Vaccine-linked chemotherapy induces IL-17 production and reduces cardiac pathology during acute Trypanosoma cruzi infection

Chagas disease resulting from Trypanosoma cruzi infection leads to a silent, long-lasting chronic neglected tropical disease affecting the poorest and underserved populations around the world. Antiparasitic treatment with benznidazole does not prevent disease progression or death in patients with established cardiac disease. Our consortium is developing a therapeutic vaccine based on the T. cruzi flagellar-derived antigen Tc24-C4 formulated with a Toll-like receptor 4 agonist adjuvant, to complement existing chemotherapy and improve treatment efficacy. Here we demonstrate that therapeutic treatment of acutely infected mice with a reduced dose of benznidazole concurrently with vaccine treatment - also known as vaccine-linked chemotherapy-induced a T(H)17 like immune response, with significantly increased production of antigen specific IL-17A, IL-23 and IL-22, and CD8+T lymphocytes, as well as significantly increased T. cruzi specific IFN gamma -producing CD4+T lymphocytes. Significantly reduced cardiac inflammation, fibrosis, and parasite burdens and improved survival were achieved by vaccine-linked chemotherapy and individual treatments. Importantly, low dose treatments were comparably efficacious to high dose treatments, demonstrating potential dose sparing effects. We conclude that through induction of T(H)17 immune responses vaccine-linked chemotherapeutic strategies could bridge the tolerability and efficacy gaps of current drug treatment in Chagasic patients.

Automated summary

Therapeutic treatment with a reduced dose of benznidazole combined with vaccine treatment induces a T(H)17 immune response, enhancing the production of specific cytokines and T lymphocytes, resulting in reduced cardiac inflammation, fibrosis, and parasite burdens, as well as improved survival in acutely infected mice. Low dose treatments show comparable efficacy to high dose treatments, suggesting potential dose sparing effects and bridging the gaps of current drug treatment in Chagasic patients by inducing T(H)17 immune responses through vaccine-linked chemotherapeutic strategies.