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1.
Int J Mol Sci ; 23(1)2021 Dec 31.
Article in English | MEDLINE | ID: covidwho-1580694

ABSTRACT

Telomeres are localized at the end of chromosomes to provide genome stability; however, the telomere length tends to be shortened with each cell division inducing a progressive telomere shortening (TS). In addition to age, other factors, such as exposure to pollutants, diet, stress, and disruptions in the shelterin protein complex or genes associated with telomerase induce TS. This phenomenon favors cellular senescence and genotoxic stress, which increases the risk of the development and progression of lung diseases such as idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, SARS-CoV-2 infection, and lung cancer. In an infectious environment, immune cells that exhibit TS are associated with severe lymphopenia and death, whereas in a noninfectious context, naïve T cells that exhibit TS are related to cancer progression and enhanced inflammatory processes. In this review, we discuss how TS modifies the function of the immune system cells, making them inefficient in maintaining homeostasis in the lung. Finally, we discuss the advances in drug and gene therapy for lung diseases where TS could be used as a target for future treatments.


Subject(s)
Lung Diseases/genetics , Lung Diseases/immunology , Telomere Shortening/immunology , Animals , COVID-19/genetics , COVID-19/immunology , Cellular Senescence/genetics , Genetic Therapy/methods , Humans , Immunotherapy/methods , Lung Diseases/drug therapy
2.
Cells ; 10(9)2021 08 25.
Article in English | MEDLINE | ID: covidwho-1374305

ABSTRACT

According to the neurological symptoms of SARS-CoV-2 infection, it is known that the nervous system is influenced by the virus. We used pediatric human cerebral cortical cell line HCN-2 as a neuronal model of SARS-CoV-2 infection, and, through transcriptomic analysis, our aim was to evaluate the effect of SARS-CoV-2 in this type of cells. Transcriptome analyses revealed impairment in TXN gene, resulting in deregulation of its antioxidant functions, as well as a decrease in the DNA-repairing mechanism, as indicated by the decrease in KAT5. Western blot analyses of SOD1 and iNOS confirmed the impairment of reduction mechanisms and an increase in oxidative stress. Upregulation of CDKN2A and a decrease in CDK4 and CDK6 point to the blocking of the cell cycle that, according to the deregulation of repairing mechanism, has apoptosis as the outcome. A high level of proapoptotic gene PMAIP1 is indeed coherent with neuronal death, as also supported by increased levels of caspase 3. The upregulation of cell-cycle-blocking genes and apoptosis suggests a sufferance state of neurons after SARS-CoV-2 infection, followed by their inevitable death, which can explain the neurological symptoms reported. Further analyses are required to deeply explain the mechanisms and find potential treatments to protect neurons from oxidative stress and prevent their death.


Subject(s)
COVID-19/genetics , COVID-19/virology , Cellular Senescence/genetics , Gene Expression Profiling , Neurons/pathology , Oxidative Stress/genetics , SARS-CoV-2/physiology , Caspase 3/metabolism , Cell Death , Cell Line , Cyclooxygenase 2/metabolism , Humans , Superoxide Dismutase/metabolism , Virus Replication/physiology
3.
Viruses ; 13(8)2021 08 12.
Article in English | MEDLINE | ID: covidwho-1355052

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), a global pandemic characterized by an exaggerated immune response and respiratory illness. Age (>60 years) is a significant risk factor for developing severe COVID-19. To better understand the host response of the aged airway epithelium to SARS-CoV-2 infection, we performed an in vitro study using primary human bronchial epithelial cells from donors >67 years of age differentiated on an air-liquid interface culture. We demonstrate that SARS-CoV-2 infection leads to early induction of a proinflammatory response and a delayed interferon response. In addition, we observed changes in the genes and pathways associated with cell death and senescence throughout infection. In summary, our study provides new and important insights into the temporal kinetics of the airway epithelial innate immune response to SARS-CoV-2 in older individuals.


Subject(s)
Bronchi/immunology , Bronchi/virology , Immunity, Innate , Respiratory Mucosa/immunology , Respiratory Mucosa/virology , SARS-CoV-2/immunology , Aged , Aging/immunology , Bronchi/cytology , Bronchi/metabolism , COVID-19/immunology , Cell Death/genetics , Cells, Cultured , Cellular Senescence/genetics , Cytokines/biosynthesis , Cytokines/genetics , Epithelial Cells/immunology , Epithelial Cells/metabolism , Epithelial Cells/virology , Female , Humans , Inflammation , Interferons/biosynthesis , Interferons/genetics , Male , RNA-Seq , Respiratory Mucosa/cytology , Respiratory Mucosa/metabolism , SARS-CoV-2/physiology , Signal Transduction/genetics
4.
J Clin Invest ; 131(11)2021 06 01.
Article in English | MEDLINE | ID: covidwho-1249494

ABSTRACT

With increasing age, individuals are more vulnerable to viral infections such as with influenza or the SARS-CoV-2 virus. One age-associated defect in human T cells is the reduced expression of miR-181a. miR-181ab1 deficiency in peripheral murine T cells causes delayed viral clearance after infection, resembling human immune aging. Here we show that naive T cells from older individuals as well as miR-181ab1-deficient murine T cells develop excessive replication stress after activation, due to reduced histone expression and delayed S-phase cell cycle progression. Reduced histone expression was caused by the miR-181a target SIRT1 that directly repressed transcription of histone genes by binding to their promoters and reducing histone acetylation. Inhibition of SIRT1 activity or SIRT1 silencing increased histone expression, restored cell cycle progression, diminished the replication-stress response, and reduced the production of inflammatory mediators in replicating T cells from old individuals. Correspondingly, treatment with SIRT1 inhibitors improved viral clearance in mice with miR-181a-deficient T cells after LCMV infection. In conclusion, SIRT1 inhibition may be beneficial to treat systemic viral infection in older individuals by targeting antigen-specific T cells that develop replication stress due to miR-181a deficiency.


Subject(s)
COVID-19/immunology , Cellular Senescence/immunology , Histones/deficiency , MicroRNAs/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Animals , COVID-19/genetics , Cellular Senescence/genetics , Female , Histones/immunology , Humans , Male , Mice, Knockout , MicroRNAs/genetics , SARS-CoV-2/genetics , Sirtuin 1/genetics , Sirtuin 1/immunology
5.
Int J Mol Sci ; 21(18)2020 Sep 05.
Article in English | MEDLINE | ID: covidwho-1215392

ABSTRACT

The transcription factor T cell factor 1 (TCF1), a pioneer transcription factor as well as a downstream effector of WNT/ß-catenin signaling, is indispensable for T cell development in the thymus. Recent studies have highlighted the additional critical role of TCF1 in peripheral T cell responses to acute and chronic infections as well as cancer. Here, we review the regulatory functions of TCF1 in the differentiation of T follicular helper cells, memory T cells and recently described stem-like exhausted T cells, where TCF1 promotes less differentiated stem-like cell states by controlling common gene-regulatory networks. These studies also provide insights into the mechanisms of defective T cell responses in older individuals. We discuss alterations in TCF1 expression and related regulatory networks with age and their consequences for T cell responses to infections and vaccination. The increasing understanding of the pathways regulating TCF1 expression and function in aged T cells holds the promise of enabling the design of therapeutic interventions aiming at improving T cell responses in older individuals.


Subject(s)
Cell Differentiation/physiology , T Cell Transcription Factor 1/metabolism , T-Lymphocytes/metabolism , Aging/genetics , Aging/physiology , Animals , CD8-Positive T-Lymphocytes/immunology , Cellular Senescence/genetics , Cellular Senescence/physiology , Gene Expression Regulation/genetics , Hematopoiesis/physiology , Humans , Lymphocyte Activation/immunology , T Cell Transcription Factor 1/physiology , Transcription Factors/genetics , Transcription Factors/metabolism , Wnt Signaling Pathway/physiology
6.
Exp Mol Med ; 52(12): 1871-1878, 2020 12.
Article in English | MEDLINE | ID: covidwho-1012677

ABSTRACT

Interleukin (IL)-11 evolved as part of the innate immune response. In the human lung, IL-11 upregulation has been associated with viral infections and a range of fibroinflammatory diseases, including idiopathic pulmonary fibrosis. Transforming growth factor-beta (TGFß) and other disease factors can initiate an autocrine loop of IL-11 signaling in pulmonary fibroblasts, which, in a largely ERK-dependent manner, triggers the translation of profibrotic proteins. Lung epithelial cells also express the IL-11 receptor and transition into a mesenchymal-like state in response to IL-11 exposure. In mice, therapeutic targeting of IL-11 with antibodies can arrest and reverse bleomycin-induced pulmonary fibrosis and inflammation. Intriguingly, fibroblast-specific blockade of IL-11 signaling has anti-inflammatory effects, which suggests that lung inflammation is sustained, in part, through IL-11 activity in the stroma. Proinflammatory fibroblasts and their interaction with the damaged epithelium may represent an important but overlooked driver of lung disease. Initially thought of as a protective cytokine, IL-11 is now increasingly recognized as an important determinant of lung fibrosis, inflammation, and epithelial dysfunction.


Subject(s)
Inflammation/etiology , Inflammation/metabolism , Interleukin-11/metabolism , Respiratory Tract Diseases/etiology , Respiratory Tract Diseases/metabolism , Signal Transduction , Animals , Biomarkers , Cellular Senescence/genetics , Cellular Senescence/immunology , Cytokines/metabolism , Disease Susceptibility , Fibroblasts/metabolism , Fibrosis , Humans , Inflammation/diagnosis , Inflammation Mediators/metabolism , MAP Kinase Signaling System , Respiratory Function Tests , Respiratory Tract Diseases/diagnosis
7.
Brief Bioinform ; 22(4)2021 07 20.
Article in English | MEDLINE | ID: covidwho-1003509

ABSTRACT

Using gene-regulatory-networks-based approach for single-cell expression profiles can reveal unprecedented details about the effects of external and internal factors. However, noise and batch effect in sparse single-cell expression profiles can hamper correct estimation of dependencies among genes and regulatory changes. Here, we devise a conceptually different method using graphwavelet filters for improving gene network (GWNet)-based analysis of the transcriptome. Our approach improved the performance of several gene network-inference methods. Most Importantly, GWNet improved consistency in the prediction of gene regulatory network using single-cell transcriptome even in the presence of batch effect. The consistency of predicted gene network enabled reliable estimates of changes in the influence of genes not highlighted by differential-expression analysis. Applying GWNet on the single-cell transcriptome profile of lung cells, revealed biologically relevant changes in the influence of pathways and master regulators due to ageing. Surprisingly, the regulatory influence of ageing on pneumocytes type II cells showed noticeable similarity with patterns due to the effect of novel coronavirus infection in human lung.


Subject(s)
COVID-19/genetics , Cellular Senescence/genetics , Gene Regulatory Networks , Lung/pathology , COVID-19/pathology , COVID-19/virology , Gene Expression Profiling , Humans , Lung/metabolism , SARS-CoV-2/isolation & purification , Sequence Analysis, RNA , Single-Cell Analysis , Transcriptome
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