Canonical PI3Kγ signaling in myeloid cells restricts Trypanosoma cruzi infection and dampens chagasic myocarditis.
Maria C SilvaMarcela Davoli-FerreiraTiago S MedinaRenata Sesti-CostaGrace K SilvaCarla D LopesLucas E CardozoFábio N GavaKonstantina LyroniFabrício C DiasAmanda F FradeMonique BaronHelder Takashi Imoto NakayaFlorêncio FigueiredoJosé C Alves-FilhoFernando Q CunhaChristos TsatsanisChristophe ChevillardEdécio Cunha-NetoEmilio HirschJoão S SilvaThiago M CunhaPublished in: Nature communications (2018)
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.
Keyphrases
- trypanosoma cruzi
- induced apoptosis
- signaling pathway
- endothelial cells
- heart failure
- oxidative stress
- high fat diet induced
- cell cycle arrest
- bone marrow
- pulmonary hypertension
- acute myeloid leukemia
- poor prognosis
- atrial fibrillation
- wild type
- endoplasmic reticulum stress
- type diabetes
- cell death
- induced pluripotent stem cells
- pluripotent stem cells
- skeletal muscle
- insulin resistance