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Mitochondrial topoisomerase 1 inhibition induces topological DNA damage and T cell dysfunction in patients with chronic viral infection

T cells are crucial for controlling viral infections; however, the mechanisms that dampen their responses during viral infections remain incompletely understood. Here, we studied the role and mechanisms of mitochondrial topoisomerase 1 (Top1mt) inhibition in mitochondrial dysfunction and T cell dysr...

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Autores principales: Dang, Xindi, Cao, Dechao, Zhao, Juan, Schank, Madison, Khanal, Sushant, Nguyen, Lam Ngoc Thao, Wu, Xiao Y., Zhang, Yi, Zhang, Jinyu, Jiang, Yong, Ning, Shunbin, Wang, Ling, El Gazzar, Mohamed, Moorman, Jonathan P., Yao, Zhi Q.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9669385/
https://www.ncbi.nlm.nih.gov/pubmed/36405960
http://dx.doi.org/10.3389/fcimb.2022.1026293
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author Dang, Xindi
Cao, Dechao
Zhao, Juan
Schank, Madison
Khanal, Sushant
Nguyen, Lam Ngoc Thao
Wu, Xiao Y.
Zhang, Yi
Zhang, Jinyu
Jiang, Yong
Ning, Shunbin
Wang, Ling
El Gazzar, Mohamed
Moorman, Jonathan P.
Yao, Zhi Q.
author_facet Dang, Xindi
Cao, Dechao
Zhao, Juan
Schank, Madison
Khanal, Sushant
Nguyen, Lam Ngoc Thao
Wu, Xiao Y.
Zhang, Yi
Zhang, Jinyu
Jiang, Yong
Ning, Shunbin
Wang, Ling
El Gazzar, Mohamed
Moorman, Jonathan P.
Yao, Zhi Q.
author_sort Dang, Xindi
collection PubMed
description T cells are crucial for controlling viral infections; however, the mechanisms that dampen their responses during viral infections remain incompletely understood. Here, we studied the role and mechanisms of mitochondrial topoisomerase 1 (Top1mt) inhibition in mitochondrial dysfunction and T cell dysregulation using CD4 T cells from patients infected with HCV or HIV and compared it with CD4 T cells from healthy individuals following treatment with Top1 inhibitor - camptothecin (CPT). We found that Top1mt protein levels and enzymatic activity are significantly decreased, along with Top1 cleavage complex (Top1cc) formation, in mitochondria of CD4 T cells from HCV- and HIV-infected patients. Notably, treatment of healthy CD4 T cells with CPT caused similar changes, including inhibition of Top1mt, accumulation of Top1cc in mitochondria, increase in PARP1 cleavage, and decrease in mtDNA copy numbers. These molecular changes resulted in mitochondrial dysfunction, T cell dysregulation, and programmed cell death through multiple signaling pathways, recapitulating the phenotype we detected in CD4 T cells from HCV- and HIV-infected patients. Moreover, treatment of CD4 T cells from HCV or HIV patients with CPT further increased cellular and mitochondrial reactive oxygen species (ROS) production and cell apoptosis, demonstrating a critical role for Top1 in preventing mtDNA damage and cell death. These results provide new insights into the molecular mechanisms underlying immune dysregulation during viral infection and indicate that Top1 inhibition during chronic HCV or HIV infection can induce mtDNA damage and T cell dysfunction. Thus, reconstituting Top1mt protein may restore the mtDNA topology and T cell functions in humans with chronic viral infection.
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spelling pubmed-96693852022-11-18 Mitochondrial topoisomerase 1 inhibition induces topological DNA damage and T cell dysfunction in patients with chronic viral infection Dang, Xindi Cao, Dechao Zhao, Juan Schank, Madison Khanal, Sushant Nguyen, Lam Ngoc Thao Wu, Xiao Y. Zhang, Yi Zhang, Jinyu Jiang, Yong Ning, Shunbin Wang, Ling El Gazzar, Mohamed Moorman, Jonathan P. Yao, Zhi Q. Front Cell Infect Microbiol Cellular and Infection Microbiology T cells are crucial for controlling viral infections; however, the mechanisms that dampen their responses during viral infections remain incompletely understood. Here, we studied the role and mechanisms of mitochondrial topoisomerase 1 (Top1mt) inhibition in mitochondrial dysfunction and T cell dysregulation using CD4 T cells from patients infected with HCV or HIV and compared it with CD4 T cells from healthy individuals following treatment with Top1 inhibitor - camptothecin (CPT). We found that Top1mt protein levels and enzymatic activity are significantly decreased, along with Top1 cleavage complex (Top1cc) formation, in mitochondria of CD4 T cells from HCV- and HIV-infected patients. Notably, treatment of healthy CD4 T cells with CPT caused similar changes, including inhibition of Top1mt, accumulation of Top1cc in mitochondria, increase in PARP1 cleavage, and decrease in mtDNA copy numbers. These molecular changes resulted in mitochondrial dysfunction, T cell dysregulation, and programmed cell death through multiple signaling pathways, recapitulating the phenotype we detected in CD4 T cells from HCV- and HIV-infected patients. Moreover, treatment of CD4 T cells from HCV or HIV patients with CPT further increased cellular and mitochondrial reactive oxygen species (ROS) production and cell apoptosis, demonstrating a critical role for Top1 in preventing mtDNA damage and cell death. These results provide new insights into the molecular mechanisms underlying immune dysregulation during viral infection and indicate that Top1 inhibition during chronic HCV or HIV infection can induce mtDNA damage and T cell dysfunction. Thus, reconstituting Top1mt protein may restore the mtDNA topology and T cell functions in humans with chronic viral infection. Frontiers Media S.A. 2022-11-03 /pmc/articles/PMC9669385/ /pubmed/36405960 http://dx.doi.org/10.3389/fcimb.2022.1026293 Text en Copyright © 2022 Dang, Cao, Zhao, Schank, Khanal, Nguyen, Wu, Zhang, Zhang, Jiang, Ning, Wang, El Gazzar, Moorman and Yao https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular and Infection Microbiology
Dang, Xindi
Cao, Dechao
Zhao, Juan
Schank, Madison
Khanal, Sushant
Nguyen, Lam Ngoc Thao
Wu, Xiao Y.
Zhang, Yi
Zhang, Jinyu
Jiang, Yong
Ning, Shunbin
Wang, Ling
El Gazzar, Mohamed
Moorman, Jonathan P.
Yao, Zhi Q.
Mitochondrial topoisomerase 1 inhibition induces topological DNA damage and T cell dysfunction in patients with chronic viral infection
title Mitochondrial topoisomerase 1 inhibition induces topological DNA damage and T cell dysfunction in patients with chronic viral infection
title_full Mitochondrial topoisomerase 1 inhibition induces topological DNA damage and T cell dysfunction in patients with chronic viral infection
title_fullStr Mitochondrial topoisomerase 1 inhibition induces topological DNA damage and T cell dysfunction in patients with chronic viral infection
title_full_unstemmed Mitochondrial topoisomerase 1 inhibition induces topological DNA damage and T cell dysfunction in patients with chronic viral infection
title_short Mitochondrial topoisomerase 1 inhibition induces topological DNA damage and T cell dysfunction in patients with chronic viral infection
title_sort mitochondrial topoisomerase 1 inhibition induces topological dna damage and t cell dysfunction in patients with chronic viral infection
topic Cellular and Infection Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9669385/
https://www.ncbi.nlm.nih.gov/pubmed/36405960
http://dx.doi.org/10.3389/fcimb.2022.1026293
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