An exacerbated metabolism and mitochondrial reactive oxygen species contribute to mitochondrial alterations and apoptosis in CD4 T cells during the acute phase of Trypanosoma cruzi infection

Ana, Yamile; Marquez, J.; Fozzatti, Laura; Baigorrí, R.E.; Marı́n, Clotilde; Maletto, Belkys A.; Cerbán, Fabio M.; Radí, Rafael; Piacenza, Lucı́a; Stempin, Cinthia Carolina

doi:10.1016/j.freeradbiomed.2020.12.009

Cited by 12 publications

(10 citation statements)

References 65 publications

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“…Although healthy cardiomyocytes preferentially metabolize fatty acids, infected iPSC-CMs adopted glycolysis with increased glucose consumption and lactate secretion. The same glycolysis activation was identified in CD4 T-cells during both the acute and chronic phases of T. cruzi infected mice ( Ana et al., 2021 ). Additionally, upregulation of glycolysis genes such as PFKB, PDK3 and PGAM1 have been described in the hearts of T. cruzi infected mice ( Bruno et al., 2020 ).…”

Section: Discussionsupporting

confidence: 58%

Cardiomyocyte infection by Trypanosoma cruzi promotes innate immune response and glycolysis activation

Venturini

Alvim

Padilha

et al. 2023

Front. Cell. Infect. Microbiol.

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IntroductionChagas cardiomyopathy, a disease caused by Trypanosoma cruzi (T. cruzi) infection, is a major contributor to heart failure in Latin America. There are significant gaps in our understanding of the mechanism for infection of human cardiomyocytes, the pathways activated during the acute phase of the disease, and the molecular changes that lead to the progression of cardiomyopathy.MethodsTo investigate the effects of T. cruzi on human cardiomyocytes during infection, we infected induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) with the parasite and analyzed cellular, molecular, and metabolic responses at 3 hours, 24 hours, and 48 hours post infection (hpi) using transcriptomics (RNAseq), proteomics (LC-MS), and metabolomics (GC-MS and Seahorse) analyses.ResultsAnalyses of multiomic data revealed that cardiomyocyte infection caused a rapid increase in genes and proteins related to activation innate and adaptive immune systems and pathways, including alpha and gamma interferons, HIF-1α signaling, and glycolysis. These responses resemble prototypic responses observed in pathogen-activated immune cells. Infection also caused an activation of glycolysis that was dependent on HIF-1α signaling. Using gene editing and pharmacological inhibitors, we found that T. cruzi uptake was mediated in part by the glucose-facilitated transporter GLUT4 and that the attenuation of glycolysis, HIF-1α activation, or GLUT4 expression decreased T. cruzi infection. In contrast, pre-activation of pro-inflammatory immune responses with LPS resulted in increased infection rates.ConclusionThese findings suggest that T. cruzi exploits a HIF-1α-dependent, cardiomyocyte-intrinsic stress-response activation of glycolysis to promote intracellular infection and replication. These chronic immuno-metabolic responses by cardiomyocytes promote dysfunction, cell death, and the emergence of cardiomyopathy.

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Section: Discussionsupporting

confidence: 58%

Cardiomyocyte infection by Trypanosoma cruzi promotes innate immune response and glycolysis activation

Venturini

Alvim

Padilha

et al. 2023

Front. Cell. Infect. Microbiol.

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“…SOD2 is a potent antioxidant enzyme, which binds to the superoxide anions to convert them to hydrogen peroxide and oxygen (53). An increase in expression could be beneficial by decreasing reactive oxygen species production as it was described in CD4 + T cells during the acute phase of Trypanosoma cruzi infection early during T cell expansion (54). Similar to SOD3, SOD2 could also control the activation and differentiation of CD4+ T cells (55).…”

Section: Discussionmentioning

confidence: 96%

Antigen-specific downregulation of miR-150 in CD4 T cells promotes cell survival

et al. 2023

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MicroRNA-150 (miR-150) has been shown to play a general role in the immune system, but very little is known about its role on CD4+ T cell responses. During T cell responses against superantigen Staphylococcal Enterotoxin A, miR-150 expression was down-regulated in antigen-specific CD4+ T cells but up-regulated in CD8+ T cells. CD4+ and CD8+ T cell clonal expansion was greater in miR-150-KO mice than in WT mice, but miR-150 selectively repressed IL-2 production in CD4+ T cells. Transcriptome analysis of CD4+ T cells demonstrated that apoptosis and mTOR pathways were highly enriched in the absence of miR-150. Mechanistic studies confirmed that miR-150 promoted apoptosis specifically in antigen-specific CD4+ T cells, but not in bystander CD4+ nor in CD8+ T cells. Furthermore, inhibition of mTOR-linked mitochondrial superoxidedismutase-2 increased apoptosis in miR-150-/- antigen-specific CD4+ T. Thus, miR-150 impacts CD4+ T cell helper activity by attenuating IL-2 production along with clonal expansion, and suppresses superoxidedismutase to promote apoptosis.

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“…To survive, parasites interact with host cells and regulate host cell apoptosis through multiple pathways, a process that has been shown to be one of the pathogenic mechanisms of parasites ( Kapczuk et al, 2020 ). Trypanosomes can induce apoptosis in mature CD 4+ T cells ( Ana et al, 2021 ). Schistosoma japonicum can promote cell apoptosis by increasing the expression of Fas and FasL in CD 4+ and CD 8+ T cells ( Lundy et al, 2001 ).…”

Section: Discussionmentioning

confidence: 99%

The role of Ca2+ in the injury of host cells during the schizogenic stage of E. tenella

Wang

Zheng

et al. 2022

Poultry Science

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An exacerbated metabolism and mitochondrial reactive oxygen species contribute to mitochondrial alterations and apoptosis in CD4 T cells during the acute phase of Trypanosoma cruzi infection

Cited by 12 publications

References 65 publications

Cardiomyocyte infection by Trypanosoma cruzi promotes innate immune response and glycolysis activation

Cardiomyocyte infection by Trypanosoma cruzi promotes innate immune response and glycolysis activation

Antigen-specific downregulation of miR-150 in CD4 T cells promotes cell survival

The role of Ca2+ in the injury of host cells during the schizogenic stage of E. tenella

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