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

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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.