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1.
Cancer Immunol Immunother ; 69(2): 163-174, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31848656

RESUMO

B7 homolog 4 (B7H4) is considered a negative regulator of immune responses, but the immunoregulatory role of B7H4 in the tumor microenvironment is not clear. Here, we assessed B7H4 expression cell types in human breast cancer tissues and addressed its potential mechanisms in the CD8 T cell immune response. The results from flow cytometry and immunohistochemistry demonstrated that B7H4 was highly expressed in 26 out of 30 (86.7%) breast invasive ductal carcinomas, and B7H4 surface expression on tumor cells was inversely correlated with CD8 T lymphocytes infiltration (p < 0.0001). In vivo, B7H4-overexpressing tumor cells showed enhanced tumor growth in immunocompetent mice with impaired CD8 T cell infiltration of the tumor. Further investigation showed that activation and expansion of CD8 T cells within the lymph nodes were suppressed in B7H4-overexpessing tumor-bearing mice. An in vitro killing assay showed that the cytotoxicity of CD8 T cells was inhibited in B7H4-overexpressing tumor cells. These findings suggest that B7H4 in tumor cells is a negative regulator of CD8 T cell activation, expansion and cytotoxicity, indicating that tumor cell-associated B7H4 might be a target for T cell-based cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Expressão Gênica , Imunidade/genética , Neoplasias/etiologia , Neoplasias/metabolismo , Inibidor 1 da Ativação de Células T com Domínio V-Set/genética , Animais , Biomarcadores , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Modelos Animais de Doenças , Feminino , Humanos , Imuno-Histoquímica , Imunofenotipagem , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Neoplasias/patologia , Neoplasias/terapia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Inibidor 1 da Ativação de Células T com Domínio V-Set/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Nat Med ; 25(12): 1873-1884, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31806906

RESUMO

Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small nucleolar RNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in small nuclear RNA and ribosomal RNA. We show that CRISPR/Cas9-introduced bi- and monoallelic SNORA31 deletions render human pluripotent stem cell (hPSC)-derived cortical neurons susceptible to HSV-1. Accordingly, SNORA31-mutated patient hPSC-derived cortical neurons are susceptible to HSV-1, like those from TLR3- or STAT1-deficient patients. Exogenous interferon (IFN)-ß renders SNORA31- and TLR3- but not STAT1-mutated neurons resistant to HSV-1. Finally, transcriptome analysis of SNORA31-mutated neurons revealed normal responses to TLR3 and IFN-α/ß stimulation but abnormal responses to HSV-1. Human SNORA31 thus controls central nervous system neuron-intrinsic immunity to HSV-1 by a distinctive mechanism.


Assuntos
Encefalite por Herpes Simples/genética , Herpesvirus Humano 1/genética , Neurônios/imunologia , RNA Nucleolar Pequeno/genética , Adulto , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/virologia , Pré-Escolar , Encefalite por Herpes Simples/imunologia , Encefalite por Herpes Simples/patologia , Encefalite por Herpes Simples/virologia , Feminino , Predisposição Genética para Doença , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/patogenicidade , Humanos , Imunidade/genética , Lactente , Masculino , Metagenoma/genética , Metagenoma/imunologia , Pessoa de Meia-Idade , Neurônios/virologia , RNA Nucleolar Pequeno/imunologia
3.
BMC Bioinformatics ; 20(Suppl 9): 495, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31757210

RESUMO

BACKGROUND: Transposable elements (TEs) are DNA sequences able to mobilize themselves and to increase their copy-number in the host genome. In the past, they have been considered mainly selfish DNA without evident functions. Nevertheless, currently they are believed to have been extensively involved in the evolution of primate genomes, especially from a regulatory perspective. Due to their recent activity they are also one of the primary sources of structural variants (SVs) in the human genome. By taking advantage of sequencing technologies and bioinformatics tools, recent surveys uncovered specific TE structural variants (TEVs) that gave rise to polymorphisms in human populations. When combined with RNA-seq data this information provides the opportunity to study the potential impact of TEs on gene expression in human. RESULTS: In this work, we assessed the effects of the presence of specific TEs in cis on the expression of flanking genes by producing associations between polymorphic TEs and flanking gene expression levels in human lymphoblastoid cell lines. By using public data from the 1000 Genome Project and the Geuvadis consortium, we exploited an expression quantitative trait loci (eQTL) approach integrated with additional bioinformatics data mining analyses. We uncovered human loci enriched for common, less common and rare TEVs and identified 323 significant TEV-cis-eQTL associations. SINE-R/VNTR/Alus (SVAs) resulted the TE class with the strongest effects on gene expression. We also unveiled differential functional enrichments on genes associated to TEVs, genes associated to TEV-cis-eQTLs and genes associated to the genomic regions mostly enriched in TEV-cis-eQTLs highlighting, at multiple levels, the impact of TEVs on the host genome. Finally, we also identified polymorphic TEs putatively embedded in transcriptional units, proposing a novel mechanism in which TEVs may mediate individual-specific traits. CONCLUSION: We contributed to unveiling the effect of polymorphic TEs on transcription in lymphoblastoid cell lines.


