Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY/ABSTRACT Chagas disease, caused by the parasite Trypanosoma cruzi, affects 6 million people and has a major economic impact due to early mortality and physical disabilities. It is endemic in Latin America but has become a global public health concern following the migration of infected people. Disease progression that varies from symptomless to severe, has been linked to both parasite heterogeneity and host-related immunity. Parasite persistence as well as the intensity of the inflammatory immune response are determinants of the clinical manifestations of the disease. Understanding components of host immunity will be crucial to the comprehension of pathogenesis and will allow design of novel therapeutics. The acute phase of Chagas disease results in polyclonal B cell activation that may be related to the important early extrafollicular plasmablast (EF-PB) response that precedes germinal center (GC) reactions. In this direction, the source of polyreactive antibodies (Abs) was not clearly identified. We initially considered that this polyclonal B cell response would restrict anti-parasite responses. However, we observed that EF-PB produce parasite-specific Abs of different isotypes and that signals via BCR, in some way, condition PB generation which requires the participation of T follicular helper (Tfh) cells. Also, the EF-PB are the main source of IL-17 in T. cruzi infected mice and a fraction of them produce IL-6 and other cytokines and express molecules related to antigen presentation. Of note, IL-17 produced by B cells/PB was shown to be key to sustain CD8+T cell activity and survival. Finally, we determined that PB from T. cruzi infected mice express high levels of the ectoenzyme CD39, higher than T cells, which combined with CD73 hydrolyze exogenous ATP to adenosine which plays immunomodulatory functions. The absence of PB in early T. cruzi infection significantly increases the parasitemia, but on the other side, favors the earlier appearance of GC and increases the frequency of TNF+IFN+ T cells suggesting a controversial role of PB. Our findings are particularly timely given reports describing poor clinical outcomes in Covid19 associated with high PB responses. Altogether, the results support our hypothesis that early EF-PB from T. cruzi infected mice have parasite control capacity and can condition disease outcome. We are focused at further characterizing these EF-PB cell population/s to determine their heterogeneity as well as its contribution to protection or pathogenicity. Using different strategies such as single-cell RNAseq, analysis of somatic hypermutation, identification of antigen-specificity and affinity we will perform detailed characterizations of EF-PB in T. cruzi infected mice. By using genetically modified mice, co- culture experiments and mixed bone marrow chimeras we will be able to delineate the role of EF-PB and CD39 in conditioning humoral as well as cellular responses in experimental Chagas disease. The identification of the EF-PB characteristics and roles will be of great significance for the development of new strategies aiming at the therapeutic targeting of B cells in the clinic. For instance, this innovative approach could provide information required to develop an effective vaccine against T. cruzi.
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