The thymus in Chagas Disease: molecular interactions involved in abnormal T-cell migration and differentiation

ANA ROSA PEREZ; JULIANA DE MEIS; RODRIGUEZ GALÁN MARIA CECILIA; WILSON SAVINO

Frontiers in immunology

Frontiers

Lugar: Lausanne; Año: 2020

Chagas disease is a prevalent parasitic disease in Latin America. Presently, it is spreading around the world by human migration, thus representing a new global health issue. The protozoan parasite Trypanosoma cruzi (T. cruzi) is the etiological agent of Chagas disease. It can be transmitted to humans by triatomine insects after skin or mucosal biting (vector transmission), congenitally (vertical transmission), by ingestion of contaminated food (oral transmission), and to a lesser extent through blood transfusion, organ transplantation and laboratory accidents. Chronically infected individuals reveal a dissimilar disease progression: while nearly 60% remain without apparent disease for life, 30% develop life-threatening pathologies, such as cardiomyopathy or megaviscerae. Concerning the immune response to T. cruzi infection, after primoinfection, there is a systemic production of proinflammatory cytokines like IL-12, IFN-γ and TNF-α, which are crucial to controlling parasitemia and host survival, through protective immunity mediated by T-helper 1 (Th1) cells, production of antibodies and conventional cytotoxic CD8+ T cells. In a second vein, during murine acute and chronic T. cruzi infection, both the lymphoid and the microenvironmental compartments of the thymus are profoundly affected. There is a severe thymic atrophy during the acute phase, mainly caused by a massive loss of CD4+CD8+ double positive thymocyte; being accompanied by a diminished recruitment of progenitors from bone marrow. Additionally, almost all stages of thymocyte development are altered with: decrease in thymocyte proliferation; changes in the amounts of CD4+Foxp3+ regulatory T cells, migratory response of thymocytes, altered expression of cell-migration related molecules ? such as extracellular matrix, chemokines and sphingosine-1-phosphate --?, with changes in the cortical and medullary epithelial cell network, altered expression of miRNA, variations in cytokine and hormone production, qualitative changes in the intrathymically generated in T-cell repertoire, together with abnormal exit of immature CD4+CD8+ and CD4-CD8- T cells. The identification of molecular mechanisms underlying thymic abnormalities occurring during T. cruzi infection may contribute to the design of innovative strategies to control Chagas disease pathology.