Assuntos
Elementos de DNA Transponíveis/genética , Bases de Dados Genéticas , Linfócitos/metabolismo , Polimorfismo Genético , Locos de Características Quantitativas/genética , Transcrição Genética , Elementos Alu/genética , Animais , Comportamento , Linhagem Celular , Genoma Humano , Humanos , Imunidade/genética , Repetições Minissatélites/genética
4.
Int J Oral Sci ; 11(3): 29, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31578319

RESUMO

Cas1-and-Cas2-mediated new spacer acquisition is an essential process for bacterial adaptive immunity. The process is critical for the ecology of the oral microflora and oral health. Although molecular mechanisms for spacer acquisition are known, it has never been established if this process is associated with the morphological changes of bacteria. In this study, we demonstrated a novel Cas2-induced filamentation phenotype in E. coli that was regulated by co-expression of the Cas1 protein. A 30 amino acid motif at the carboxyl terminus of Cas2 is necessary for this function. By imaging analysis, we provided evidence to argue that Cas-induced filamentation is a step coupled with new spacer acquisition during which filaments are characterised by polyploidy with asymmetric cell division. This work may open new opportunities to investigate the adaptive immune response and microbial balance for oral health.


Assuntos
Proteínas de Bactérias/metabolismo , Sistemas CRISPR-Cas/genética , Sistemas CRISPR-Cas/imunologia , DNA Bacteriano/genética , Escherichia coli/imunologia , Saúde Bucal , Adaptação Biológica/genética , Imunidade Adaptativa , Proteínas de Bactérias/genética , Sistemas CRISPR-Cas/fisiologia , Endonucleases , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli , Humanos , Imunidade/genética
5.
Int J Mol Sci ; 20(18)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491977

RESUMO

In this experiment, the effects of a sudden drop of salinity on the immune response mechanisms of the ark shell Anadara kagoshimensis were examined by simulating the sudden drop of salinity that occurs in seawater after a rainstorm. Additionally, the differentially expressed genes (DEGs) were identified using transcriptome sequencing. When the salinity dropped from 30‱ (S30) to 14‱ (S14), the phagocytic activity of blood lymphocytes, the O2- levels produced from respiratory burst, the content of reactive oxygen species, and the activities of lysozymes and acid phosphatases increased significantly, whereas the total count of blood lymphocytes did not increase. Total count of blood lymphocytes in 22‱ salinity (S22) was significantly higher than that in any other group. The raw data obtained from sequencing were processed with Trimmomatic (Version 0.36). The expression levels of unigenes were calculated using transcripts per million (TPM) based on the effects of sequencing depth, gene length, and sample on reads. Differential expression analysis was performed using DESeq (Version 1.12.4). Transcriptome sequencing revealed 269 (101 up-regulated, 168 down-regulated), 326 (246 up-regulated, 80 down-regulated), and 185 (132 up-regulated, 53 down-regulated) significant DEGs from comparison of the S14 vs. S22, S22 vs. S30, and S14 vs. S30 groups, respectively. Gene Ontology enrichment analysis of the DEGs in these salinity comparison groups revealed that the cellular amino acid metabolic process, the regulation of protein processing, the regulation of response to stress, and other terms were significantly enriched. Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that nucleotide-binding, oligomerization domain (NOD)-like receptor signaling pathway (ko04621), apoptosis-multiple species (ko04215), Toll and Imd signaling pathway (ko04624), NF-κB signaling pathway (ko04064), apoptosis (ko04210), and focal adhesion (ko04510) were significantly enriched in all salinity comparison groups. qRT-PCR verification of 12 DEGs in the above six pathways was conducted, and the results were consistent with the transcriptome sequencing results in terms of up-regulation and down-regulation, which illustrates that the transcriptome sequencing data are credible. These results were used to preliminarily explore the effects of a sudden drop of salinity on blood physiological and biochemical indexes and immunoregulatory mechanisms of A. kagoshimensis. They also provide a theoretical basis for the selection of bottom areas optimal for release and proliferation of A. kagoshimensis required to restore the declining populations of this species.


Assuntos
Arcidae/fisiologia , Imunidade , Salinidade , Animais , Biomarcadores , Biologia Computacional/métodos , Meio Ambiente , Perfilação da Expressão Gênica , Imunidade/genética , Contagem de Linfócitos , Linfócitos/imunologia , Linfócitos/metabolismo , Anotação de Sequência Molecular , Oxigênio/metabolismo , Fagocitose/genética , Fagocitose/imunologia , Espécies Reativas de Oxigênio , Explosão Respiratória , Transdução de Sinais , Transcriptoma
6.
J Dairy Sci ; 102(10): 9107-9116, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31400895

