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1.
Front Immunol ; 12: 681516, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489933

RESUMO

Coronavirus disease 2019 (COVID-19) broke out and then became a global epidemic at the end of 2019. With the increasing number of deaths, early identification of disease severity and interpretation of pathogenesis are very important. Aiming to identify biomarkers for disease severity and progression of COVID-19, 75 COVID-19 patients, 34 healthy controls and 23 patients with pandemic influenza A(H1N1) were recruited in this study. Using liquid chip technology, 48 cytokines and chemokines were examined, among which 33 were significantly elevated in COVID-19 patients compared with healthy controls. HGF and IL-1ß were strongly associated with APACHE II score in the first week after disease onset. IP-10, HGF and IL-10 were correlated positively with virus titers. Cytokines were significantly correlated with creatinine, troponin I, international normalized ratio and procalcitonin within two weeks after disease onset. Univariate analyses were carried out, and 6 cytokines including G-CSF, HGF, IL-10, IL-18, M-CSF and SCGF-ß were found to be associated with the severity of COVID-19. 11 kinds of cytokines could predict the severity of COVID-19, among which IP-10 and M-CSF were excellent predictors for disease severity. In conclusion, the levels of cytokines in COVID-19 were significantly correlated with the severity of the disease in the early stage, and serum cytokines could be used as warning indicators of the severity and progression of COVID-19. Early stratification of disease and intervention to reduce hypercytokinaemia may improve the prognosis of COVID-19 patients.


Assuntos
COVID-19/imunologia , Citocinas/genética , Citocinas/imunologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Transcriptoma/imunologia , Adulto , Idoso , Biomarcadores/sangue , Quimiocinas/sangue , Quimiocinas/genética , Quimiocinas/imunologia , Citocinas/sangue , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Influenza Humana/sangue , Influenza Humana/imunologia , Masculino , Pessoa de Meia-Idade
2.
Signal Transduct Target Ther ; 6(1): 342, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34531370

RESUMO

While some individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) present mild-to-severe disease, many SARS-CoV-2-infected individuals are asymptomatic. We sought to identify the distinction of immune response between asymptomatic and moderate patients. We performed single-cell transcriptome and T-cell/B-cell receptor (TCR/BCR) sequencing in 37 longitudinal collected peripheral blood mononuclear cell samples from asymptomatic, moderate, and severe patients with healthy controls. Asymptomatic patients displayed increased CD56briCD16- natural killer (NK) cells and upregulation of interferon-gamma in effector CD4+ and CD8+ T cells and NK cells. They showed more robust TCR clonal expansion, especially in effector CD4+ T cells, but lack strong BCR clonal expansion compared to moderate patients. Moreover, asymptomatic patients have lower interferon-stimulated genes (ISGs) expression in general but large interpatient variability, whereas moderate patients showed various magnitude and temporal dynamics of the ISGs expression across multiple cell populations but lower than a patient with severe disease. Our data provide evidence of different immune signatures to SARS-CoV-2 in asymptomatic infections.


Assuntos
COVID-19 , Portador Sadio/imunologia , Linfócitos/imunologia , SARS-CoV-2/imunologia , Análise de Célula Única , Transcriptoma/imunologia , Adolescente , Adulto , COVID-19/genética , COVID-19/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , SARS-CoV-2/genética
4.
Front Immunol ; 12: 660361, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34526984

RESUMO

Gamma delta (γδ) T cells, especially the Vγ9Vδ2 subtype, have been implicated in cancer therapy and thus have earned the spotlight in the past decade. Although one of the most important properties of γδ T cells is their activation by phosphoantigens, which are intermediates of the Mevalonate and Rohmer pathway of isoprenoid biosynthesis, such as IPP and HDMAPP, respectively, the global effects of such treatments on Vγ9Vδ2 T cells remain elusive. Here, we used the high-throughput transcriptomics approach to elucidate the transcriptional changes in human Vγ9Vδ2 T cells upon HDMAPP, IPP, and anti-CD3 treatments in combination with interleukin 2 (IL2) cytokine stimulation. These activation treatments exhibited a dramatic surge in transcription with distinctly enriched pathways. We further assessed the transcriptional dynamics upon inhibition of Notch signaling coupled with activation treatments. We observed that the metabolic processes are most affected upon Notch inhibition via GSI-X. The key effector genes involved in gamma-delta cytotoxic function were downregulated upon Notch blockade even in combination with activation treatment, suggesting a transcriptional crosstalk between T-cell receptor (TCR) signaling and Notch signaling in Vγ9Vδ2 T cells. Collectively, we demonstrate the effect of the activation of TCR signaling by phosphoantigens or anti-CD3 on the transcriptional status of Vγ9Vδ2 T cells along with IL2 stimulation. We further show that the blockade of Notch signaling antagonistically affects this activation.


