HIF-1/CD73 REGULATORY PATHWAY DETERMINES CHRONIC INFLAMMATORY RESPONSE AND TISSUE DAMAGE IN AN EXPERIMENTAL MODEL OF TRYPANOSOMA CRUZI INFECTION

BERGERO GASTÓN; EBERHARDT NATALIA; MAZZOCO YANINA; JUAN MLADIN; FERNANDO ALFONSO

Congreso; REUNIÓN DE SOCIEDADES DE BIOCIENCIAS 2020; 2020

REUNIÓN DE SOCIEDADES DE BIOCIENCIAS 2020

The transcription factor HIF-1 regulates the expression of the CD39 and CD73 ectonucleotidases, which drive the catabolism of the pro-inflammatory molecule ATP towards the anti-inflammatory mediator adenosine. We have reported that CD73 activity has a tissue-dependent impact on the host immune response against acute Trypanosoma cruzi infection. Here, we explored the effect of CD73 deficiency (CD73KO) on immune cells infiltrating target tissues during chronic T. cruzi murine infection. Through flow cytometry, we found that CD73KO mice exhibited higher CD4/CD8 ratio in peripheral blood (p <0.001), in parallel with the lower CD4/CD8 ratio observed in heart and liver at 250 days post-infection (dpi), compared to the wild-type (WT) counterpart (p <0.001 and p = 0.052, respectively). The frequency of infiltrating HIF-1α+ CD4+ T cells and CD8+ T cells diminished in CD73KO compared to WT mice (p <0.05). In the heart, a higher frequency of IFN-+ CD8+ T cells was observed in CD73-deficient mice (p <0.05) in agreement with the intense infiltrate perceived in histological studies. In addition, the echocardiography (ECO) analysis showed that cardiac functionality was altered in CD73KO mice (left ventricular systolic diameter/weight: p <0.05). In the same way, in CD73-deficient liver, higher frequency of IFN-+ CD8 T cells were observed (p <0.001), in accordance with the liver tissue damage evaluated by the analysis of the histology. On the other hand, in visceral adipose tissue, no differences were observed regarding the expression of HIF-1α in T cells in both groups of mice. However, a higher degree of infiltration was observed in visceral adipose tissue from CD73-deficient mice. These data suggest that HIF-1α/purinergic system could drive the inflammatory response against chronic T. cruzi infection and its resolution.