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

Maria M Silva (1) , Marcela Davoli-Ferreira , Tiago Medina , Renata Sesti-Costa , Grace Silva , Carla Lopes (2) , Lucas Cardozo , Fábio Gava , Konstantina Lyroni , Fabrício Dias (3) , Amanda Farage Frade (4) , Monique Baron , Helder Nakaya (5) , Florêncio Figueiredo , José Alves-Filho , Fernando Cunha , Christos Tsatsanis , Christophe Chevillard (6) , Edecio Cunha , Emilio Hirsch (7) , João Nuno Silva (8) , Thiago Cunha

1 University of Minho [Braga]
2 Universidade do Porto = University of Porto
3 FMRP - School of Medicine of Ribeirão Preto
4 InCor - Heart Institute
5 Yerkes National Primate Research Center [Lawrenceville, GA]
6 TAGC - Theories and Approaches of Genomic Complexity
7 Department of Genetics, Biology and Biochemistry
8 INESC-ID - Instituto de Engenharia de Sistemas e Computadores Investigação e Desenvolvimento em Lisboa

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.

Keywords: Chagas disease; Protozoan infections; Heart disease; Cardiomyopathy; Canonical; Mice; Molecular mechanisms

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]; Biochemistry, Molecular Biology; Life Sciences [q-bio]; Biochemistry, Molecular Biology; Molecular biology; Life Sciences [q-bio]; Microbiology and Parasitology; Life Sciences [q-bio]; Microbiology and Parasitology; Parasitology

Maria M Silva, Marcela Davoli-Ferreira, Tiago Medina, Renata Sesti-Costa, Grace Silva, et al.. Canonical PI3Kγ signaling in myeloid cells restricts Trypanosoma cruzi infection and dampens chagasic myocarditis. Nature Communications, 2018, 9 (1), ⟨10.1038/s41467-018-03986-3⟩. ⟨hal-01784218⟩