Assuntos
Antígenos/farmacologia , Perfilação da Expressão Gênica , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores Notch/imunologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Transcriptoma/imunologia , Antígenos/química , Humanos , Interleucina-2/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores Notch/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/imunologia , Transcriptoma/genética
5.
Nat Commun ; 12(1): 4854, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381049

RESUMO

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56dimCD57+ natural killer (NK) cells and exhausted CD8+ T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8+ T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Transcriptoma/imunologia , Adolescente , Antígeno CD56/metabolismo , Antígenos CD57/metabolismo , Linfócitos T CD8-Positivos/metabolismo , COVID-19/genética , Criança , Pré-Escolar , Regulação para Baixo , Feminino , Humanos , Lactente , Recém-Nascido , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Síndrome de Linfonodos Mucocutâneos/genética , Síndrome de Linfonodos Mucocutâneos/imunologia , SARS-CoV-2/patogenicidade , Síndrome de Resposta Inflamatória Sistêmica/genética , Adulto Jovem
6.
Nat Commun ; 12(1): 4907, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389726

RESUMO

The intestinal mucosa constitutes an environment of closely regulated immune cells. Dendritic cells (DC) interact with the gut microbiome and antigens and are important in maintaining gut homeostasis. Here, we investigate DC transcriptome, phenotype and function in five anatomical locations of the gut lamina propria (LP) which constitute different antigenic environments. We show that DC from distinct gut LP compartments induce distinct T cell differentiation and cytokine secretion. We also find that PD-L1+ DC in the duodenal LP and XCR1+ DC in the colonic LP comprise distinct tolerogenic DC subsets that are crucial for gut homeostasis. Mice lacking PD-L1+ and XCR1+ DC have a proinflammatory gut milieu associated with an increase in Th1/Th17 cells and a decrease in Treg cells and have exacerbated disease in the models of 5-FU-induced mucositis and DSS-induced colitis. Our findings identify PD-L1+ and XCR1+ DC as region-specific physiologic regulators of intestinal homeostasis.


Assuntos
Antígeno B7-H1/imunologia , Células Dendríticas/imunologia , Homeostase/imunologia , Mucosa Intestinal/imunologia , Receptores de Quimiocinas/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Colite/genética , Colite/imunologia , Colite/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/metabolismo , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/imunologia , Homeostase/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma/genética , Transcriptoma/imunologia
7.
Front Immunol ; 12: 716075, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34394120

RESUMO

The existence of asymptomatic and re-detectable positive coronavirus disease 2019 (COVID-19) patients presents the disease control challenges of COVID-19. Most studies on immune responses in COVID-19 have focused on moderately or severely symptomatic patients; however, little is known about the immune response in asymptomatic and re-detectable positive (RP) patients. Here we performed a comprehensive analysis of the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from 48 COVID-19 patients which included 8 asymptomatic, 13 symptomatic, 15 recovered and 12 RP patients. The weighted gene co-expression network analysis (WGCNA) identified six co-expression modules, of which the turquoise module was positively correlated with the asymptomatic, symptomatic, and recovered COVID-19 patients. The red module positively correlated with symptomatic patients only and the blue and brown modules positively correlated with the RP patients. The analysis by single sample gene set enrichment analysis (ssGSEA) revealed a lower level of IFN response and complement activation in the asymptomatic patients compared with the symptomatic, indicating a weaker immune response of the PBMCs in the asymptomatic patients. In addition, gene set enrichment analysis (GSEA) analysis showed the enrichment of TNFα/NF-κB and influenza infection in the RP patients compared with the recovered patients, indicating a hyper-inflammatory immune response in the PBMC of RP patients. Thus our findings could extend our understanding of host immune response during the progression of COVID-19 disease and assist clinical management and the immunotherapy development for COVID-19.


