Topological DNA Damage, Telomere Attrition and T Cell Senescence During Chronic Viral Infections
Background: T cells play a key role in controlling viral infections; however, the underlying mechanisms regulating their functions during human viral infections remain incompletely understood. Here, we used CD4 T cells derived from individuals with chronic viral infections or healthy T cells treated with camptothecin (CPT) - a topoisomerase I (Top 1) inhibitor - as a model to investigate the role of DNA topology in reprogramming telomeric DNA damage responses (DDR) and remodeling T cell functions.
Results: We demonstrated that Top 1 protein expression and enzyme activity were significantly inhibited, while the Top 1 cleavage complex (TOP1cc) was trapped in genomic DNA, in T cells derived from individuals with chronic viral (HCV, HBV, or HIV) infections. Top 1 inhibition by CPT treatment of healthy CD4 T cells caused topological DNA damage, telomere attrition, and T cell apoptosis or dysfunction via inducing Top1cc accumulation, PARP1 cleavage, and failure in DNA repair, thus recapitulating T cell dysregulation in the setting of chronic viral infections. Moreover, T cells from virally infected subjects with inhibited Top 1 activity were more vulnerable to CPT-induced topological DNA damage and cell apoptosis, indicating an important role for Top 1 in securing DNA integrity and cell survival.
Conclusion: These findings provide novel insights into the molecular mechanisms for immunomodulation by chronic viral infections via disrupting DNA topology to induce telomeric DNA damage, T cell senescence, apoptosis and dysfunction. As such, restoring the impaired DNA topologic machinery may offer a new strategy for maintaining T cell function against human viral diseases.
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Ji, Yingjie; Dang, Xindi; Nguyen, Lam Ngoc Thao; Nguyen, Lam Nhat; Zhao, Jaun; Cao, Dechao; Khanal, Sushant; Schank, Madison; Wu, Xiao Y.; Morrison, Zheng D.; Zou, Yue; El Gazzar, Mohamed; Ning, Shunbin; Wang, Ling; Moorman, Jonathan P.; and Yao, Zhi Q.. 2019. Topological DNA Damage, Telomere Attrition and T Cell Senescence During Chronic Viral Infections. Immunity and Aging. Vol.16(12). 1-15. https://doi.org/10.1186/s12979-019-0153-z ISSN: 1742-4933
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