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LitCovid-PMC-OGER-BB

LitCovid-PD-FMA-UBERON

LitCovid-PD-UBERON

{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T23","span":{"begin":2015,"end":2037},"obj":"Body_part"},{"id":"T24","span":{"begin":2023,"end":2037},"obj":"Body_part"},{"id":"T25","span":{"begin":2076,"end":2081},"obj":"Body_part"},{"id":"T26","span":{"begin":2145,"end":2151},"obj":"Body_part"},{"id":"T27","span":{"begin":2207,"end":2218},"obj":"Body_part"},{"id":"T28","span":{"begin":2292,"end":2305},"obj":"Body_part"},{"id":"T29","span":{"begin":4834,"end":4847},"obj":"Body_part"},{"id":"T30","span":{"begin":6881,"end":6894},"obj":"Body_part"},{"id":"T31","span":{"begin":7022,"end":7035},"obj":"Body_part"},{"id":"T32","span":{"begin":7564,"end":7577},"obj":"Body_part"}],"attributes":[{"id":"A23","pred":"uberon_id","subj":"T23","obj":"http://purl.obolibrary.org/obo/UBERON_0001017"},{"id":"A24","pred":"uberon_id","subj":"T24","obj":"http://purl.obolibrary.org/obo/UBERON_0001016"},{"id":"A25","pred":"uberon_id","subj":"T25","obj":"http://purl.obolibrary.org/obo/UBERON_0000955"},{"id":"A26","pred":"uberon_id","subj":"T26","obj":"http://purl.obolibrary.org/obo/UBERON_0002106"},{"id":"A27","pred":"uberon_id","subj":"T27","obj":"http://purl.obolibrary.org/obo/UBERON_0002371"},{"id":"A28","pred":"uberon_id","subj":"T28","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"A29","pred":"uberon_id","subj":"T29","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"A30","pred":"uberon_id","subj":"T30","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"A31","pred":"uberon_id","subj":"T31","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"A32","pred":"uberon_id","subj":"T32","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"}],"text":"DISCUSSION\nHere, we present a comprehensive and integrated single-cell landscape of human circulating immune cell aging and single-cell analysis of immune cells in young and aged COVID-19 patients at the transcriptomic and protein level. The primary discoveries in the current study are as follows: 1) aging reprograms the human immune cell landscape toward polarized and inflammatory states; 2) aging increases the expression of SARS-CoV-2 susceptibility genes, especially in TCs; 3) an increase in immune cell polarization and circulatory inflammation during aging can be amplified by virus infection in COVID-19; 4) age-associated dendritic cells have increased IFN-stimulated gene expression and a decreased antigen-presenting ability; 5) single-cell TCR and BCR analysis shows that aging is associated with decreased diversity and increased clonality of effector, cytotoxic and exhausted CD8+ TC subsets and ABC subset; 6) single-cell chromosomal accessibility profiles of immune cells shows that the AP-1 family TFs are the most affected by ageing across all cell types and subtypes and are further upregulated in COVID-19.\nNumerous studies have reported important observations about the composition and functional alterations of immune cells in animal aging models. However, animal models fail to recapitulate the human immune environment adequately. What we know about human immune cells is primarily based on flow cytometric analysis, relying on previously described markers for pooled cell populations. These analytical methods are too biased to reveal information on selected and not all cells or cell populations. Single-cell technologies open new avenues in many research fields but are particularly important for analyzing human cells in aging and diseases in an unbiased and global fashion (He et al., 2020; Wang et al., 2020; Zhang et al., 2020). Using scRNA-seq, recent studies have reported transcriptomic and functional changes in immune cells during aging in mouse cells and tissues such as the central nervous system (Mrdjen et al., 2018), macrophages in brain (Martinez-Jimenez et al., 2017; Van Hove et al., 2019), TCs in spleen (Dulken et al., 2019), and hematopoietic stem cells in bone marrow (Leins et al., 2018). Recently, our group revealed how aging affects the immune system in rats (Ma et al., 2020). For humans, mass cytometry analysis showed that aging increased epigenetic variations in circulatory immune cells (Cheung et al., 2018). However, a comprehensive atlas of immune cell aging has not yet been constructed. Here, we depicted such an atlas from PBMCs harvested from healthy young and old research subjects and young and old patients with COVID-19. First, scRNA-seq and CyTOF reveal that aging causes cell compositional changes at the cell type and subtype levels. Second, our study provides the first high-quality analysis of TCR and BCR repertoires in young and aged adults at a single-cell resolution. Third, our study provides the first chromosomal accessibility profiles of major immune cells in young and aged healthy research subjects at the single-cell level. Combined with several novel single-cell methodologies, this study represents a state-of-the-art unbiased and systematic analysis of human immune cell aging.