Assuntos
Doenças Assintomáticas , COVID-19/imunologia , Portador Sadio/imunologia , Leucócitos Mononucleares/imunologia , SARS-CoV-2/imunologia , Transcriptoma/genética , Adulto , Portador Sadio/virologia , Ativação do Complemento/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Inflamação/imunologia , Influenza Humana/complicações , Interferons/sangue , Interferons/imunologia , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Transcriptoma/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
8.
Front Immunol ; 12: 614773, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276642

RESUMO

Human leukocyte antigen G (HLA-G) is known as a novel immune checkpoint molecule in cancer; thus, HLA-G and its receptors might be targets for immune checkpoint blockade in cancer immunotherapy. The aim of this study was to systematically identify the roles of checkpoint HLA-G molecules across various types of cancer. ONCOMINE, GEPIA, CCLE, TRRUST, HAP, PrognoScan, Kaplan-Meier Plotter, cBioPortal, LinkedOmics, STRING, GeneMANIA, DAVID, TIMER, and CIBERSORT were utilized. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. In this study, we comprehensively analysed the heterogeneous expression of HLA-G molecules in various types of cancer and focused on genetic alterations, coexpression patterns, gene interaction networks, HLA-G interactors, and the relationships between HLA-G and pathological stage, prognosis, and tumor-infiltrating immune cells. We first identified that the mRNA expression levels of HLA-G were significantly upregulated in both most tumor tissues and tumor cell lines on the basis of in-depth analysis of RNAseq data. The expression levels of HLA-G were positively associated with those of the other immune checkpoints PD-1 and CTLA-4. Abnormal expression of HLA-G was significantly correlated with the pathological stage of some but not all tumor types. There was a significant difference between the high and low HLA-G expression groups in terms of overall survival (OS) or disease-free survival (DFS). The results showed that HLA-G highly expressed have positive associations with tumor-infiltrating immune cells in the microenvironment in most types of tumors (P<0.05). Additionally, we identified the key transcription factor (TF) targets in the regulation of HLA-G expression, including HIVEP2, MYCN, CIITA, MYC, and IRF1. Multiple mutations (missense, truncating, etc.) and the methylation status of the HLA-G gene may explain the differential expression of HLA-G across different tumors. Functional enrichment analysis showed that HLA-G was primarily related to T cell activation, T cell regulation, and lymphocyte-mediated immunity. The data may provide novel insights for blockade of the HLA-G/ILT axis, which holds potential for the development of more effective antitumour treatments.


Assuntos
Perfilação da Expressão Gênica , Antígenos HLA-G/genética , Antígenos HLA-G/imunologia , Proteínas de Checkpoint Imunológico/genética , Neoplasias/genética , Transcriptoma/imunologia , Microambiente Tumoral/imunologia , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Proteínas de Checkpoint Imunológico/imunologia , Estimativa de Kaplan-Meier , Neoplasias/classificação , Neoplasias/imunologia
9.
Immunity ; 54(8): 1883-1900.e5, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34331874

RESUMO

Mononuclear phagocytes (MNPs) encompass dendritic cells, monocytes, and macrophages (MoMac), which exhibit antimicrobial, homeostatic, and immunoregulatory functions. We integrated 178,651 MNPs from 13 tissues across 41 datasets to generate a MNP single-cell RNA compendium (MNP-VERSE), a publicly available tool to map MNPs and define conserved gene signatures of MNP populations. Next, we generated a MoMac-focused compendium that revealed an array of specialized cell subsets widely distributed across multiple tissues. Specific pathological forms were expanded in cancer and inflammation. All neoplastic tissues contained conserved tumor-associated macrophage populations. In particular, we focused on IL4I1+CD274(PD-L1)+IDO1+ macrophages, which accumulated in the tumor periphery in a T cell-dependent manner via interferon-γ (IFN-γ) and CD40/CD40L-induced maturation from IFN-primed monocytes. IL4I1_Macs exhibited immunosuppressive characteristics through tryptophan degradation and promoted the entry of regulatory T cell into tumors. This integrated analysis provides a robust online-available platform for uniform annotation and dissection of specific macrophage functions in healthy and pathological states.


