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

Autor(es)

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

• Tipo de documento: Artigo Científico
• Fonte: Acta Tropica; v. 240, p. 9-pg., 2023-02-01.

Resumo

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)

• Processo FAPESP: 17/13706-0 - Perfil completo de anticorpos contra T. cruzi e auto-anticorpo na cardiomiopatia chagásica: utilizando tecnologias de phage display e sequenciamento da próxima geração para reavaliar uma hipótese antiga
• Beneficiário: Gabriela Venturini da Silva
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 16/25845-1 - Avaliação do papel da via glicolítica, estresse oxidativo e síntese de ácidos graxos na infecção de cardiomiócitos por Trypanosoma cruzi
• Beneficiário: Juliana Morais Alvim
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 19/11821-1 - Construção de uma biblioteca de phage display de epítopos de Trypanosoma cruzi para identificação de um perfil de anticorpos em cardiomiopatia chagásica crônica
• Beneficiário: Gabriela Venturini da Silva
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado