronic lymphocytic leukemia cell; cytokine; driving force; endoplasmic reticulum stress; experimental study; fighting; human model; in vivo; new therapeutic target; novel therapeutic intervention; pathogen; response; single-cell RNA sequencing; targeted treatment; tool

Project Summary/Abstract We have gathered undoubted evidence demonstrating the detrimental roles of the African trypanosome infections on B cell biology. For example, these parasites are able to wipe out homeostatic B cell development as well as existing B cell-associated memory compartment against unrelated pathogens, rendering them as susceptible as naïve host. In this proposal, we have taken advantage of this parasite-associated peculiar property on B cells to identify a “beneficial” role of trypanosome infections on the outcome of detrimental B cell responses, such B cell-mediated rheumatoid arthritis, and the progression of malignant plasma cells (multiple myeloma). The main goal of this research proposal is to use this parasite as a tool to find potential new immunological strategies against malignant B cells, such as chronic lymphocytic leukemia (CLL). CLL represents 30% of adult leukemia, and is still incurable. According to the National Cancer Institute (NCI), approximately 21,040 new cases of CLL and 4,060 deaths from CLL are projected in the United States alone in 2020. Although apoptosis seems to be the major driving force leading to B cell dysfunction, the exact mechanism(s) utilized by the African trypanosomes to undermine B cell responses are yet to be found and characterized. To achieve this goal, we will focus on i) characterizing CLL-intrinsic apoptotic mechanisms via activation of cGAS in response to African trypanosome infections, and ii) identifying the host immunity-derived cellular and molecular mechanisms leading to apoptosis of CLL cells in African trypanosome-infected mice, with an emphasis on analyzing the roles of CD4+ T cells as well as pro-inflammatory cytokines such as IFNɣ. A thorough understanding of the molecular mechanisms implicated in the apoptotic processes of CLL cells resulted from African trypanosome infections might potentially lead to the development of a new strategy/intervention against not only CLL but also other types of B cell-derived cancers, such as multiple myeloma.

项目总结/摘要 我们已经收集了大量证据，证明非洲锥虫的有害作用， 感染对B细胞生物学的影响。例如，这些寄生虫能够消灭体内平衡的B细胞发育 以及现有的B细胞相关的记忆隔室对不相关的病原体，使它们成为 像幼稚的宿主一样敏感。在这个提议中，我们利用了这种寄生虫相关的特殊性， 确定锥虫感染对有害B细胞的结果的“有益”作用 反应，如B细胞介导的类风湿性关节炎，和恶性浆细胞的进展（多个 骨髓瘤）。这项研究提案的主要目标是利用这种寄生虫作为工具， 针对恶性B细胞如慢性淋巴细胞白血病（CLL）的免疫策略。CLL 占成人白血病的30%，仍然无法治愈。根据美国国家癌症研究所（NCI）的数据， 预计仅在美国就有大约21，040例CLL新发病例和4，060例CLL死亡， 2020.虽然细胞凋亡似乎是导致B细胞功能障碍的主要驱动力，但确切的细胞凋亡是由细胞凋亡引起的。 非洲锥虫破坏B细胞应答的机制尚未发现， 表征了为了实现这一目标，我们将集中于i）通过以下途径表征CLL内在凋亡机制： 响应于非洲锥虫感染的cGAS的活化，和ii）鉴定宿主免疫源性 导致非洲锥虫感染小鼠中CLL细胞凋亡的细胞和分子机制， 重点分析了CD 4 + T细胞以及促炎细胞因子如IFN γ的作用。 深入了解CLL细胞凋亡过程中的分子机制 非洲锥虫感染引起的疾病可能会导致一种新的 不仅针对CLL，而且针对其他类型的B细胞衍生的癌症，如多发性骨髓瘤， 骨髓瘤

项目成果

Loss of AID exacerbates the malignant progression of CLL.

• DOI: 10.1038/s41375-022-01663-5
• 发表时间: 2022-10
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Lee, Avery C.;Pingali, Sai Ravi;Pinilla-Ibarz, Javier A.;Atchison, Michael L.;Koumenis, Constantinos;Argon, Yair;Thomas-Tikhonenko, Andrei;De Trez, Carl;Hu, Chih-Chi Andrew;Tang, Chih-Hang Anthony
• 通讯作者: Tang, Chih-Hang Anthony

The Role of MIF and IL-10 as Molecular Yin-Yang in the Modulation of the Host Immune Microenvironment During Infections: African Trypanosome Infections as a Paradigm.

• DOI: 10.3389/fimmu.2022.865395
• 发表时间: 2022
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Stijlemans, Benoit;Schoovaerts, Maxime;De Baetselier, Patrick;Magez, Stefan;De Trez, Carl
• 通讯作者: De Trez, Carl