Assuntos
Células Dendríticas/imunologia , Expressão Gênica/imunologia , Monócitos/imunologia , Transcriptoma/genética , Macrófagos Associados a Tumor/imunologia , Artrite Reumatoide/imunologia , COVID-19/imunologia , Expressão Gênica/genética , Perfilação da Expressão Gênica , Humanos , Interferon gama/imunologia , L-Aminoácido Oxidase/metabolismo , Cirrose Hepática/imunologia , Macrófagos/imunologia , Neoplasias/imunologia , RNA Citoplasmático Pequeno/genética , Análise de Célula Única , Linfócitos T Reguladores/imunologia , Transcriptoma/imunologia
10.
Mol Immunol ; 137: 94-104, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34242922

RESUMO

The signaling adapter MyD88 is critical for immune cell activation in response to viral or bacterial pathogens via several TLRs, IL-1ßR and IL-18R. However, the essential role of MyD88 during activations mediated by germline-encoded NK cell receptors (NKRs), such as Ly49H or NKG2D, has yet to be investigated. To define the NK cell-intrinsic function of MyD88, we generated a novel NK cell conditional knockout mouse for MyD88 (Myd88fl/flNcr1Cre/+). Phenotypic characterization of these mice demonstrated that MyD88 is dispensable for NK cell development and maturation. However, the MyD88-deficient NK cells exhibited significantly reduced cytotoxic potentials in vivo. In addition, the lack of MyD88 significantly reduced the NKG2D-mediated inflammatory cytokine production in vitro. Consistent with this, mice lacking MyD88 were unable to respond and clear MCMV infection. Transcriptomic analyses of splenic NK cells following MCMV infection revealed that inflammatory gene signatures were upregulated in Ly49H+. In contrast, Ly49H- NK cells have significant enrichment in G2M checkpoint genes, revealing distinct transcriptomic profiles of these subsets. Our results identify a central role for MyD88 in Ly49H-dependent gene signatures, including alterations in genes regulating proliferation in Ly49H+ NK cells. In summary, our study reveals a previously unknown function of MyD88 in Ly49H-dependent signaling and in vivo functions of NK cells.


Assuntos
Infecções por Herpesviridae/imunologia , Células Matadoras Naturais/imunologia , Muromegalovirus/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Animais , Proliferação de Células/fisiologia , Citocinas/imunologia , Feminino , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptores de Células Matadoras Naturais/imunologia , Transdução de Sinais/imunologia , Transcriptoma/imunologia
11.
Mol Immunol ; 137: 145-154, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34247100

RESUMO

Previous studies have found that the expression level of Megalobrama amblycephala intelectin (MaINTL) increased significantly post Aeromonas hydrophila infection, and recombinant MaINTL (rMaINTL) protein could activate macrophages and enhance the phagocytosis and killing activity of macrophages. In order to reveal the immune regulatory mechanisms of MaINTL, primary M. amblycephala macrophages were treated with endotoxin-removed rMaINTL and GST-tag proteins, then total RNA were extracted and used for comparative Digital Gene Expression Profiling (DGE). 1247 differentially expressed genes were identified by comparing rMaINTL and GST-tag treated macrophage groups, including 482 up-regulated unigenes and 765 down-regulated unigenes. In addition, eleven randomly selected differentially expressed genes were verified by qRT-PCR, and most of them shared the similar expression patterns as that of DGE results. GO enrichment revealed that the differentially expressed genes were mainly concentrated in the membrane part and cytoskeleton of cellular component, the binding and signal transducer activity of molecular function, the cellular process, regulation of biological process, signaling and localization of biological process, most of which might related with the phagocytosis and killing activity of macrophages. KEGG analysis revealed the activation and involvement of differentially expressed genes in immune related pathways, such as Tumor necrosis factor (TNF) signaling pathway, Interleukin 17 (IL-17) signaling pathway, Toll-like receptor signaling pathway, and NOD like receptor signaling pathway, etc. In these pathways, TNF-ɑ, Activator protein-1 (AP-1), Myeloid differentiation primary response protein MyD88 (MyD88), NF-kappa-B inhibitor alpha (ikBɑ) and other key signaling factors were significantly up-regulated. These results will be helpful to clarify the immune regulatory mechanisms of fish intelectin on macrophages, thus providing a theoretical basis for the prevention and control of fish bacterial diseases.


