The Redox Homeostasis of Skeletal Muscle Cells Regulates Stage Differentiation of Toxoplasma gondii

Toxoplasma gondii is an obligatory intracellular parasite that causes persistent infections in birds and mammals including ~30% of the world’s human population. Differentiation from proliferative and metabolically active tachyzoites to largely dormant bradyzoites initiates the chronic phase of infec...

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Autores principales:	Md. Taibur Rahman, Izabela J. Swierzy, Bryan Downie, Gabriela Salinas, Martin Blume, Malcolm J. McConville, Carsten G. K. Lüder
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Toxoplasma gondii stage conversion skeletal muscle redox homeostasis host metabolism Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c5e5abb9b8f842f2bf5b69645e92e298
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spelling	oai:doaj.org-article:c5e5abb9b8f842f2bf5b69645e92e2982021-11-22T07:25:31ZThe Redox Homeostasis of Skeletal Muscle Cells Regulates Stage Differentiation of Toxoplasma gondii2235-298810.3389/fcimb.2021.798549https://doaj.org/article/c5e5abb9b8f842f2bf5b69645e92e2982021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcimb.2021.798549/fullhttps://doaj.org/toc/2235-2988Toxoplasma gondii is an obligatory intracellular parasite that causes persistent infections in birds and mammals including ~30% of the world’s human population. Differentiation from proliferative and metabolically active tachyzoites to largely dormant bradyzoites initiates the chronic phase of infection and occurs predominantly in brain and muscle tissues. Here we used murine skeletal muscle cells (SkMCs) to decipher host cellular factors that favor T. gondii bradyzoite formation in terminally differentiated and syncytial myotubes, but not in proliferating myoblast precursors. Genome-wide transcriptome analyses of T. gondii-infected SkMCs and non-infected controls identified ~6,500 genes which were differentially expressed (DEGs) in myotubes compared to myoblasts, largely irrespective of infection. On the other hand, genes related to central carbohydrate metabolism, to redox homeostasis, and to the Nrf2-dependent stress response pathway were enriched in both infected myoblast precursors and myotubes. Stable isotope-resolved metabolite profiling indicated increased fluxes into the oxidative branch of the pentose phosphate pathway (OxPPP) in infected myoblasts and into the TCA cycle in infected myotubes. High OxPPP activity in infected myoblasts was associated with increased NADPH/NADP+ ratio while myotubes exhibited higher ROS levels and lower expression of anti-oxidants and detoxification enzymes. Pharmacological reduction of ROS levels in SkMCs inhibited bradyzoite differentiation, while increased ROS induced bradyzoite formation. Thus, we identified a novel host cell-dependent mechanism that triggers stage conversion of T. gondii into persistent tissue cysts in its natural host cell type.Md. Taibur RahmanMd. Taibur RahmanIzabela J. SwierzyBryan DownieGabriela SalinasMartin BlumeMartin BlumeMalcolm J. McConvilleCarsten G. K. LüderFrontiers Media S.A.articleToxoplasma gondiistage conversionskeletal muscleredox homeostasishost metabolismMicrobiologyQR1-502ENFrontiers in Cellular and Infection Microbiology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Toxoplasma gondii stage conversion skeletal muscle redox homeostasis host metabolism Microbiology QR1-502
spellingShingle	Toxoplasma gondii stage conversion skeletal muscle redox homeostasis host metabolism Microbiology QR1-502 Md. Taibur Rahman Md. Taibur Rahman Izabela J. Swierzy Bryan Downie Gabriela Salinas Martin Blume Martin Blume Malcolm J. McConville Carsten G. K. Lüder The Redox Homeostasis of Skeletal Muscle Cells Regulates Stage Differentiation of Toxoplasma gondii
description	Toxoplasma gondii is an obligatory intracellular parasite that causes persistent infections in birds and mammals including ~30% of the world’s human population. Differentiation from proliferative and metabolically active tachyzoites to largely dormant bradyzoites initiates the chronic phase of infection and occurs predominantly in brain and muscle tissues. Here we used murine skeletal muscle cells (SkMCs) to decipher host cellular factors that favor T. gondii bradyzoite formation in terminally differentiated and syncytial myotubes, but not in proliferating myoblast precursors. Genome-wide transcriptome analyses of T. gondii-infected SkMCs and non-infected controls identified ~6,500 genes which were differentially expressed (DEGs) in myotubes compared to myoblasts, largely irrespective of infection. On the other hand, genes related to central carbohydrate metabolism, to redox homeostasis, and to the Nrf2-dependent stress response pathway were enriched in both infected myoblast precursors and myotubes. Stable isotope-resolved metabolite profiling indicated increased fluxes into the oxidative branch of the pentose phosphate pathway (OxPPP) in infected myoblasts and into the TCA cycle in infected myotubes. High OxPPP activity in infected myoblasts was associated with increased NADPH/NADP+ ratio while myotubes exhibited higher ROS levels and lower expression of anti-oxidants and detoxification enzymes. Pharmacological reduction of ROS levels in SkMCs inhibited bradyzoite differentiation, while increased ROS induced bradyzoite formation. Thus, we identified a novel host cell-dependent mechanism that triggers stage conversion of T. gondii into persistent tissue cysts in its natural host cell type.
format	article
author	Md. Taibur Rahman Md. Taibur Rahman Izabela J. Swierzy Bryan Downie Gabriela Salinas Martin Blume Martin Blume Malcolm J. McConville Carsten G. K. Lüder
author_facet	Md. Taibur Rahman Md. Taibur Rahman Izabela J. Swierzy Bryan Downie Gabriela Salinas Martin Blume Martin Blume Malcolm J. McConville Carsten G. K. Lüder
author_sort	Md. Taibur Rahman
title	The Redox Homeostasis of Skeletal Muscle Cells Regulates Stage Differentiation of Toxoplasma gondii
title_short	The Redox Homeostasis of Skeletal Muscle Cells Regulates Stage Differentiation of Toxoplasma gondii
title_full	The Redox Homeostasis of Skeletal Muscle Cells Regulates Stage Differentiation of Toxoplasma gondii
title_fullStr	The Redox Homeostasis of Skeletal Muscle Cells Regulates Stage Differentiation of Toxoplasma gondii
title_full_unstemmed	The Redox Homeostasis of Skeletal Muscle Cells Regulates Stage Differentiation of Toxoplasma gondii
title_sort	redox homeostasis of skeletal muscle cells regulates stage differentiation of toxoplasma gondii
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/c5e5abb9b8f842f2bf5b69645e92e298
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The Redox Homeostasis of Skeletal Muscle Cells Regulates Stage Differentiation of Toxoplasma gondii

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