Chagas disease, caused by the parasite Trypanosoma cruzi, affects 8 million people and imposes a major economic burden due to early mortality and physical disabilities. It is endemic in Latin America but became a global public health concern possibly by migration of infected people. Disease progression, from symptomless to severe, is linked to parasite heterogeneity and a variable host immune response. It has been reported that parasite persistence as well as the intensity of the inflammatory immune response are determinants of the clinical manifestations of the disease. Even though inflammation is indispensable for host defense, when deregulated, it can contribute to continuous tissue injury and organ dysfunction. Consequently, defining the nature of cells and molecules able to maintain the host s integrity as well as the pathogen replication is crucial for our understanding of the pathogenesis of Chagas disease and also for the design of novel therapeutic approaches. The acute phase of Chagas disease in mice and humans is marked by a state of immunosuppression in which T. cruzi replicates extensively and induces immune- modulatory molecules that delay parasite-specific T cell responses. This T cell status coexists with polyclonal B cell activation, suggesting that B cells can influence T cell function and vice versa. Terminally differentiated B cells, the plasma cells, have been primarily known for their unique capacity to secrete antibodies. Remarkably, recent studies identified antibody-secreting cells (ASC) as the main type of activated B cells which produce anti-inflammatory cytokines and so a new role of regulatory cells was proposed for them. In this proposal we will study the Ab-independent function of ASC in T. cruzi infection. We will particularly investigate whether ASC elicited by the infection that show a uniformly high expression of PD-L1 (PD-L1hi ASC) are able to condition T cell responses. By using genetically-modified mice, co-culture experiments and mixed bone marrow chimeras we will determine the characteristic of PD-L1hi ASC and their function in T. cruzi infection. By infection of mice with genetic modifications in molecules involved in several signaling pathways and by cell culture assays, we will evaluate the signals, intracellular pathways and transcriptional programs involved in the generation of PD-L1hi ASC. The identification of the phenotypic and longevity features that characterize regulatory plasma cells will be of great significance for the development of new strategies aiming at the therapeutic targeting of B cells in the clinic. For instance, such knowledge could help to develop novel tools to selectively deplete those ASC that negatively regulate T cell response without affecting high affinity ASC which play a protective role in infections.

Public Health Relevance

This project will provide information about the antibody-independent function of plasma cells (Ab- secreting cells) in the development of robust protective T cell immunity to Trypanosoma cruzi, the parasite that causes Chagas disease. Specifically, we propose: - studying the role of Ab-secreting cells which unexpectedly express high levels of the immune-modulatory molecule PD-L1, - identifying the phenotypic and longevity features which distinguish PD-L1hi Ab-secreting cells and - dissecting the signaling pathways and transcriptional programs involved in their generation. Results will be of great significance for the development of new therapeutic treatments aimed at enhancing protective T cell responses in Chagas disease and other chronic infections which course with strong plasma cells response.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Pesce, John T
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National Research Council of Argentina
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Zacca, Estefanía R; Onofrio, Luisina I; Acosta, Cristina D V et al. (2018) PD-L1+ Regulatory B Cells Are Significantly Decreased in Rheumatoid Arthritis Patients and Increase After Successful Treatment. Front Immunol 9:2241
Gorosito Serrán, Melisa; Tosello Boari, Jimena; Fiocca Vernengo, Facundo et al. (2017) Unconventional Pro-inflammatory CD4+ T Cell Response in B Cell-Deficient Mice Infected with Trypanosoma cruzi. Front Immunol 8:1548