Assuntos
Aeromonas hydrophila/imunologia , Cyprinidae/imunologia , Cyprinidae/microbiologia , Infecções por Bactérias Gram-Negativas/imunologia , Macrófagos/imunologia , Fagocitose/imunologia , Animais , Regulação para Baixo/imunologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/métodos , Infecções por Bactérias Gram-Negativas/microbiologia , Fatores Imunológicos/imunologia , Macrófagos/microbiologia , Transdução de Sinais/imunologia , Transcriptoma/imunologia , Fator de Necrose Tumoral alfa/imunologia , Regulação para Cima/imunologia
12.
Commun Biol ; 4(1): 681, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083746

RESUMO

T cells rely for their development and function on the correct folding and turnover of proteins generated in response to a broad range of molecular cues. In the absence of the eukaryotic type II chaperonin complex, CCT, T cell activation induced changes in the proteome are compromised including the formation of nuclear actin filaments and the formation of a normal cell stress response. Consequently, thymocyte maturation and selection, and T cell homeostatic maintenance and receptor-mediated activation are severely impaired. In the absence of CCT-controlled protein folding, Th2 polarization diverges from normal differentiation with paradoxical continued IFN-γ expression. As a result, CCT-deficient T cells fail to generate an efficient immune protection against helminths as they are unable to sustain a coordinated recruitment of the innate and adaptive immune systems. These findings thus demonstrate that normal T cell biology is critically dependent on CCT-controlled proteostasis and that its absence is incompatible with protective immunity.


Assuntos
Chaperonina com TCP-1/imunologia , Proteostase/imunologia , Linfócitos T/imunologia , Timócitos/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Chaperonina com TCP-1/genética , Chaperonina com TCP-1/metabolismo , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteoma/imunologia , Proteoma/metabolismo , Proteostase/genética , Linfócitos T/citologia , Linfócitos T/metabolismo , Timócitos/citologia , Timócitos/metabolismo , Transcriptoma/genética , Transcriptoma/imunologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
13.
Hum Genet ; 140(9): 1313-1328, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34155559

RESUMO

The coronavirus disease 2019 (COVID-19) is an infectious disease that mainly affects the host respiratory system with ~ 80% asymptomatic or mild cases and ~ 5% severe cases. Recent genome-wide association studies (GWAS) have identified several genetic loci associated with the severe COVID-19 symptoms. Delineating the genetic variants and genes is important for better understanding its biological mechanisms. We implemented integrative approaches, including transcriptome-wide association studies (TWAS), colocalization analysis, and functional element prediction analysis, to interpret the genetic risks using two independent GWAS datasets in lung and immune cells. To understand the context-specific molecular alteration, we further performed deep learning-based single-cell transcriptomic analyses on a bronchoalveolar lavage fluid (BALF) dataset from moderate and severe COVID-19 patients. We discovered and replicated the genetically regulated expression of CXCR6 and CCR9 genes. These two genes have a protective effect on lung, and a risk effect on whole blood, respectively. The colocalization analysis of GWAS and cis-expression quantitative trait loci highlighted the regulatory effect on CXCR6 expression in lung and immune cells. In the lung-resident memory CD8+ T (TRM) cells, we found a 2.24-fold decrease of cell proportion among CD8+ T cells and lower expression of CXCR6 in the severe patients than moderate patients. Pro-inflammatory transcriptional programs were highlighted in the TRM cellular trajectory from moderate to severe patients. CXCR6 from the 3p21.31 locus is associated with severe COVID-19. CXCR6 tends to have a lower expression in lung TRM cells of severe patients, which aligns with the protective effect of CXCR6 from TWAS analysis.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19 , Memória Imunológica/genética , Pulmão/imunologia , Locos de Características Quantitativas/imunologia , Receptores CXCR6 , SARS-CoV-2/imunologia , Transcriptoma/imunologia , COVID-19/genética , COVID-19/imunologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Pulmão/virologia , Masculino , Receptores CCR/genética , Receptores CCR/imunologia , Receptores CXCR6/genética , Receptores CXCR6/imunologia , Fatores de Risco , Índice de Gravidade de Doença
14.
Cell ; 184(13): 3573-3587.e29, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34062119