\nMechanistically, we observed age-associated alterations in immune cell type and subtype composition, gene expression, transcriptional regulation, chromosomal accessibility, TCR and BCR repertoires, and cell-cell communication across multiple cell types and subtypes. Our data suggest that increased numbers of MCs may contribute to cytokine storms in coronavirus infection, as indicated by increased numbers of MCs during aging and further increases in COVID-19, whereas TCs that are critical for virus clearance (Hickman et al., 2015; Herzig et al., 2019) were decreased during aging and further reduced in COVID-19. Through the analysis of cell subtype composition, we found that naive subsets were profoundly decreased with age, likely weakening the responsive capacity of TCs during viral infection. In addition, the polarization from naive to effector cells was further enhanced by SARS-CoV-2 infection in COVID-19. Inflammatory genes such as IL1B, TNF, and CXCL8 were also increased during aging and were further upregulated in COVID-19. Notably, aging promoted the expression of coronavirus receptor-related genes, such as BSG (encoding CD147), DPP4 (encoding CD26), ITGB1, NFATC1, PPIB and ANPEP, in immune cells. Collectively, these findings reveal that aging reprograms the landscape of human immune cells toward polarized and inflammatory states and thus increases the susceptibility of COVID-19 in the elderly. In turn, COVID-19 causes more “aging” of polarization and inflammatory states in immune cells. This reinforcing feedback loop may underlie the immune system collapse in aged people.\nDue to technical limitations, high-dimensional molecular profiles in aging for rare cells such as DCs are lacking. Here, we overcame this challenge with a novel single-cell method. Aging increased the percentage of cDC2 cells and decreased the percentage of pDCs that engage antiviral activities by priming CD8+ TCs. By comparison, aging decreased the expression of CLEC12A, TXNIP, AHR and MALAT1 and increased the expression of HLA-DQA2 and IFN-stimulated genes. CLEC12A (Hutten et al., 2016) and TXNIP (Son et al., 2008) are critical for the antigen-presentation function of DCs, whereas MALAT1 and AHR are critical for tolerogenic DC differentiation (Takenaka and Quintana, 2017; Wu et al., 2018), and their dysregulation hampers DC function. Interestingly, HLA-DQA2 and IFN-stimulated genes were distinctly expressed in the cDC2 subset during aging. Moreover, our functional analysis of DEGs indicates that the aging of DCs was associated with a decrease in the antigen-presenting ability and an increase in activation of inflammatory signaling pathways, such as the response to hypoxia and IFN signaling. These findings highlight how aging affects DCs composition and function.\nIn this study, we provide a comprehensive atlas of human circulating immune cell aging. Furthermore, we reveal novel aging-related genes and adaptive immune dysregulation, thus defining the potential contributions of aging-related immune cell disorganization to the high severity rate of aged COVID-19 patients (Fig. 8). We believe that these findings will serve as a foundation from which to explore unknown facets of aging etiology and a reference for the broad scientific community interested in immunology and aging.\nFigure 8 Aging reprograms human immune cell landscape, and increases the susceptibility and vulnerability of COVID-19. Schematic illustrating the key innate and adaptive immune functional alterations identified in PBMCs influenced by aging and COVID-19. Young healthy individuals maintain homeostasis in immune system which could timely eliminate pathogen. Aging leads to the increase of monocytes (MCs) and the decrease of T cells (TCs) in the immune system. Aging promotes the polarization of TCs from naive and memory to effector, exhausted and regulatory subtypes and increases the numbers of late natural killer (NK) cells, age-associated B cells, inflammatory MCs, and dysfunctional dendritic cells (DCs). Moreover, aging induces increased expression of genes related to SARS-CoV-2 susceptibility, suggesting increased susceptibility in the elderly. Importantly, aging induces DCs to lose the antigen-presenting ability, and turn to an inflammatory state. Together, a dysregulated immune system and increased expression of genes associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly"}

