Canonical PI3Kγ signaling in myeloid cells restricts Trypanosoma cruzi infection and dampens chagasic myocarditis

authors

Silva Maria M
Davoli-Ferreira Marcela
Medina Tiago
Sesti-Costa Renata
Silva Grace
Lopes Carla
Cardozo Lucas
Gava Fábio
Lyroni Konstantina
Dias Fabrício
Frade Amanda Farage
Baron Monique
Nakaya Helder
Figueiredo Florêncio
Alves-Filho José
Cunha Fernando
Tsatsanis Christos
Chevillard Christophe
Cunha Edecio
Hirsch Emilio
Silva João Nuno
Cunha Thiago

keywords

Chagas disease
Protozoan infections
Heart disease
Cardiomyopathy
Canonical
Mice
Molecular mechanisms

document type

ART

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.

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