RESUMO

The dynamic interaction between the host and pathogens, along with environmental factors, influences the regulation of mammalian immune responses. Therefore, comprehensive in vivo immune-phenotyping during an active response to a pathogen can be complex and prone to confounding effects. Evaluating critical fundamental aspects of the immune system at a cellular level is an alternative approach to reduce this complexity. Therefore, the objective of the current study was to examine an in vitro model for functional phenotyping of bovine monocyte-derived macrophages (MDM), cells which play a crucial role at all phases of inflammation, as well influence downstream immune responses. As indicators of MDM function, phagocytosis and nitric oxide (NO-) production were tested in MDM of 16 cows in response to 2 common bacterial pathogens of dairy cows, Escherichia coli and Staphylococcus aureus. Notable functional variations were observed among the individuals (coefficient of variation: 33% for phagocytosis and 70% in the production of NO-). The rank correlation analysis revealed a significant, positive, and strong correlation (rho = 0.92) between NO- production in response to E. coli and S. aureus, and a positive but moderate correlation (rho = 0.58) between phagocytosis of E. coli and S. aureus. To gain further insight into this trait, another 58 cows were evaluated solely for NO- response against E. coli. The pedigree of the tested animals was added to the statistical model and the heritability was estimated to be 0.776. Overall, the finding of this study showed a strong effect of host genetics on the in vitro activities of MDM and the possibility of ranking Holstein cows based on the in vitro functional variation of MDM.


Assuntos
Doenças dos Bovinos/genética , Doenças dos Bovinos/imunologia , Infecções por Escherichia coli/veterinária , Macrófagos/imunologia , Infecções Estafilocócicas/veterinária , Animais , Bovinos , Doenças dos Bovinos/microbiologia , Escherichia coli/imunologia , Infecções por Escherichia coli/imunologia , Feminino , Imunidade/genética , Macrófagos/efeitos dos fármacos , Óxido Nítrico/metabolismo , Linhagem , Fagocitose , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia
7.
Int J Mol Sci ; 20(16)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398943

RESUMO

The immune response is essential to protect organisms from infection and an altered self. An organism's overall metabolic status is now recognized as an important and long-overlooked mediator of immunity and has spurred new explorations of immune-related metabolic abnormalities. Peroxisomes are essential metabolic organelles with a central role in the synthesis and turnover of complex lipids and reactive species. Peroxisomes have recently been identified as pivotal regulators of immune functions and inflammation in the development and during infection, defining a new branch of immunometabolism. This review summarizes the current evidence that has helped to identify peroxisomes as central regulators of immunity and highlights the peroxisomal proteins and metabolites that have acquired relevance in human pathologies for their link to the development of inflammation, neuropathies, aging and cancer. This review then describes how peroxisomes govern immune signaling strategies such as phagocytosis and cytokine production and their relevance in fighting bacterial and viral infections. The mechanisms by which peroxisomes either control the activation of the immune response or trigger cellular metabolic changes that activate and resolve immune responses are also described.


Assuntos
Suscetibilidade a Doenças , Imunidade , Inflamação/etiologia , Inflamação/metabolismo , Peroxissomos/metabolismo , Envelhecimento/genética , Envelhecimento/imunologia , Envelhecimento/metabolismo , Animais , Biomarcadores , Metabolismo Energético , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade/genética , Imunomodulação , Fagocitose/genética , Fagocitose/imunologia , Transdução de Sinais
8.
J Dairy Res ; 86(3): 307-314, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31451129

RESUMO

This study aimed to evaluate the transcriptional changes occurring in isolated perfused mammary alveolar tissue in response to inoculation with S. agalactiae and to identify the most affected biological functions and pathways after 3 h. Four udders taken at slaughter from cows with healthy mammary gland were perfused ex situ with warmed and gassed Tyrode's solution. Mammary alveolar tissue samples were taken from the left fore and rear quarters (IQ-inoculated quarters) before inoculation (hour 0) and at 3 h post inoculation (hpi) and at the same times from control right fore and rear quarters (not inoculated: NIQ). A total of 1756 differentially expressed genes (DEGs) were identified between IQ and NIQ at 3 hpi using edgeR package. Within this set of DEGs, 952 were up regulated and mainly involved with innate immune response and inflammatory response, e.g., CD14, CCL5, TLR2, IL-8, SAA3, as well as in transcriptional regulation such as FOS, STAT3 and NFKBIA. Genes down-regulated (804) included those involved with lipid synthesis e.g., APOC2, SCD, FABP3 and FABP4. The most affected pathways were chemokine signaling, Wnt signaling and complement and coagulation cascades, which likely reflects the early stage response of mammary tissue to S. agalactiae infection. No significant gene expression changes were detected by RNA-Seq in the others contrasts. Real time-PCR confirmed the increase in mRNA abundance of immune-related genes: TLR2, TLR4, IL-1ß, and IL-10 at 3 hpi between IQ and NIQ. The expression profiles of Casp1 and Bax for any contrasts were unaffected whereas Bcl2 was increased in IQ, which suggests no induction of apoptosis during the first hours after infection. Results provided novel information regarding the early functional pathways and gene network that orchestrate innate immune responses to S. agalactiae infection. This knowledge could contribute to new strategies to enhance resistance to this disease, such as genomic selection.