RESUMO

The simultaneous measurement of multiple modalities represents an exciting frontier for single-cell genomics and necessitates computational methods that can define cellular states based on multimodal data. Here, we introduce "weighted-nearest neighbor" analysis, an unsupervised framework to learn the relative utility of each data type in each cell, enabling an integrative analysis of multiple modalities. We apply our procedure to a CITE-seq dataset of 211,000 human peripheral blood mononuclear cells (PBMCs) with panels extending to 228 antibodies to construct a multimodal reference atlas of the circulating immune system. Multimodal analysis substantially improves our ability to resolve cell states, allowing us to identify and validate previously unreported lymphoid subpopulations. Moreover, we demonstrate how to leverage this reference to rapidly map new datasets and to interpret immune responses to vaccination and coronavirus disease 2019 (COVID-19). Our approach represents a broadly applicable strategy to analyze single-cell multimodal datasets and to look beyond the transcriptome toward a unified and multimodal definition of cellular identity.


Assuntos
SARS-CoV-2/imunologia , Análise de Célula Única/métodos , Células 3T3 , Animais , COVID-19/imunologia , Linhagem Celular , Perfilação da Expressão Gênica/métodos , Humanos , Imunidade/imunologia , Leucócitos Mononucleares/imunologia , Linfócitos/imunologia , Camundongos , Análise de Sequência de RNA/métodos , Transcriptoma/imunologia , Vacinação
15.
Biomed Res Int ; 2021: 8836243, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34124262

RESUMO

Severe burns are acute wounds caused by local heat exposure, resulting in life-threatening systemic effects and poor survival. However, the specific molecular mechanisms remain unclear. First, we downloaded gene expression data related to severe burns from the GEO database (GSE19743, GSE37069, and GSE77791). Then, a gene expression analysis was performed to identify differentially expressed genes (DEGs) and construct protein-protein interaction (PPI) network. The molecular mechanism was identified by enrichment analysis and Gene Set Enrichment Analysis. In addition, STEM software was used to screen for genes persistently expressed during response to severe burns, and receiver operating characteristic (ROC) curve was used to identify key DEGs. A total of 2631 upregulated and 3451 downregulated DEGs were identified. PPI network analysis clustered these DEGs into 13 modules. Importantly, module genes mostly related with immune responses and metabolism. In addition, we identified genes persistently altered during the response to severe burns corresponding to survival and death status. Among the genes with high area under the ROC curve in the PPI network gene, CCL5 and LCK were identified as key DEGs, which may affect the prognosis of burn patients. Gene set variation analysis showed that the immune response was inhibited and several types of immune cells were decreased, while the metabolic response was enhanced. The results showed that persistent gene expression changes occur in response to severe burns, which may underlie chronic alterations in physiological pathways. Identifying the key altered genes may reveal potential therapeutic targets for mitigating the effects of severe burns.


