Abstract
Chagas disease is caused by infection with the protozoan Trypanosoma cruzi (T. cruzi) and is an important cause of severe inflammatory heart disease. However, the mechanisms driving Chagas disease cardiomyopathy have not been completely elucidated. Here, we show that the canonical PI3Kγ pathway is upregulated in both human chagasic hearts and hearts of acutely infected mice. PI3Kγ-deficient mice and mutant mice carrying catalytically inactive PI3Kγ are more susceptible to T. cruzi infection. The canonical PI3Kγ signaling in myeloid cells is essential to restrict T. cruzi heart parasitism and ultimately to avoid myocarditis, heart damage, and death of mice. Furthermore, high PIK3CG expression correlates with low parasitism in human Chagas’ hearts. In conclusion, these results indicate an essential role of the canonical PI3Kγ signaling pathway in the control of T. cruzi infection, providing further insight into the molecular mechanisms involved in the pathophysiology of chagasic heart disease.
Highlights
Chagas disease is caused by infection with the protozoan Trypanosoma cruzi (T. cruzi) and is an important cause of severe inflammatory heart disease
Akt2−/− mice were as resistant to T. cruzi infection as WT mice (Fig. 8c), indicating that AKT1, but not AKT2, was involved in the downstream events of PI3Kγ signaling responsible for the control of T. cruzi infection. These results indicated that a canonical PI3Kγ/ AKT1 signaling deficiency in myeloid cells led to an inability to control heart T. cruzi infection and avoid heart damage and host death
Characterization of the pathophysiological aspects of heart T. cruzi infection and the mechanisms that lead to resistance or susceptibility of the host is fundamental to understand the Chagas disease and to propose novel targets to prevent the development of the severe form of this disease
Summary
Chagas disease is caused by infection with the protozoan Trypanosoma cruzi (T. cruzi) and is an important cause of severe inflammatory heart disease. The canonical PI3Kγ signaling in myeloid cells is essential to restrict T. cruzi heart parasitism and to avoid myocarditis, heart damage, and death of mice. High PIK3CG expression correlates with low parasitism in human Chagas’ hearts These results indicate an essential role of the canonical PI3Kγ signaling pathway in the control of T. cruzi infection, providing further insight into the molecular mechanisms involved in the pathophysiology of chagasic heart disease. The canonical PI3Kγ pathway is upregulated in both human chagasic hearts and hearts of acutely infected mice. High PIK3CG expression correlates with low parasitism in human chagasic hearts These data identify a previously unrecognized role of the canonical PI3Kγ signaling pathway in the control of T
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