Assuntos
Perfilação da Expressão Gênica/veterinária , Glândulas Mamárias Animais/metabolismo , Infecções Estreptocócicas/veterinária , Streptococcus agalactiae , Animais , Bovinos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Imunidade/genética , Inflamação/genética , Mastite Bovina/genética , Mastite Bovina/imunologia , Mastite Bovina/microbiologia , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Infecções Estreptocócicas/genética , Infecções Estreptocócicas/imunologia
9.
J Dairy Sci ; 102(9): 8343-8351, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301830

RESUMO

Methionine (Met) is one of the 2 most limiting amino acids for milk production in dairy cow diets. The accepted "ideal" ratio of lysine (Lys) to Met (L:M) when formulating diets is 3:1. However, blood from cows fed corn silage-based diets without supplemental rumen-protected Met averages approximately 3.6:1 L:M. Recent in vivo research on cattle immunonutrition has revealed that the immune system could benefit from greater Met supply. To study more closely the effects of different L:M ratios, blood polymorphonuclear cells (PMN) were isolated from 5 Holstein cows in mid-lactation (238 ± 20 d postpartum, 33.8 ± 3.8 kg of milk/d; mean ± SD). The PMN were incubated at 3 different levels of L:M (3.6:1, 2.9:1, or 2.4:1) and stimulated with lipopolysaccharide (LPS) at either 0 or 50 µg/mL for 2 h at 37°C. Target genes were associated with cytokines, pathogen recognition, nuclear receptors, killing mechanisms, and Met and glutathione metabolism. Data were subjected to ANOVA using PROC MIXED in SAS, with L:M, LPS, and their interaction as fixed effects. Stimulation with LPS upregulated genes related to cytokines (IL1B, TNF, IL10 and IL6) and nuclear receptors, including nuclear factor kappa B (NFKB1) and glucocorticoid receptor (NR3C1), and downregulated the mRNA abundance of chemokine receptor 1 (CXCR1), lysozyme (LYZ) and glutathione reductase (GSR). A linear decrease was observed in the mRNA abundance of TNF when L:M was decreased. A similar response was observed for interleukin-1 receptor-associated kinase 1 (IRAK1) and NFKB1 abundance in cells stimulated with LPS (linear effect). A linear increase of LYZ mRNA expression as L:M decreased was detected in unstimulated cells. Furthermore, a decrease in L:M led to a linear decrease of superoxide dismutase 1 (SOD1) mRNA abundance in cells challenged with LPS. Overall, LPS challenge triggered the activation of isolated PMN from mid-lactation cows. However, data suggest the use of a shorter incubation time to capture the peak response and not the resolution of the inflammatory response as in the present study. Our results indicate a possible involvement of Met in modulating PMN inflammatory and oxidative stress status and in helping the resolution of inflammation after initial stimulation.


Assuntos
Bovinos/imunologia , Redes Reguladoras de Genes , Imunidade/genética , Metionina/farmacologia , Neutrófilos/imunologia , Animais , Bovinos/genética , Células Cultivadas , Dieta/veterinária , Suplementos Nutricionais , Feminino , Lactação/fisiologia , Lipopolissacarídeos/imunologia , Metionina/administração & dosagem , Leite/química , Rúmen/metabolismo
10.
Mol Immunol ; 112: 360-368, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31261021

RESUMO

Hemocyanin is primarily a respiratory copper-containing glycoprotein present in the hemolymph of mollusks and arthropods. Recently, hemocyanin has attracted huge research interest due to its multifunctionality and polymorphism. Most previous immune-related studies on shrimp hemocyanin have focused on the C-terminal. Moreover, we previously reported that the C-terminal domain of Litopenaeus vannamei hemocyanin possesses single nucleotide polymorphisms (SNPs), but little is known about the molecular diversity of the N-terminal domain. In the current study, diversity within the N-terminal domain of L. vannamei hemocyanin (LvHMC-N) was explored using bioinformatics and molecular biology techniques as well as immune challenge. Twenty-five LvHMC-N variants were identified using polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and DNA sequencing, with multiple sequence alignment showing that the 25 variants shared 87%-99 % sequence homology with LvHMC (AJ250830.1). In different shrimp individuals and different shrimp tissues (i.e., hemocytes, stomach, muscle and hepatopancreas), the LvHMC-N variants were expressed differently. Pathogen challenge could modulate the molecular diversity of LvHMC-N, as three LvHMC-Nr variants (LvHMC-Nr1, LvHMC-Nr2 and LvHMC-Nr3) were identified by sequencing following Vibrio parahaemolyticus challenge. Most importantly, recombinant proteins of these three variants (rLvHMC-Nr1, rLvHMC-Nr2 and rLvHMC- Nr3) had relatively high in vitro agglutinative activities against V. parahaemolyticus, Vibrio alginolyticus and Streptoccocus iniae. Our present data indicates that the N-terminus of L. vannamei hemocyanin also possess molecular diversity, which seems to be associated with immune resistance to pathogenic infections.