Assuntos
Queimaduras , Bases de Dados de Ácidos Nucleicos , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/imunologia , Mapas de Interação de Proteínas/imunologia , Transcriptoma/imunologia , Queimaduras/genética , Queimaduras/imunologia , Queimaduras/patologia , Biologia Computacional , Humanos , Índices de Gravidade do Trauma
16.
Front Immunol ; 12: 599805, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079535

RESUMO

Background: Dengue virus (DENV) infection has a global impact on public health. The clinical outcomes (of DENV) can vary from a flu-like illness called dengue fever (DF), to a more severe form, known as dengue hemorrhagic fever (DHF). The underlying innate immune mechanisms leading to protective or detrimental outcomes have not been fully elucidated. Helper innate lymphoid cells (hILCs), an innate lymphocyte recently discovered, functionally resemble T-helper cells and are important in inflammation and homeostasis. However, the role of hILCs in DENV infection had been unexplored. Methods: We performed flow cytometry to investigate the frequency and phenotype of hILCs in peripheral blood mononuclear cells from DENV-infected patients of different disease severities (DF and DHF), and at different phases (febrile and convalescence) of infection. Intracellular cytokine staining of hILCs from DF and DHF were also evaluated by flow cytometry after ex vivo stimulation. Further, the hILCs were sorted and subjected to transcriptome analysis using RNA sequencing. Differential gene expression analysis was performed to compare the febrile and convalescent phase samples in DF and DHF. Selected differentially expressed genes were then validated by quantitative PCR. Results: Phenotypic analysis showed marked activation of all three hILC subsets during the febrile phase as shown by higher CD69 expression when compared to paired convalescent samples, although the frequency of hILCs remained unchanged. Upon ex vivo stimulation, hILCs from febrile phase DHF produced significantly higher IFN-γ and IL-4 when compared to those of DF. Transcriptomic analysis showed unique hILCs gene expression in DF and DHF, suggesting that divergent functions of hILCs may be associated with different disease severities. Differential gene expression analysis indicated that hILCs function both in cytokine secretion and cytotoxicity during the febrile phase of DENV infection. Conclusions: Helper ILCs are activated in the febrile phase of DENV infection and display unique transcriptomic changes as well as cytokine production that correlate with severity. Targeting hILCs during early innate response to DENV might help shape subsequent immune responses and potentially lessen the disease severity in the future.


Assuntos
Vírus da Dengue/imunologia , Dengue/imunologia , Imunidade Inata , Linfócitos T Auxiliares-Indutores/imunologia , Transcriptoma/imunologia , Dengue/patologia , Feminino , Humanos , Interferon gama/imunologia , Interleucina-4/imunologia , Masculino , Pessoa de Meia-Idade , RNA-Seq , Linfócitos T Auxiliares-Indutores/patologia
17.
Aging (Albany NY) ; 13(9): 12691-12709, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33973529

RESUMO

Due to its effectiveness, cancer immunotherapy has attracted widespread attention from clinicians and scientific researchers. Numerous studies have proven that effective stratification of cancer patients would promote the personalized application of immunotherapy. Therefore, we used the transcriptome data of nearly 1,000 patients with non-small cell lung cancer (NSCLC) to construct a new immune subgroup. We found that the new immune subgroup, named cluster 2, was a mixture of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and showed poor overall survival, which was further verified in the independent validation set. Immune infiltration correlation analysis showed that the Mast cell type and its status subdivisions had a predictive effect on the prognosis of NSCLC, especially in LUAD. Phenotypic analysis suggested that epithelial-mesenchymal transition (EMT) was positively correlated with immunosuppression, supporting the correlation between tumor phenotype and immune background. Although immune subtypes failed to significantly distinguish the progression-free survival (PFS) of immunotherapy patients, they showed the expected trend; the sample size needs to be further expanded for verification. In addition, some results indicated that the two cancer types, LUAD and LUSC, might require independent analyses.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/mortalidade , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/mortalidade , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Masculino , Mastócitos/imunologia , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , RNA-Seq , Transcriptoma/imunologia , Evasão Tumoral/genética
18.
Front Immunol ; 12: 639634, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34025649

RESUMO

The prognosis of acute myeloid leukemia (AML) is closely related to immune response changes. Further exploration of the pathobiology of AML focusing on immune-related genes would contribute to the development of more advanced evaluation and treatment strategies. In this study, we established a novel immune-17 signature based on transcriptome data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) databases. We found that immune biology processes and transcriptional dysregulations are critical factors in the development of AML through enrichment analyses. We also formulated a prognostic model to predict the overall survival of AML patients by using LASSO (Least Absolute Shrinkage and Selection Operator) regression analysis. Furthermore, we incorporated the immune-17 signature to improve the prognostic accuracy of the ELN2017 risk stratification system. We concluded that the immune-17 signature represents a novel useful model for evaluating AML survival outcomes and may be implemented to optimize treatment selection in the next future.


