Immune Activation Induces Telomeric DNA Damage and Promotes Short‐Lived Effector T Cell Differentiation in Chronic HCV Infection

Nguyen, Lam Nhat; Zhao, Juan; Schank, Madison; Dang, Xindi; Cao, Dechao; Khanal, Sushant; Thakuri, Bal Krishna Chand; Zhang, Jinyu; Lu, Zeyuan; Wu, Xiao Y.; Gazzar, Mohamed El; Ning, Shunbin; Moorman, Jonathan P.; Yao, Zhi Q.

doi:10.1002/hep.32008

Cited by 13 publications

(16 citation statements)

References 46 publications

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“…Research highlights the role of mitochondria in regulating macrophage polarization and the release of pro-inflammatory cytokines (40). In line with this, we have previously shown that HCV infection can induce CD4 T cell dysfunction, characterized by aberrant cell differentiation, ROS overproduction, accelerated DNA damage and telomere attrition, increased cellular senescence, impaired DNA damage repair pathways, and increased apoptosis (19,22,23,41).…”

Section: Discussionmentioning

confidence: 67%

“…Recently, we have shown CD4 T cell hyperactivation of Akt/mTOR/pS6 signaling following TCR stimulation, which in turn led to elevated expression of inflammatory cytokines and increased DNA damage and cellular apoptosis ( 41 ). Other studies revealed that inhibition of mTOR signaling can reduce ROS production and restore T cell functions ( 42 , 43 ).…”

Section: Discussionmentioning

confidence: 99%

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Oxidative Stress Induces Mitochondrial Compromise in CD4 T Cells From Chronically HCV-Infected Individuals

et al. 2021

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We have previously shown that chronic Hepatitis C virus (HCV) infection can induce DNA damage and immune dysfunctions with excessive oxidative stress in T cells. Furthermore, evidence suggests that HCV contributes to increased susceptibility to metabolic disorders. However, the underlying mechanisms by which HCV infection impairs cellular metabolism in CD4 T cells remain unclear. In this study, we evaluated mitochondrial mass and intracellular and mitochondrial reactive oxygen species (ROS) production by flow cytometry, mitochondrial DNA (mtDNA) content by real-time qPCR, cellular respiration by seahorse analyzer, and dysregulated mitochondrial-localized proteins by Liquid Chromatography-Mass Spectrometry (LC-MS) in CD4 T cells from chronic HCV-infected individuals and health subjects. Mitochondrial mass was decreased while intracellular and mitochondrial ROS were increased, expressions of master mitochondrial regulators peroxisome proliferator-activated receptor 1 alpha (PGC-1α) and mitochondrial transcription factor A (mtTFA) were down-regulated, and oxidative stress was increased while mitochondrial DNA copy numbers were reduced. Importantly, CRISPR/Cas9-mediated knockdown of mtTFA impaired cellular respiration and reduced mtDNA copy number. Furthermore, proteins responsible for mediating oxidative stress, apoptosis, and mtDNA maintenance were significantly altered in HCV-CD4 T cells. These results indicate that mitochondrial functions are compromised in HCV-CD4 T cells, likely via the deregulation of several mitochondrial regulatory proteins.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Oxidative Stress Induces Mitochondrial Compromise in CD4 T Cells From Chronically HCV-Infected Individuals

et al. 2021

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“…Infection of PBMCs results in persistence of infection, chronic immune activation, and exhaustion of the immune system (17,31,32). Similar to other viral infections, HCV infection often induces an IFN response which is recognized by the production and secretion of proinflammatory cytokines, including IL-6 and IFN type-1, which have antimicrobial and antiproliferative characteristics, and activate the adaptive immune responses.…”

Section: Infection Of Peripheral Blood Mononuclear Cells With Hepatitis C Virus and Disruption Of Cell Signaling Pathwaysmentioning

confidence: 99%

Impact of Hepatitis C Virus Infection of Peripheral Blood Mononuclear Cells on the Immune System

Alhetheel

2022

Front.Virol.

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Hepatitis C is a worldwide liver disease caused by hepatitis C virus (HCV) infection. The virus causes acute and chronic liver inflammation, and it is transmitted mainly by exposure to contaminated blood. HCV is capable of infecting hepatocytes and peripheral blood mononuclear cells, causing complications and disease progression. This mini review provides an overview of HCV infection, including details on the virological aspects, infection of the immune cells, and its impact on the immune system.

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“…Recently, Yao's group demonstrated that circulating CD4 + T cells from patients who are chronically HCV infected exhibit an immune activation status that leads to telomere damage (74). Heroin use has been related to immune impairment in the brain and increased neuroinflammatory response; moreover, studies have revealed TL attrition and decreased telomerase activity in the blood of heroin users when compared to controls (37,75,76).…”

Section: Discussionmentioning

confidence: 99%

Mental Disorders Are Associated With Leukocytes Telomere Shortening Among People Who Inject Drugs

et al. 2022

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Premature biological aging, assessed by shorter telomere length (TL) and mitochondrial DNA (mtDNA) alterations, has been reported among people with major depressive disorders or psychotic disorders. However, these markers have never been assessed together among people who inject drugs (PWIDs), although mental disorders are highly prevalent in this population, which, in addition, is subject to other aggravating exposures. Diagnosis of mental disorders was performed by a psychiatrist using the Mini International Neuropsychiatric Interview test among active PWIDs in Haiphong, Vietnam. mtDNA copy number (MCN), mtDNA deletion, and TL were assessed by quantitative PCR and compared to those without any mental disorder. We next performed a multivariate analysis to identify risk factors associated with being diagnosed with a major depressive episode (MDE) or a psychotic syndrome (PS). In total, 130 and 136 PWIDs with and without psychiatric conditions were analyzed. Among PWIDs with mental disorders, 110 and 74 were diagnosed with MDE and PS, respectively. TL attrition was significantly associated with hepatitis C virus-infected PWIDs with MDE or PS (adjusted odds ratio [OR]: 0.53 [0.36; 0.80] and 0.59 [0.39; 0.88], respectively). TL attrition was even stronger when PWIDs cumulated at least two episodes of major depressive disorders. On the other hand, no difference was observed in mtDNA alterations between groups. The telomeric age difference with drug users without a diagnosis of psychiatric condition was estimated during 4.2–12.8 years according to the number of MDEs, making this group more prone to age-related diseases.

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Immune Activation Induces Telomeric DNA Damage and Promotes Short‐Lived Effector T Cell Differentiation in Chronic HCV Infection

Cited by 13 publications

References 46 publications

Oxidative Stress Induces Mitochondrial Compromise in CD4 T Cells From Chronically HCV-Infected Individuals

Oxidative Stress Induces Mitochondrial Compromise in CD4 T Cells From Chronically HCV-Infected Individuals

Impact of Hepatitis C Virus Infection of Peripheral Blood Mononuclear Cells on the Immune System

Mental Disorders Are Associated With Leukocytes Telomere Shortening Among People Who Inject Drugs

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