Assuntos
Hemocianinas/genética , Hemocianinas/imunologia , Imunidade/genética , Imunidade/imunologia , Penaeidae/genética , Penaeidae/imunologia , Sequência de Aminoácidos , Animais , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/imunologia , Sequência de Bases , Clonagem Molecular/métodos , Biologia Computacional/métodos , Hemócitos/imunologia , Hemócitos/microbiologia , Hemolinfa/imunologia , Hemolinfa/microbiologia , Hepatopâncreas/imunologia , Hepatopâncreas/microbiologia , Alinhamento de Sequência , Análise de Sequência de DNA , Vibrioses/genética , Vibrioses/imunologia , Vibrioses/microbiologia , Vibrio parahaemolyticus/imunologia
11.
J Dairy Sci ; 102(9): 7684-7696, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31255276

RESUMO

Oxidative stress is the basic reason for aging and age-related diseases. In this study, we investigated the protective effect of 2 strains of lactic acid bacteria (LAB), Lactobacillus rhamnosus GG and L. plantarum J26, against oxidative stress in Caco-2 cells, and gave an overview of the mechanisms of lactic acid bacteria antioxidant activity using digital gene expression profiling. The 2 LAB strains provided significant protection against hydrogen peroxide (H2O2)-induced reduction in superoxide dismutase activity and increase in glutathione peroxidase activity in Caco-2 cells. However, inactive bacteria had little effect on alleviating oxidation stress in Caco-2 cells. Eight genes related to oxidative stress-FOSB, TNF, PPP1R15A, NUAK2, ATF3, TNFAIP3, EGR2, and FBN2-were significantly upregulated in H2O2-induced Caco-2 cells compared with untreated Caco-2 cells. After incubation of the H2O2-induced Caco-2 cells with L. rhamnosus GG and L. plantarum J26, 5 genes (TNF, EGR2, NUAK2, FBN2, and TNFAIP3) and 2 genes (NUAK2 and FBN2) were downregulated, respectively. In addition, the Kyoto Encyclopedia of Genes and Genomes indicated that some signaling pathways associated with inflammation, immune response, and apoptosis, such as Janus kinase/signal transducers and activators of transcription (Jak-STAT), mitogen-activated protein kinase (MAPK), nuclear factor-κB, and tumor necrosis factor, were all negatively modulated by the 2 strains, especially L. rhamnosus GG. In this paper, we reveal the mechanism of LAB in relieving oxidative stress and provide a theoretical basis for the rapid screening and evaluation of new LAB resources.


Assuntos
Enterócitos/metabolismo , Lactobacillus plantarum/fisiologia , Lactobacillus rhamnosus/fisiologia , Estresse Oxidativo/genética , Transcriptoma/genética , Animais , Apoptose/genética , Células CACO-2 , Enterócitos/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/fisiologia , Humanos , Peróxido de Hidrogênio/farmacologia , Imunidade/genética , Inflamação/genética , Probióticos/farmacologia
12.
J Immunol Res ; 2019: 8732191, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183393

RESUMO

Routine vaccination is among the most effective clinical interventions to prevent diseases as it is estimated to save over 3 million lives every year. However, the full potential of global immunization programs is not realised because population coverage is still suboptimal. This is also due to the inadequate immune response and paucity of informative correlates of protection upon immunization of vulnerable individuals such as newborns, preterm infants, pregnant women, and elderly individuals as well as those patients affected by chronic and immune compromising medical conditions. In addition, these groups are undervaccinated for a number of reasons, including lack of awareness of vaccine-preventable diseases and uncertainty or misconceptions about the safety and efficacy of vaccination by parents and healthcare providers. The presence of these nonresponders/undervaccinated individuals represents a major health and economic burden to society, which will become particularly difficult to address in settings with limited public resources. This review describes innovative and experimental approaches that can help identify specific genomic profiles defining nonresponder individuals for whom specific interventions might be needed. We will provide examples that show how such information can be useful to identify novel biomarkers of safety and immunogenicity for future vaccine trials. Finally, we will discuss how system biology "OMICs" data can be used to design bioinformatic tools to predict the vaccination outcome providing genetic and molecular "signatures" of protective immune response. This strategy may soon enable identification of signatures highly predictive of vaccine safety, immunogenicity, and efficacy/protection thereby informing personalized vaccine interventions in vulnerable populations.


Assuntos
Imunidade/genética , Vacinação , Vacinas/imunologia , Idoso , Biomarcadores , Biologia Computacional , Feminino , Genômica , Humanos , Programas de Imunização , Recém-Nascido , Medicina de Precisão , Gravidez , Resultado do Tratamento
13.
J Dairy Sci ; 102(8): 7408-7420, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31178180