LitCovid-PD-MONDO

LitCovid-PD-CLO

LitCovid-PD-CHEBI

LitCovid-PD-GO-BP

LitCovid-sentences

LitCovid-PD-HP

{"project":"LitCovid-PD-HP","denotations":[{"id":"T10","span":{"begin":3600,"end":3615},"obj":"Phenotype"},{"id":"T11","span":{"begin":5956,"end":5963},"obj":"Phenotype"},{"id":"T12","span":{"begin":6206,"end":6226},"obj":"Phenotype"}],"attributes":[{"id":"A10","pred":"hp_id","subj":"T10","obj":"http://purl.obolibrary.org/obo/HP_0033041"},{"id":"A11","pred":"hp_id","subj":"T11","obj":"http://purl.obolibrary.org/obo/HP_0012418"},{"id":"A12","pred":"hp_id","subj":"T12","obj":"http://purl.obolibrary.org/obo/HP_0002958"}],"text":"DISCUSSION\nHere, we present a comprehensive and integrated single-cell landscape of human circulating immune cell aging and single-cell analysis of immune cells in young and aged COVID-19 patients at the transcriptomic and protein level. The primary discoveries in the current study are as follows: 1) aging reprograms the human immune cell landscape toward polarized and inflammatory states; 2) aging increases the expression of SARS-CoV-2 susceptibility genes, especially in TCs; 3) an increase in immune cell polarization and circulatory inflammation during aging can be amplified by virus infection in COVID-19; 4) age-associated dendritic cells have increased IFN-stimulated gene expression and a decreased antigen-presenting ability; 5) single-cell TCR and BCR analysis shows that aging is associated with decreased diversity and increased clonality of effector, cytotoxic and exhausted CD8+ TC subsets and ABC subset; 6) single-cell chromosomal accessibility profiles of immune cells shows that the AP-1 family TFs are the most affected by ageing across all cell types and subtypes and are further upregulated in COVID-19.\nNumerous studies have reported important observations about the composition and functional alterations of immune cells in animal aging models. However, animal models fail to recapitulate the human immune environment adequately. What we know about human immune cells is primarily based on flow cytometric analysis, relying on previously described markers for pooled cell populations. These analytical methods are too biased to reveal information on selected and not all cells or cell populations. Single-cell technologies open new avenues in many research fields but are particularly important for analyzing human cells in aging and diseases in an unbiased and global fashion (He et al., 2020; Wang et al., 2020; Zhang et al., 2020). Using scRNA-seq, recent studies have reported transcriptomic and functional changes in immune cells during aging in mouse cells and tissues such as the central nervous system (Mrdjen et al., 2018), macrophages in brain (Martinez-Jimenez et al., 2017; Van Hove et al., 2019), TCs in spleen (Dulken et al., 2019), and hematopoietic stem cells in bone marrow (Leins et al., 2018). Recently, our group revealed how aging affects the immune system in rats (Ma et al., 2020). For humans, mass cytometry analysis showed that aging increased epigenetic variations in circulatory immune cells (Cheung et al., 2018). However, a comprehensive atlas of immune cell aging has not yet been constructed. Here, we depicted such an atlas from PBMCs harvested from healthy young and old research subjects and young and old patients with COVID-19. First, scRNA-seq and CyTOF reveal that aging causes cell compositional changes at the cell type and subtype levels. Second, our study provides the first high-quality analysis of TCR and BCR repertoires in young and aged adults at a single-cell resolution. Third, our study provides the first chromosomal accessibility profiles of major immune cells in young and aged healthy research subjects at the single-cell level. Combined with several novel single-cell methodologies, this study represents a state-of-the-art unbiased and systematic analysis of human immune cell aging.