mTOR signaling inhibition decreases lysosome migration and impairs the success of Trypanosoma cruzi infection and replication in cardiomyocytes

Author(s)

Alvim, Juliana M. ; Venturini, Gabriela ; Oliveira, Theo G. M. ; Seidman, Jonathan G. ; Seidman, Christine E. ; Krieger, Jose E. ; Pereira, Alexandre C.

• Document type: Journal article
• Source: Acta Tropica; v. 240, p. 9-pg., 2023-02-01.

Abstract

Chagas disease is caused by the parasite Trypanosoma cruzi (T. cruzi) and, among all the chronic manifestations of the disease, Chronic Chagas Cardiomyopathy (CCC) is the most severe outcome. Despite high burden and public health importance in Latin America, there is a gap in understanding the molecular mechanisms that results in CCC development. Previous studies showed that T. cruzi uses the host machinery for infection and replication, including the repurposing of the responses to intracellular infection such as mitochondrial activity, vacuolar membrane, and lysosomal activation in benefit of parasite infection and replication. One common signaling upstream to many responses to parasite infection is mTOR pathway, previous associated to several downstream cellular mechanisms including autophagy, mitophagy and lysosomal activation. Here, using human iPSC derived cardiomyocytes (hiPSC-CM), we show the mTOR pathway is activated in hiPSC-CM after T. cruzi infection, and the inhibition of mTOR with rapamycin reduced number of T. cruzi 48 h post infection (hpi). Rapamycin treatment also reduced lysosome migration from nuclei region to cell periphery resulting in less T. cruzi inside the parasitophorous vacuole (PV) in the first hour of infection. In addition, the number of parasites leaving the PV to the cytoplasm to replicate in later times of infection was also lower after rapamycin treatment. Altogether, our data suggest that host's mTOR activation concomitant with parasite infection modulates lysosome migration and that T. cruzi uses this mechanism to achieve infection and replication. Modulating this mechanism with rapamycin impaired the success of T. cruzi life cycle independent of mitophagy. (AU)

• FAPESP's process: 17/13706-0 - Comprehensive T. cruzi and auto-antibody profiling in Chagas cardiomyopathy: leveraging phage-display and next-generation sequencing to reassess an old hypothesis
• Grantee: Gabriela Venturini da Silva
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/25845-1 - Evaluation of the importance of glycolytic pathway, oxidative stress and fatty acid synthesis in the infection of cardiomyocytes by Trypanosoma cruzi
• Grantee: Juliana Morais Alvim
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 19/11821-1 - Construction of Trypanosoma cruzi epitope phage display library to identify antibody profile in chronic Chagas cardiomyopathy
• Grantee: Gabriela Venturini da Silva
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor