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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2019 |
|---|---|
| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
|---|---|
| Enthalten in: |
Immunity & ageing : I & A - 16(2019) vom: 04., Seite 12 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Ji, Yingjie [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
HBV |
|---|
| Anmerkungen: |
Date Revised 18.04.2024 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.1186/s12979-019-0153-z |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM298990873 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM298990873 | ||
| 003 | DE-627 | ||
| 005 | 20240418232102.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2019 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1186/s12979-019-0153-z |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1379.xml |
| 035 | |a (DE-627)NLM298990873 | ||
| 035 | |a (NLM)31285747 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Ji, Yingjie |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Topological DNA damage, telomere attrition and T cell senescence during chronic viral infections |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 18.04.2024 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a HBV | |
| 650 | 4 | |a HCV | |
| 650 | 4 | |a HIV | |
| 650 | 4 | |a T cell senescence | |
| 650 | 4 | |a Telomere attrition | |
| 650 | 4 | |a Topological DNA damage | |
| 700 | 1 | |a Dang, Xindi |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Lam Ngoc Thao |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Lam Nhat |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Juan |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Dechao |e verfasserin |4 aut | |
| 700 | 1 | |a Khanal, Sushant |e verfasserin |4 aut | |
| 700 | 1 | |a Schank, Madison |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Xiao Y |e verfasserin |4 aut | |
| 700 | 1 | |a Morrison, Zheng D |e verfasserin |4 aut | |
| 700 | 1 | |a Zou, Yue |e verfasserin |4 aut | |
| 700 | 1 | |a El Gazzar, Mohamed |e verfasserin |4 aut | |
| 700 | 1 | |a Ning, Shunbin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Moorman, Jonathan P |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Zhi Q |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Immunity & ageing : I & A |d 2004 |g 16(2019) vom: 04., Seite 12 |w (DE-627)NLM153387815 |x 1742-4933 |7 nnns |
| 773 | 1 | 8 | |g volume:16 |g year:2019 |g day:04 |g pages:12 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1186/s12979-019-0153-z |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 16 |j 2019 |b 04 |h 12 | ||