\nMechanistically, we observed age-associated alterations in immune cell type and subtype composition, gene expression, transcriptional regulation, chromosomal accessibility, TCR and BCR repertoires, and cell-cell communication across multiple cell types and subtypes. Our data suggest that increased numbers of MCs may contribute to cytokine storms in coronavirus infection, as indicated by increased numbers of MCs during aging and further increases in COVID-19, whereas TCs that are critical for virus clearance (Hickman et al., 2015; Herzig et al., 2019) were decreased during aging and further reduced in COVID-19. Through the analysis of cell subtype composition, we found that naive subsets were profoundly decreased with age, likely weakening the responsive capacity of TCs during viral infection. In addition, the polarization from naive to effector cells was further enhanced by SARS-CoV-2 infection in COVID-19. Inflammatory genes such as IL1B, TNF, and CXCL8 were also increased during aging and were further upregulated in COVID-19. Notably, aging promoted the expression of coronavirus receptor-related genes, such as BSG (encoding CD147), DPP4 (encoding CD26), ITGB1, NFATC1, PPIB and ANPEP, in immune cells. Collectively, these findings reveal that aging reprograms the landscape of human immune cells toward polarized and inflammatory states and thus increases the susceptibility of COVID-19 in the elderly. In turn, COVID-19 causes more “aging” of polarization and inflammatory states in immune cells. This reinforcing feedback loop may underlie the immune system collapse in aged people.\nDue to technical limitations, high-dimensional molecular profiles in aging for rare cells such as DCs are lacking. Here, we overcame this challenge with a novel single-cell method. Aging increased the percentage of cDC2 cells and decreased the percentage of pDCs that engage antiviral activities by priming CD8+ TCs. By comparison, aging decreased the expression of CLEC12A, TXNIP, AHR and MALAT1 and increased the expression of HLA-DQA2 and IFN-stimulated genes. CLEC12A (Hutten et al., 2016) and TXNIP (Son et al., 2008) are critical for the antigen-presentation function of DCs, whereas MALAT1 and AHR are critical for tolerogenic DC differentiation (Takenaka and Quintana, 2017; Wu et al., 2018), and their dysregulation hampers DC function. Interestingly, HLA-DQA2 and IFN-stimulated genes were distinctly expressed in the cDC2 subset during aging. Moreover, our functional analysis of DEGs indicates that the aging of DCs was associated with a decrease in the antigen-presenting ability and an increase in activation of inflammatory signaling pathways, such as the response to hypoxia and IFN signaling. These findings highlight how aging affects DCs composition and function.\nIn this study, we provide a comprehensive atlas of human circulating immune cell aging. Furthermore, we reveal novel aging-related genes and adaptive immune dysregulation, thus defining the potential contributions of aging-related immune cell disorganization to the high severity rate of aged COVID-19 patients (Fig. 8). We believe that these findings will serve as a foundation from which to explore unknown facets of aging etiology and a reference for the broad scientific community interested in immunology and aging.\nFigure 8 Aging reprograms human immune cell landscape, and increases the susceptibility and vulnerability of COVID-19. Schematic illustrating the key innate and adaptive immune functional alterations identified in PBMCs influenced by aging and COVID-19. Young healthy individuals maintain homeostasis in immune system which could timely eliminate pathogen. Aging leads to the increase of monocytes (MCs) and the decrease of T cells (TCs) in the immune system. Aging promotes the polarization of TCs from naive and memory to effector, exhausted and regulatory subtypes and increases the numbers of late natural killer (NK) cells, age-associated B cells, inflammatory MCs, and dysfunctional dendritic cells (DCs). Moreover, aging induces increased expression of genes related to SARS-CoV-2 susceptibility, suggesting increased susceptibility in the elderly. Importantly, aging induces DCs to lose the antigen-presenting ability, and turn to an inflammatory state. Together, a dysregulated immune system and increased expression of genes associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly"}

2_test

{"project":"2_test","denotations":[{"id":"32780218-29706550-132718710","span":{"begin":1817,"end":1821},"obj":"29706550"},{"id":"32780218-29891535-132718711","span":{"begin":1836,"end":1840},"obj":"29891535"},{"id":"32780218-29891535-132718712","span":{"begin":1856,"end":1860},"obj":"29891535"},{"id":"32780218-29706550-132718713","span":{"begin":2054,"end":2058},"obj":"29706550"},{"id":"32780218-29891535-132718714","span":{"begin":2108,"end":2112},"obj":"29891535"},{"id":"32780218-29891535-132718715","span":{"begin":2131,"end":2135},"obj":"29891535"},{"id":"32780218-29706550-132718716","span":{"begin":2168,"end":2172},"obj":"29706550"},{"id":"32780218-29891535-132718717","span":{"begin":2234,"end":2238},"obj":"29891535"},{"id":"32780218-29706550-132718718","span":{"begin":2326,"end":2330},"obj":"29706550"},{"id":"32780218-29706550-132718719","span":{"begin":2463,"end":2467},"obj":"29706550"},{"id":"32780218-29706550-132718720","span":{"begin":3798,"end":3802},"obj":"29706550"},{"id":"32780218-29706550-132718721","span":{"begin":3819,"end":3823},"obj":"29706550"},{"id":"32780218-29706550-132718722","span":{"begin":5361,"end":5365},"obj":"29706550"},{"id":"32780218-29706550-132718723","span":{"begin":5390,"end":5394},"obj":"29706550"},{"id":"32780218-29891535-132718724","span":{"begin":5550,"end":5554},"obj":"29891535"},{"id":"32780218-29706550-132718725","span":{"begin":5567,"end":5571},"obj":"29706550"}],"text":"DISCUSSION\nHere, we present a comprehensive and integrated single-cell landscape of human circulating immune cell aging and single-cell analysis of immune cells in young and aged COVID-19 patients at the transcriptomic and protein level. The primary discoveries in the current study are as follows: 1) aging reprograms the human immune cell landscape toward polarized and inflammatory states; 2) aging increases the expression of SARS-CoV-2 susceptibility genes, especially in TCs; 3) an increase in immune cell polarization and circulatory inflammation during aging can be amplified by virus infection in COVID-19; 4) age-associated dendritic cells have increased IFN-stimulated gene expression and a decreased antigen-presenting ability; 5) single-cell TCR and BCR analysis shows that aging is associated with decreased diversity and increased clonality of effector, cytotoxic and exhausted CD8+ TC subsets and ABC subset; 6) single-cell chromosomal accessibility profiles of immune cells shows that the AP-1 family TFs are the most affected by ageing across all cell types and subtypes and are further upregulated in COVID-19.\nNumerous studies have reported important observations about the composition and functional alterations of immune cells in animal aging models. However, animal models fail to recapitulate the human immune environment adequately. What we know about human immune cells is primarily based on flow cytometric analysis, relying on previously described markers for pooled cell populations. These analytical methods are too biased to reveal information on selected and not all cells or cell populations. Single-cell technologies open new avenues in many research fields but are particularly important for analyzing human cells in aging and diseases in an unbiased and global fashion (He et al., 2020; Wang et al., 2020; Zhang et al., 2020). Using scRNA-seq, recent studies have reported transcriptomic and functional changes in immune cells during aging in mouse cells and tissues such as the central nervous system (Mrdjen et al., 2018), macrophages in brain (Martinez-Jimenez et al., 2017; Van Hove et al., 2019), TCs in spleen (Dulken et al., 2019), and hematopoietic stem cells in bone marrow (Leins et al., 2018). Recently, our group revealed how aging affects the immune system in rats (Ma et al., 2020). For humans, mass cytometry analysis showed that aging increased epigenetic variations in circulatory immune cells (Cheung et al., 2018). However, a comprehensive atlas of immune cell aging has not yet been constructed. Here, we depicted such an atlas from PBMCs harvested from healthy young and old research subjects and young and old patients with COVID-19. First, scRNA-seq and CyTOF reveal that aging causes cell compositional changes at the cell type and subtype levels. Second, our study provides the first high-quality analysis of TCR and BCR repertoires in young and aged adults at a single-cell resolution. Third, our study provides the first chromosomal accessibility profiles of major immune cells in young and aged healthy research subjects at the single-cell level. Combined with several novel single-cell methodologies, this study represents a state-of-the-art unbiased and systematic analysis of human immune cell aging.