Tissue damage during acuteTrypanosoma cruziinfection is associated with reduced reparative regulatory T cell response and can be attenuated by early interleukin-33 administration
Authors: Boccardo Santiago , Rodriguez Constanza , Furlan Cintia L. Araujo , Abrate Carolina P. , Almada Laura , Giménez Camila M. S. , Concepción Manuel A. Saldivia , Skewes-Cox Peter , Rao Srinivasa P. S. , Montes Carolina L. , Gruppi Adriana , Rodríguez Eva V. Acosta 
Published: February 2024

ABSTRACTTissue-repair regulatory T cells (trTregs) constitute a specialized regulatory subset renowned for orchestrating tissue homeostasis and repair. While extensively investigated in sterile injury models, their role in infection-induced tissue damage and the regulation of protective antimicrobial immunity remains largely unexplored. This investigation examines trTregs dynamics during acuteTrypanosoma cruziinfection, a unique scenario combining extensive tissue damage with robust antiparasitic CD8+ immunity. Contrary to conventional models of sterile injury, our findings reveal a pronounced reduction of trTregs in secondary lymphoid organs and tissues during acuteT. cruziinfection. This unexpected decline correlates with systemic as well local tissue damage, as evidenced by histological alterations and downregulation of repair-associated genes in skeletal muscle. Remarkably, a parallel decrease in systemic levels of IL-33, a crucial factor for trTregs survival and expansion, was detected. We found that early treatment with systemic recombinant IL-33 during infection induces a notable surge in trTregs, accompanied by an expansion of type 2 innate lymphoid cells and parasite-specific CD8+ cells. This intervention results in a mitigated tissue damage profile and reduced parasite burden in infected mice. These findings shed light on trTregs biology during infection-induced injury and demonstrate the feasibility of enhancing a specialized Tregs response without impairing the magnitude of effector immune mechanisms, ultimately benefiting the host. Furthermore, this study settles groundwork of relevance for potential therapeutic strategies in Chagas’ disease and other infections.AUTHOR SUMMARYChagas’ disease, caused by the protozoanTrypanosoma cruzi, induces severe organ damage caused by the interplay between the parasite and the immune response. In our investigation, we delved into the role of tissue-repair regulatory T cells (trTregs) during the acute phase ofT. cruziinfection in mice. Surprisingly, we observed a reduction in trTregs during the peak of tissue damage, contrary to their usual accumulation after injury in other contexts. This decline aligned with decreased levels of interleukin-33, a critical factor for trTregs survival. Administering interleukin-33 at early infection times not only boosted trTregs but also expanded other reparative and antiparasitic immune cells. Consequently, these treated mice exhibited reduced damage and lower parasite levels in tissues. Our findings offer insights into trTregs’ behavior during infection-induced injury, suggesting a promising avenue for therapeutic interventions in Chagas’ disease and related conditions. This study lays the groundwork for potential strategies that balance the immune response, supporting tissue repair without compromising the ability to control the infection, which could have broader implications for infectious diseases and tissue damage-related pathologies.