Modulation of purinergic signaling has a tissue-dependent impact on the immune response against Trypanosoma cruzi infection

SANMARCO, LM; THEUMER, M; GARCÍA, MC; AOKI, MP; EBERHARDT, N; PONCE, NE

Congreso; Reunión conjunta de Sociedades de Biociencias; 2017

Adenosine (ADO), an immune-regulatory metabolite, is produced by hydrolysis of ATP that accumulates during tissue injury and inflammation. ADO generated through CD73 activity is an extracellular signaling molecule that is involved in anti-inflammatory mechanisms and provides a feedback to control tissue damage mediated by the host immune response to several infections. We hypothesize that the balance between ATP and ADO is crucial in the development of Chagas disease. The aim of this study was to determine the balance of purinergic signals and its impact in the host immune response developed in different T. cruzitarget tissues. The kinetic of cardiac macrophage (Ma) subsets showed a predominant inflammatory/M1 profile throughout the acute infection (p<0.001) with higher frequency of IL-12+ and iNOS+ M1 Ma (p<0.05) and augmented cardiac NO levels (p<0.001) in CD73-deficient (KO) compared to C57BL/6 (WT) mice. Moreover, KO mice exhibited increased frequency of cardiac IFN-γ+ and CD107a+ CD8 T lymphocytes (p<0.05) and a consequent lower cardiac parasite load (p<0.05). Nevertheless, these mice had higher parasitemia (p<0.05) associated to lower plasmatic NO levels. Strikingly, in visceral adipose tissue (VAT), parasite load was increased (p<0.01) in KO mice, this may be due to an increased basal VAT/body weight ratio (p<0.001) compared to uninfected WT mice, generating an important niche for parasite growth. As in VAT, parasite load in KO liver was augmented compared to WT (p<0.05). Furthermore, CD73 abrogation significantly decreased extracellular release of ADO in infected heart and VAT but not in liver. These findings could be explained by the different purinergic signaling impact in the target tissues evidenced by about 12-fold increase in ATP/ADO ratio in KO/WT heart compared to a 5 and 1 in VAT and liver respectively. In conclusion, purinergic system differentially modulates the host immune response against T. cruziinfection in a target tissue-dependent manner