\nMechanistically, we observed age-associated alterations in immune cell type and subtype composition, gene expression, transcriptional regulation, chromosomal accessibility, TCR and BCR repertoires, and cell-cell communication across multiple cell types and subtypes. Our data suggest that increased numbers of MCs may contribute to cytokine storms in coronavirus infection, as indicated by increased numbers of MCs during aging and further increases in COVID-19, whereas TCs that are critical for virus clearance (Hickman et al., 2015; Herzig et al., 2019) were decreased during aging and further reduced in COVID-19. Through the analysis of cell subtype composition, we found that naive subsets were profoundly decreased with age, likely weakening the responsive capacity of TCs during viral infection. In addition, the polarization from naive to effector cells was further enhanced by SARS-CoV-2 infection in COVID-19. Inflammatory genes such as IL1B, TNF, and CXCL8 were also increased during aging and were further upregulated in COVID-19. Notably, aging promoted the expression of coronavirus receptor-related genes, such as BSG (encoding CD147), DPP4 (encoding CD26), ITGB1, NFATC1, PPIB and ANPEP, in immune cells. Collectively, these findings reveal that aging reprograms the landscape of human immune cells toward polarized and inflammatory states and thus increases the susceptibility of COVID-19 in the elderly. In turn, COVID-19 causes more “aging” of polarization and inflammatory states in immune cells. This reinforcing feedback loop may underlie the immune system collapse in aged people.\nDue to technical limitations, high-dimensional molecular profiles in aging for rare cells such as DCs are lacking. Here, we overcame this challenge with a novel single-cell method. Aging increased the percentage of cDC2 cells and decreased the percentage of pDCs that engage antiviral activities by priming CD8+ TCs. By comparison, aging decreased the expression of CLEC12A, TXNIP, AHR and MALAT1 and increased the expression of HLA-DQA2 and IFN-stimulated genes. CLEC12A (Hutten et al., 2016) and TXNIP (Son et al., 2008) are critical for the antigen-presentation function of DCs, whereas MALAT1 and AHR are critical for tolerogenic DC differentiation (Takenaka and Quintana, 2017; Wu et al., 2018), and their dysregulation hampers DC function. Interestingly, HLA-DQA2 and IFN-stimulated genes were distinctly expressed in the cDC2 subset during aging. Moreover, our functional analysis of DEGs indicates that the aging of DCs was associated with a decrease in the antigen-presenting ability and an increase in activation of inflammatory signaling pathways, such as the response to hypoxia and IFN signaling. These findings highlight how aging affects DCs composition and function.\nIn this study, we provide a comprehensive atlas of human circulating immune cell aging. Furthermore, we reveal novel aging-related genes and adaptive immune dysregulation, thus defining the potential contributions of aging-related immune cell disorganization to the high severity rate of aged COVID-19 patients (Fig. 8). We believe that these findings will serve as a foundation from which to explore unknown facets of aging etiology and a reference for the broad scientific community interested in immunology and aging.\nFigure 8 Aging reprograms human immune cell landscape, and increases the susceptibility and vulnerability of COVID-19. Schematic illustrating the key innate and adaptive immune functional alterations identified in PBMCs influenced by aging and COVID-19. Young healthy individuals maintain homeostasis in immune system which could timely eliminate pathogen. Aging leads to the increase of monocytes (MCs) and the decrease of T cells (TCs) in the immune system. Aging promotes the polarization of TCs from naive and memory to effector, exhausted and regulatory subtypes and increases the numbers of late natural killer (NK) cells, age-associated B cells, inflammatory MCs, and dysfunctional dendritic cells (DCs). Moreover, aging induces increased expression of genes related to SARS-CoV-2 susceptibility, suggesting increased susceptibility in the elderly. Importantly, aging induces DCs to lose the antigen-presenting ability, and turn to an inflammatory state. Together, a dysregulated immune system and increased expression of genes associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly"}

LitCovid-PubTator

PMC:7417788 / 50515-58241 JSONTXT

Annnotations TAB JSON ListView MergeView

PMC:7417788 / 50515-58241 JSON TXT