RESUMO

The high metabolic demand during the transition into lactation places cows at greater risk of metabolic and infectious disease than at any other time in their lactation cycle. Additionally, a change occurs in the innate immune response during this period, which contributes to increased risk of disease. In the current study, we compared the transcriptomes of neutrophils from dairy cows divergent in their metabolic health post-calving. Cows (n = 5 per risk group) were selected from a parent experiment (n = 45 cows). Those with high or low concentrations of plasma nonesterified fatty acids, plasma ß-hydroxybutyrate, and liver triacylglycerol in both wk 1 and 2 were deemed to be at "high risk" (HR) or "low risk" (LR) of metabolic dysfunction, respectively. Circulating neutrophils were isolated at 3 time points during the transition period (d 0 and wk 1 and 4 post-calving), and gene expression was analyzed using RNA sequencing. Differential gene expression between the risk groups was determined using edgeR (http://bioconductor.org), and pathway analysis was conducted using Ingenuity Pathway Analysis (Ingenuity Systems, Qiagen, Valencia, CA). Statistical analysis indicated no interaction between risk and week. Therefore, the overall effect of risk was analyzed across all time points. In total, 3,500 genes were differentially expressed between the HR and LR cows (false discovery rate < 0.05). Of these, 2,897 genes were identified by Ingenuity Pathway Analysis and used for pathway analysis. Of the relevant pathways identified, neutrophils isolated from HR cows showed downregulation of genes involved in the recruitment of granulocytes, interferon signaling, and apoptosis, and upregulation of genes involved in cell survival. The results indicate that metabolically stressed cows had reduced neutrophil function during the peripartum period, highlighting a potential relationship between subclinical metabolic disease and innate immune function that suggests that metabolic health negatively affects the innate immune system and may contribute to the state of immunosuppression during the peripartum period. In this way, the metabolic stress among the HR cows may reduce their ability to combat infection during the transition period.


Assuntos
Bovinos/imunologia , Perfilação da Expressão Gênica/veterinária , Neutrófilos/imunologia , Período Periparto/imunologia , Estresse Fisiológico/imunologia , Ácido 3-Hidroxibutírico/sangue , Animais , Bovinos/genética , Doenças dos Bovinos/imunologia , Ácidos Graxos não Esterificados/sangue , Feminino , Expressão Gênica , Imunidade/genética , Lactação/fisiologia , Fígado/química , Fatores de Risco , Análise de Sequência de RNA/veterinária , Triglicerídeos/análise , Regulação para Cima
14.
Immunity ; 51(1): 155-168.e5, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31248780

RESUMO

Genetic variation influences how the genome is interpreted in individuals and in mouse strains used to model immune responses. We developed approaches to utilize next-generation sequencing datasets to identify sequence variation in genes and enhancer elements in congenic and backcross mouse models. We defined genetic variation in the widely used B6-CD45.2 and B6.SJL-CD45.1 congenic model, identifying substantial differences in SJL genetic content retained in B6.SJL-CD45.1 strains on the basis of the vendor source of the mice. Genes encoding PD-1, CD62L, Bcl-2, cathepsin E, and Cxcr4 were within SJL genetic content in at least one vendor source of B6.SJL-CD45.1 mice. SJL genetic content affected enhancer elements, gene regulation, protein expression, and amino acid content in CD4+ T helper 1 cells, and mice infected with influenza showed reduced expression of Cxcr4 on B6.SJL-CD45.1 T follicular helper cells. These findings provide information on experimental variables and aid in creating approaches that account for genetic variables.


Assuntos
Catepsina E/metabolismo , Elementos Facilitadores Genéticos/genética , Imunidade/genética , Receptores CXCR4/metabolismo , Células Th1/imunologia , Animais , Catepsina E/genética , Comércio , Regulação da Expressão Gênica , Patrimônio Genético , Variação Genética , Centro Germinativo/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Endogamia , Antígenos Comuns de Leucócito/genética , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Modelos Animais , Receptores CXCR4/genética
15.
G3 (Bethesda) ; 9(8): 2761-2774, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31213516

RESUMO

Evolutionary changes in enhancers are widely associated with variation in human traits and diseases. However, studies comprehensively quantifying levels of selection on enhancers at multiple evolutionary periods during recent human evolution and how enhancer evolution varies across human tissues are lacking. To address these questions, we integrated a dataset of 41,561 transcribed enhancers active in 41 different human tissues (FANTOM Consortium) with whole genome sequences of 1,668 individuals from the African, Asian, and European populations (1000 Genomes Project). Our analyses based on four different metrics (Tajima's D, F ST, H12, nS L) showed that ∼5.90% of enhancers showed evidence of recent positive selection and that genes associated with enhancers under very recent positive selection are enriched for diverse immune-related functions. The distributions of these metrics for brain and testis enhancers were often statistically significantly different and in the direction suggestive of less positive selection compared to those of other tissues; the same was true for brain and testis enhancers that are tissue-specific compared to those that are tissue-broad and for testis enhancers associated with tissue-enriched and non-tissue-enriched genes. These differences varied considerably across metrics and tissues and were generally in the form of changes in distributions' shapes rather than shifts in their values. Collectively, these results suggest that many human enhancers experienced recent positive selection throughout multiple time periods in human evolutionary history, that this selection occurred in a tissue-dependent and immune-related functional context, and that much like the evolution of their protein-coding gene counterparts, the evolution of brain and testis enhancers has been markedly different from that of enhancers in other tissues.


