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

Maria C. Silva, Marcela Davoli-Ferreira, Tiago S. Medina, Renata Sesti-Costa, Grace K. Silva, Carla D. Lopes, Lucas E. Cardozo, Fábio N. Gava, Konstantina Lyroni, Fabrício C. Dias, Amanda F. Frade, Monique Baron, Helder I. Nakaya, Florêncio Figueiredo, José C. Alves-Filho, Fernando Q. Cunha, Christos Tsatsanis, Christophe Chevillard, Edecio Cunha-Neto, Emilio Hirsch, João S. Silva () and Thiago M. Cunha ()
Additional contact information
Maria C. Silva: University of Sao Paulo
Marcela Davoli-Ferreira: University of Sao Paulo
Tiago S. Medina: University of Sao Paulo
Renata Sesti-Costa: University of Sao Paulo
Grace K. Silva: University of Sao Paulo
Carla D. Lopes: University of Sao Paulo
Lucas E. Cardozo: University of São Paulo
Fábio N. Gava: University of Sao Paulo
Konstantina Lyroni: University of Crete
Fabrício C. Dias: University of Sao Paulo
Amanda F. Frade: University of São Paulo
Monique Baron: University of São Paulo
Helder I. Nakaya: University of São Paulo
Florêncio Figueiredo: University of Brasilia, Campus Universitário Darcy Ribeiro
José C. Alves-Filho: University of Sao Paulo
Fernando Q. Cunha: University of Sao Paulo
Christos Tsatsanis: University of Crete
Christophe Chevillard: Aix Marseille Université AMU, Parc Scientifique de Luminy case 928
Edecio Cunha-Neto: University of São Paulo
Emilio Hirsch: University of Torino
João S. Silva: University of Sao Paulo
Thiago M. Cunha: University of Sao Paulo

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03986-3

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