Mycophenolate drives Trypanosoma cruzi reactivation via CD8+ T cell depletion and splenic and bone marrow...

Reactivation of Trypanosoma cruzi (T. cruzi) infection poses a life-threatening risk in immunosuppressed hosts, particularly transplant recipients. Current clinical evidence guiding immunosuppressive drug selection in Chagas disease remains limited. Using a murine model of chronic T. cruzi infection, we evaluated transplant-relevant immunosuppressants- the calcineurin inhibitor tacrolimus, the antiproliferative drugs mycophenolate mofetil (MMF) and azathioprine) leflunomide and corticosteroids -for their impact on parasite reactivation and host responses. We tested them alone or in the clinically used combinations at equivalent immunosuppressive doses. We evaluated parasitemia, tissue parasite load, histopathological changes and immune response markers. MMF induced the highest parasitemia and tissue parasite load (p < 0.05). This risk aligned with a significant reduction in CD8+ T cells-critical for parasitic control-and disrupted splenic and bone marrow architecture, indicative of extramedullary hematopoiesis. Moreover, the combination of MMF and corticosteroids exhibited a synergistic effect in T. cruzi reactivation. Yet, the association of tacrolimus with MMF or azathioprine did not increase reactivation risk. Azathioprine showed moderate reactivation but increased skeletal muscle fibrosis, while tacrolimus and leflunomide did not trigger significant reactivation. Our findings reveal that T. cruzi reactivation risk is drug-specific, with MMF posing the greatest threat due to its impact on adaptive immunity. This translational approach bridges experimental findings with clinical practice, providing critical insights to optimize immunosuppressive strategies and monitoring for people living with Chagas disease, ultimately improving patient outcomes.