Assuntos
Elementos Facilitadores Genéticos , Genômica , Seleção Genética , Elementos de DNA Transponíveis , Bases de Dados Genéticas , Evolução Molecular , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Imunidade/genética , Especificidade de Órgãos , Característica Quantitativa Herdável
16.
Breast Cancer Res Treat ; 177(2): 335-343, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31222709

RESUMO

PURPOSE: Breast cancer (BC) is a heterogeneous disorder, with variable response to systemic chemotherapy. Likewise, BC shows highly complex immune activation patterns, only in part reflecting classical histopathological subtyping. Schlafen-11 (SLFN11) is a nuclear protein we independently described as causal factor of sensitivity to DNA damaging agents (DDA) in cancer cell line models. SLFN11 has been reported as a predictive biomarker for DDA and PARP inhibitors in human neoplasms. SLFN11 has been implicated in several immune processes such as thymocyte maturation and antiviral response through the activation of interferon signaling pathway, suggesting its potential relevance as a link between immunity and cancer. In the present work, we investigated the transcriptional landscape of SLFN11, its potential prognostic value, and the clinico-pathological associations with its variability in BC. METHODS: We assessed SLFN11 determinants in a gene expression meta-set of 5061 breast cancer patients annotated with clinical data and multigene signatures. RESULTS: We found that 537 transcripts are highly correlated with SLFN11, identifying "immune response", "lymphocyte activation", and "T cell activation" as top Gene Ontology processes. We established a strong association of SLFN11 with stromal signatures of basal-like phenotype and response to chemotherapy in estrogen receptor negative (ER-) BC. We identified a distinct subgroup of patients, characterized by high SLFN11 levels, ER- status, basal-like phenotype, immune activation, and younger age. Finally, we observed an independent positive predictive role for SLFN11 in BC. CONCLUSIONS: Our findings are suggestive of a relevant role for SLFN11 in BC and its immune and molecular variability.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Regulação Neoplásica da Expressão Gênica , Imunidade/genética , Neoplasia de Células Basais/genética , Neoplasia de Células Basais/imunologia , Proteínas Nucleares/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Biologia Computacional/métodos , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Imunomodulação/genética , Neoplasia de Células Basais/mortalidade , Neoplasia de Células Basais/patologia , Fenótipo , Prognóstico
17.
Cancer Sci ; 110(8): 2348-2356, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31222843

RESUMO

Immune checkpoint blockade (ICB) therapy has achieved remarkable clinical benefit in non-small-cell lung cancer (NSCLC), but our understanding of biomarkers that predict the response to ICB remain obscure. Here we integrated somatic mutational profile and clinicopathologic information from 113 NSCLC patients treated by ICB (CTLA-4/PD-1). High tumor mutation burden (TMB) and neoantigen burden were identified significantly associated with improved efficacy in NSCLC immunotherapy. Furthermore, we identified apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) mutational signature was markedly associated with responding of ICB therapy (log-rank test, P = .001; odds ratio (OR), 0.18 [95% CI, 0.06-0.50], P < .001). The association with progression-free survival remained statistically significant after controlling for age, sex, histological type, smoking, PD-L1 expression, hypermutation, smoking signature and mismatch repair (MMR) (HR, 0.30 [95% CI, 0.12-0.75], P = .010). Combined high TMB with APOBEC signature preferably predict immunotherapy responders in NSCLC cohort. The CIBERSORT algorithm revealed that high APOBEC mutational activity samples were associated with increased infiltration of CD4 memory activated T cells, CD8+ T cells and natural killer (NK) cells, but reduced infiltration of regulatory T cells. Besides, individual genes mutation of IFNGR1 or VTCN1 were only found in responders; however, the PTEN mutation was only found in non-responders (Fisher's exact test, all P < .05). These findings may be applicable for guiding immunotherapy for patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Imunidade/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Imunidade/imunologia , Memória Imunológica/genética , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Mutação/imunologia , Intervalo Livre de Progressão , Linfócitos T Reguladores/imunologia , Carga Tumoral/genética , Carga Tumoral/imunologia
18.
BMC Genomics ; 20(1): 516, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31226933

RESUMO

BACKGROUND: Bovine viral diarrhea virus (BVDV) is an economically important viral pathogen of domestic and wild ruminants. Apart from cattle, small ruminants (goats and sheep) are also the susceptible hosts for BVDV. BVDV infection could interfere both of the innate and adaptive immunity of the host, while the genes and mechanisms responsible for these effects have not yet been fully understood. Peripheral blood mononuclear cells (PBMCs) play a pivotal role in the immune responses to viral infection, and these cells were the target of BVDV infection. In the present study, the transcriptome of goat peripheral blood mononuclear cells (PBMCs) infected with BVDV-2 was explored by using RNA-Seq technology. RESULTS: Goat PBMCs were successfully infected by BVDV-2, as determined by RT-PCR and quantitative real-time RT-PCR (qRT-PCR). RNA-Seq analysis results at 12 h post-infection (hpi) revealed 499 differentially expressed genes (DEGs, fold-change ≥ ± 2, p < 0.05) between infected and mock-infected PBMCs. Of these genes, 97 were up-regulated and the remaining 352 genes were down-regulated. The identified DEGs were found to be significantly enriched for locomotion/ localization, immune response, inflammatory response, defense response, regulation of cytokine production, etc., under GO enrichment analysis. Cytokine-cytokine receptor interaction, TNF signaling pathway, chemokine signaling pathway, etc., were found to be significantly enriched in KEGG pathway database. Protein-protein interaction (PPI) network analysis indicated most of the DEGs related to innate or adaptive immune responses, inflammatory response, and cytokine/chemokine-mediated signaling pathway. TNF, IL-6, IL-10, IL-12B, GM-CSF, ICAM1, EDN1, CCL5, CCL20, CXCL10, CCL2, MAPK11, MAPK13, CSF1R and LRRK1 were located in the core of the network and highly connected with other DGEs. CONCLUSIONS: BVDV-2 infection of goat PBMCs causes the transcription changes of a series of DEGs related to host immune responses, including inflammation, defense response, cell locomotion, cytokine/chemokine-mediated signaling, etc. The results will be useful for exploring and further understanding the host responses to BVDV-2 infection in goats.


Assuntos
Vírus da Diarreia Viral Bovina Tipo 2/genética , Doenças das Cabras/imunologia , Doenças das Cabras/virologia , Infecções por Pestivirus/veterinária , Animais , Vírus da Diarreia Viral Bovina Tipo 2/imunologia , Perfilação da Expressão Gênica , Regulação Viral da Expressão Gênica , Doenças das Cabras/genética , Cabras , Imunidade/genética , Leucócitos Mononucleares/virologia , Infecções por Pestivirus/genética , Infecções por Pestivirus/imunologia , Análise de Sequência de RNA , Replicação Viral
19.
Nat Immunol ; 20(6): 687-700, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31061528

RESUMO

Most tissue-resident macrophage populations develop during embryogenesis, self-renew in the steady state and expand during type 2 immunity. Whether shared mechanisms regulate the proliferation of macrophages in homeostasis and disease is unclear. Here we found that the transcription factor Bhlhe40 was required in a cell-intrinsic manner for the self-renewal and maintenance of large peritoneal macrophages (LPMs), but not that of other tissue-resident macrophages. Bhlhe40 was necessary for the proliferation, but not the polarization, of LPMs in response to the cytokine IL-4. During infection with the helminth Heligmosomoides polygyrus bakeri, Bhlhe40 was required for cell cycling of LPMs. Bhlhe40 repressed the expression of genes encoding the transcription factors c-Maf and Mafb and directly promoted expression of transcripts encoding cell cycle-related proteins to enable the proliferation of LPMs. In LPMs, Bhlhe40 bound to genomic sites co-bound by the macrophage lineage-determining factor PU.1 and to unique sites, including Maf and loci encoding cell-cycle-related proteins. Our findings demonstrate a tissue-specific control mechanism that regulates the proliferation of resident macrophages in homeostasis and type 2 immunity.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Homeodomínio/genética , Homeostase/genética , Homeostase/imunologia , Imunidade/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biomarcadores , Ciclo Celular/genética , Ciclo Celular/imunologia , Proliferação de Células , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Infecções por Helicobacter/genética , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Proteínas de Homeodomínio/metabolismo , Imunofenotipagem , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Transgênicos , Monócitos/imunologia , Monócitos/metabolismo , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Transcriptoma
20.
Scand J Immunol ; 90(1): e12771, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31054156

RESUMO

Immunopolymorphism is considered as an important aspect behind the resistance or susceptibility of the host to an infectious disease. Over the years, researchers have explored many genetic factors for their role in immune surveillance against infectious diseases. Polymorphic characters in the gene encoding Toll-like receptors (TLRs) play profound roles in inducing differential immune responses by the host against parasitic infections. Protein(s) encoded by TLR gene(s) are immensely important due to their ability of recognizing different types of pathogen associated molecular patterns (PAMPs). This study reviews the polymorphic residues present in the nucleotide or in the amino acid sequence of TLRs and their influence on alteration of inflammatory signalling pathways promoting either susceptibility or resistance to major infectious diseases, including tuberculosis, leishmaniasis, malaria and filariasis. Population-based studies exploring TLR polymorphisms in humans are primarily emphasized to discuss the association of the polymorphic residues with the occurrence and epidemiology of the mentioned infectious diseases. Principal polymorphic residues in TLRs influencing immunity to infection are mostly single nucleotide polymorphisms (SNPs). I602S (TLR1), R677W (TLR2), P554S (TLR3), D299G (TLR4), F616L (TLR5), S249P (TLR6), Q11L (TLR7), M1V (TLR8), G1174A (TLR9) and G1031T (TLR10) are presented as the major influential SNPs in shaping immunity to pathogenic infections. The contribution of these SNPs in the structure-function relationship of TLRs is yet not clear. Therefore, molecular studies on such polymorphisms can improve our understanding on the genetic basis of the immune response and pave the way for therapeutic intervention in a more feasible way.


Assuntos
Doenças Transmissíveis/genética , Receptores Toll-Like/genética , Animais , Predisposição Genética para Doença , Humanos , Imunidade/genética , Vigilância Imunológica , Padrões Moleculares Associados a Patógenos/imunologia , Polimorfismo Genético , Relação Estrutura-Atividade
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