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

项目摘要/摘要 我们收集了确凿的证据证明非洲锥虫的有害作用。 B细胞生物学上的感染。例如，这些寄生虫能够破坏体内平衡的B细胞发育 以及现有的与B细胞相关的记忆隔间对抗无关的病原体，使它们成为 像天真的主人一样容易受影响。在这项提议中，我们利用了这种与寄生虫相关的特殊 属性，以确定锥虫感染对有害B细胞转归的“有益”作用 反应，如B细胞介导的类风湿性关节炎，以及恶性浆细胞的进展(多发性 骨髓瘤)。这项研究计划的主要目标是利用这种寄生虫作为一种工具来寻找潜在的新的 针对恶性B细胞的免疫学策略，如慢性淋巴细胞白血病(CLL)。CLL 占成人白血病的30%，目前仍无法治愈。根据国家癌症研究所(NCI)的数据， 年，仅在美国就预计约有21,040例新的慢性淋巴细胞性白血病病例和4,060例慢性淋巴细胞性白血病死亡病例。 2020年。尽管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 非洲锥虫破坏B细胞反应的机制(S)尚不清楚， 特色化的。为了实现这一目标，我们将集中在：1)通过以下途径表征CLL固有的凋亡机制 非洲锥虫感染后cGAs的激活，以及ii)鉴定宿主免疫衍生的 非洲锥虫感染小鼠CLL细胞凋亡的细胞和分子机制， 重点分析CD_4~+T细胞以及干扰素、ɣ等促炎细胞因子的作用。 深入了解CLL细胞凋亡过程中的分子机制 由非洲锥虫感染引起的可能导致一种新的 策略/干预不仅针对慢性淋巴细胞性白血病，而且针对其他类型的B细胞来源的癌症，如多发性 骨髓瘤。

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.