Assuntos
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Transcrição Genética/genética , Transcrição Genética/imunologia , Transcriptoma/genética , Transcriptoma/imunologia
19.
Biomed Res Int ; 2021: 6655425, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33959663

RESUMO

The central component of sepsis pathogenesis is inflammatory disorder, which is related to dysfunction of the immune system. However, the specific molecular mechanism of sepsis has not yet been fully elucidated. The aim of our study was to identify genes that are significantly changed during sepsis development, for the identification of potential pathogenic factors. Differentially expressed genes (DEGs) were identified in 88 control and 214 septic patient samples. Gene ontology (GO) and pathway enrichment analyses were performed using David. A protein-protein interaction (PPI) network was established using STRING and Cytoscape. Further validation was performed using real-time polymerase chain reaction (RT-PCR). We identified 37 common DEGs. GO and pathway enrichment indicated that enzymes and transcription factors accounted for a large proportion of DEGs; immune system and inflammation signaling demonstrated the most significant changes. Furthermore, eight hub genes were identified via PPI analysis. Interestingly, four of the top five upregulated and all downregulated DEGs were involved in immune and inflammation signaling. In addition, the most intensive hub gene AKT1 and the top DEGs in human clinical samples were validated using RT-PCR. This study explored the possible molecular mechanisms underpinning the inflammatory, immune, and PI3K/AKT pathways related to sepsis development.


Assuntos
Neutrófilos , Sepse , Transcriptoma , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/metabolismo , Mapas de Interação de Proteínas/genética , Mapas de Interação de Proteínas/imunologia , Sepse/genética , Sepse/imunologia , Sepse/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Transcriptoma/genética , Transcriptoma/imunologia , Adulto Jovem
20.
Biomed Res Int ; 2021: 6680036, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33997040

RESUMO

Backgrounds: The dysregulated long noncoding RNAs (lncRNAs) have been described to be crucial regulators in the progression of ovarian carcinoma. The infiltration status of immune cells is also related to the clinical outcomes in ovarian carcinoma. The present research is aimed at constructing an immune-associated lncRNA signature with potential prognostic value for ovarian carcinoma patients. Methods: We obtained 379 ovarian carcinoma cases with available clinical data and transcriptome data from The Cancer Genome Atlas database to evaluate the infiltration status of immune cells, thereby generating high and low immune cell infiltration groups. According to the expression of the immune-associated lncRNA signature, the risk score of each case was calculated. The high- and low-risk groups were classified using the median risk score as threshold. Results: A total of 169 immune-associated lncRNAs that differentially expressed in ovarian carcinoma were included. According to the Lasso regression analysis and Cox univariate and multivariate analyses, 5 immune-associated lncRNAs, including AC134312.1, AL133467.1, CHRM3-AS2, LINC01722, and LINC02207, were identified as a predictive signature with significant prognostic value in ovarian carcinoma. The following Kaplan-Meier analysis, ROC analysis, and Cox univariate and multivariate analyses further suggested that the predicted signature may be an independent prognosticator for patients with ovarian carcinoma. The following gene set enrichment analysis showed that this 5 immune-associated lncRNAs signature was significantly related to the hedgehog pathway, basal cell carcinoma, Wnt signaling pathway, cytokine receptor interaction, antigen processing and presentation, and T cell receptor pathway. Conclusion: : This study suggested a predictive model with 5 immune-associated lncRNAs that has an independent prognostic value for ovarian carcinoma patients.


Assuntos
Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/mortalidade , RNA Longo não Codificante/imunologia , Transdução de Sinais/imunologia , Transcriptoma/imunologia , Biologia Computacional , Feminino , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Prognóstico , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Transdução de Sinais/genética , Transcriptoma/genética
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