Canonical PI3K gamma signaling in myeloid cells restricts Trypanosoma cruzi infection and dampens chagasic myocarditis

Author(s):Show less -

Silva, Maria C. ^{[1, 2, 3]} ; Davoli-Ferreira, Marcela ^{[1, 2]} ; Medina, Tiago S. ^[2] ; Sesti-Costa, Renata ^[2] ; Silva, Grace K. ^[2] ; Lopes, Carla D. ^[2] ; Cardozo, Lucas E. ^[4] ; Gava, Fabio N. ^[5] ; Lyroni, Konstantina ^[6] ; Dias, Fabricio C. ^[2] ; Frade, Amanda F. ^{[7, 8]} ; Baron, Monique ^[7] ; Nakaya, Helder I. ^[4] ; Figueiredo, Florencio ^[9] ; Alves-Filho, Jose C. ^[1] ; Cunha, Fernando Q. ^[1] ; Tsatsanis, Christos ^[6] ; Chevillard, Christophe ^[10] ; Cunha-Neto, Edecio ^{[7, 11, 12]} ; Hirsch, Emilio ^[13] ; Silva, Joao S. ^[2] ; Cunha, Thiago M. ^[1]

Affiliation:Show less -

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Bandeirantes Ave 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Fiocruz Bi Inst Translat Med Plataform, Dept Biochem & Immunol, Bandeirantes Ave 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Univ Catolica Dom Bosco, Post Grad Program Biotechnol, Campo Grande, MS - Brazil

^[4] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, BR-05508900 Sao Paulo, SP - Brazil

^[5] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Physiol, Bandeirantes Ave 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[6] Univ Crete, Sch Med, Lab Clin Chem, Iraklion 71003 - Greece

^[7] Univ Sao Paulo, Sch Med, Heart Inst InCor, Lab Immunol, BR-05403900 Sao Paulo, SP - Brazil

^[8] Brazil Univ, Dept Bioengn, Rua Carolina Fonseca 234 Campus II, BR-08230030 Sao Paulo, SP - Brazil

^[9] Univ Brasilia, Sch Med, Lab Pathol, Campus Univ Darcy Ribeiro, BR-70910900 Brasilia, DF - Brazil

^[10] Aix Marseille Univ AMU, TAGC INSERM U1090, Parc Sci Luminy Case 928, 163 Ave Luminy, F-13288 Marseille 09 - France

^[11] Univ Sao Paulo, Sch Med, Div Clin Immunol & Allergy, BR-05403900 Sao Paulo, SP - Brazil

^[12] Inst Invest Immunol Iii INCT, BR-05403900 Sao Paulo, SP - Brazil

^[13] Univ Torino, Dept Mol Biotechnol & Hlth Sci, Mol Biotechnol Ctr, I-10126 Turin - Italy

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 9, APR 17 2018.
• Web of Science Citations: 6

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 PI3K gamma pathway is upregulated in both human chagasic hearts and hearts of acutely infected mice. PI3K gamma-deficient mice and mutant mice carrying catalytically inactive PI3K gamma are more susceptible to T. cruzi infection. The canonical PI3K gamma 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 PI3K gamma signaling pathway in the control of T. cruzi infection, providing further insight into the molecular mechanisms involved in the pathophysiology of chagasic heart disease. (AU)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 12/14524-9 - Modulation of T lymphocytes differentiation in infections by Protozoa, Fungi and Bacteria
• Grantee: João Santana da Silva
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 11/09488-0 - Investigation of the mechanisms involved in the susceptibility to Trypanosoma cruzi infection in phosphatidylinositol 3-kinase gamma (PI3Kgama) deficient mouse
• Grantee: Maria Cláudia da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate