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1.
Gene ; 764: 145101, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32877747

RESUMO

India is the world's largest milk producing country because of massive contribution made by cattle and buffaloes. In the present investigation, comprehensive comparative profiling of transcriptomic landscape of milk somatic cells of Sahiwal cattle and Murrah buffaloes was carried out. Genes with highest transcript abundance in both species were enriched for biological processes such as lactation, immune response, cellular oxidant detoxification and response to hormones. Analysis of differential expression identified 377 significantly up-regulated and 847 significantly down-regulated genes with fold change >1.5 in Murrah buffaloes as compared to Sahiwal cattle (padj <0.05). Marked enrichment of innate and adaptive immune response related GO terms and higher expression of genes for various host defense peptides such as lysozyme, defensin ß and granzymes were evident in buffaloes. Genes related to ECM-receptor interaction, complement and coagulation cascades, cytokine-cytokine receptor interaction and keratinization pathway showed more abundant expression in cattle. Network analysis of the up-regulated genes delineated highly connected genes representing immunity and haematopoietic cell lineage (CBL, CD28, CD247, PECAM1 and ITGA4). For the down-regulated dataset, genes with highest interactions were KRT18, FGFR1, GPR183, ITGB3 and DKK3. Our results lend support to more robust immune mechanisms in buffaloes, possibly explaining lower susceptibility to mammary infections as compared to cattle.


Assuntos
Búfalos/imunologia , Bovinos/imunologia , Imunidade/genética , Transcriptoma/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Búfalos/genética , Bovinos/genética , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Regulação para Baixo/imunologia , Feminino , Hematopoese/genética , Hematopoese/imunologia , Índia , Lactação/genética , Lactação/imunologia , Leite/citologia , Leite/imunologia , RNA-Seq , Transcriptoma/genética , Regulação para Cima/imunologia
2.
PLoS Biol ; 18(9): e3000849, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32898168

RESUMO

Despite limited genomic diversity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown a wide range of clinical manifestations in different patient populations. The mechanisms behind these host differences are still unclear. Here, we examined host response gene expression across infection status, viral load, age, and sex among shotgun RNA sequencing profiles of nasopharyngeal (NP) swabs from 430 individuals with PCR-confirmed SARS-CoV-2 and 54 negative controls. SARS-CoV-2 induced a strong antiviral response with up-regulation of antiviral factors such as OAS1-3 and IFIT1-3 and T helper type 1 (Th1) chemokines CXCL9/10/11, as well as a reduction in transcription of ribosomal proteins. SARS-CoV-2 culture in human airway epithelial (HAE) cultures replicated the in vivo antiviral host response 7 days post infection, with no induction of interferon-stimulated genes after 3 days. Patient-matched longitudinal specimens (mean elapsed time = 6.3 days) demonstrated reduction in interferon-induced transcription, recovery of transcription of ribosomal proteins, and initiation of wound healing and humoral immune responses. Expression of interferon-responsive genes, including ACE2, increased as a function of viral load, while transcripts for B cell-specific proteins and neutrophil chemokines were elevated in patients with lower viral load. Older individuals had reduced expression of the Th1 chemokines CXCL9/10/11 and their cognate receptor CXCR3, as well as CD8A and granzyme B, suggesting deficiencies in trafficking and/or function of cytotoxic T cells and natural killer (NK) cells. Relative to females, males had reduced B cell-specific and NK cell-specific transcripts and an increase in inhibitors of nuclear factor kappa-B (NF-κB) signaling, possibly inappropriately throttling antiviral responses. Collectively, our data demonstrate that host responses to SARS-CoV-2 are dependent on viral load and infection time course, with observed differences due to age and sex that may contribute to disease severity.


Assuntos
Antivirais/imunologia , Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Feminino , Regulação da Expressão Gênica , Humanos , Imunidade/genética , Cinética , Masculino , Pessoa de Meia-Idade , Nasofaringe/imunologia , Nasofaringe/virologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Proteínas Ribossômicas/genética , Fatores Sexuais , Transdução de Sinais/genética , Carga Viral , Cicatrização/genética , Adulto Jovem
3.
Nature ; 585(7825): 390-396, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32939067

RESUMO

The maritime expansion of Scandinavian populations during the Viking Age (about AD 750-1050) was a far-flung transformation in world history1,2. Here we sequenced the genomes of 442 humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci-including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response-in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent.


Assuntos
Fluxo Gênico/genética , Genética Populacional , Genoma Humano/genética , Genômica , Migração Humana/história , Alelos , Conjuntos de Dados como Assunto , Inglaterra , Evolução Molecular , Groenlândia , História Medieval , Humanos , Imunidade/genética , Irlanda , Lactase/genética , Lactase/metabolismo , Masculino , Países Escandinavos e Nórdicos , Seleção Genética , Análise Espaço-Temporal , Adulto Jovem
4.
Nucleic Acids Res ; 48(16): 9204-9217, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32766806

RESUMO

The type III CRISPR-Cas systems provide immunity against invading nucleic acids through the coordinated transcription-dependent DNA targeting and cyclic adenylate (cAn)-activated RNA degradation. Here, we show that both these pathways contribute to the Streptococcus thermophilus (St) type III-A CRISPR-Cas immunity. HPLC-MS analysis revealed that in the heterologous Escherichia coli host the StCsm effector complex predominantly produces cA5 and cA6. cA6 acts as a signaling molecule that binds to the CARF domain of StCsm6 to activate non-specific RNA degradation by the HEPN domain. By dissecting StCsm6 domains we demonstrate that both CARF and HEPN domains act as ring nucleases that degrade cAns to switch signaling off. CARF ring nuclease converts cA6 to linear A6>p and to the final A3>p product. HEPN domain, which typically degrades RNA, also shows ring nuclease activity and indiscriminately degrades cA6 or other cAns down to A>p. We propose that concerted action of both ring nucleases enables self-regulation of the RNase activity in the HEPN domain and eliminates all cAn secondary messengers in the cell when viral infection is combated by a coordinated action of Csm effector and the cA6-activated Csm6 ribonuclease.


Assuntos
Sistemas CRISPR-Cas/genética , Imunidade/genética , Streptococcus thermophilus/genética , Transcrição Genética/genética , Cromatografia Líquida de Alta Pressão , Endonucleases/genética , Escherichia coli/genética , Escherichia coli/imunologia , Domínios Proteicos/genética , Estabilidade de RNA/genética , Estabilidade de RNA/imunologia , Ribonucleases/genética , Transdução de Sinais/genética , Streptococcus thermophilus/imunologia , Transcrição Genética/imunologia
5.
Nature ; 583(7817): 590-595, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32669714

RESUMO

Ageing is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death1. Despite rapid advances over recent years, many of the molecular and cellular processes that underlie the progressive loss of healthy physiology are poorly understood2. To gain a better insight into these processes, here we generate a single-cell transcriptomic atlas across the lifespan of Mus musculus that includes data from 23 tissues and organs. We found cell-specific changes occurring across multiple cell types and organs, as well as age-related changes in the cellular composition of different organs. Using single-cell transcriptomic data, we assessed cell-type-specific manifestations of different hallmarks of ageing-such as senescence3, genomic instability4 and changes in the immune system2. This transcriptomic atlas-which we denote Tabula Muris Senis, or 'Mouse Ageing Cell Atlas'-provides molecular information about how the most important hallmarks of ageing are reflected in a broad range of tissues and cell types.


Assuntos
Envelhecimento/genética , Senescência Celular/genética , Especificidade de Órgãos/genética , Análise de Célula Única , Transcriptoma/genética , Animais , Análise Mutacional de DNA , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Instabilidade Genômica , Imunidade/genética , Imunidade/imunologia , Fígado/citologia , Fígado/metabolismo , Masculino , Camundongos , Modelos Animais , Linfócitos T/citologia , Linfócitos T/metabolismo
6.
Nature ; 583(7817): 578-584, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32699395

RESUMO

Bats possess extraordinary adaptations, including flight, echolocation, extreme longevity and unique immunity. High-quality genomes are crucial for understanding the molecular basis and evolution of these traits. Here we incorporated long-read sequencing and state-of-the-art scaffolding protocols1 to generate, to our knowledge, the first reference-quality genomes of six bat species (Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Pipistrellus kuhlii and Molossus molossus). We integrated gene projections from our 'Tool to infer Orthologs from Genome Alignments' (TOGA) software with de novo and homology gene predictions as well as short- and long-read transcriptomics to generate highly complete gene annotations. To resolve the phylogenetic position of bats within Laurasiatheria, we applied several phylogenetic methods to comprehensive sets of orthologous protein-coding and noncoding regions of the genome, and identified a basal origin for bats within Scrotifera. Our genome-wide screens revealed positive selection on hearing-related genes in the ancestral branch of bats, which is indicative of laryngeal echolocation being an ancestral trait in this clade. We found selection and loss of immunity-related genes (including pro-inflammatory NF-κB regulators) and expansions of anti-viral APOBEC3 genes, which highlights molecular mechanisms that may contribute to the exceptional immunity of bats. Genomic integrations of diverse viruses provide a genomic record of historical tolerance to viral infection in bats. Finally, we found and experimentally validated bat-specific variation in microRNAs, which may regulate bat-specific gene-expression programs. Our reference-quality bat genomes provide the resources required to uncover and validate the genomic basis of adaptations of bats, and stimulate new avenues of research that are directly relevant to human health and disease1.


Assuntos
Adaptação Fisiológica/genética , Quirópteros/genética , Evolução Molecular , Genoma/genética , Genômica/normas , Adaptação Fisiológica/imunologia , Animais , Quirópteros/classificação , Quirópteros/imunologia , Elementos de DNA Transponíveis/genética , Imunidade/genética , Anotação de Sequência Molecular/normas , Filogenia , RNA não Traduzido/genética , Padrões de Referência , Reprodutibilidade dos Testes , Integração Viral/genética , Vírus/genética
7.
Life Sci ; 256: 117906, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32504750

RESUMO

AIMS: Head and neck squamous cell carcinoma (HNSCC) is an highly aggressive tumor with heterogeneous prognosis. We here report that immune-related genes (IRGs) could effectively distinguish prognostically different HNSCC patients. MATERIALS AND METHODS: MRNA levels of 1333 IRGs that from ImmPort database in HNSCC samples were acquired from the Cancer Genome Atlas (TCGA). H2o, a machine learning-based R package, was used for screening the top most representative genes from the IRGs. Univariate Cox-regression analysis was performed to identify prognostically-related genes based on the randomly generated training samples from TCGA set. LASSO Cox-regression analysis was applied for the construction of prognostic model for HNSCC. A total of six IRGs were finally retained for their prognostic significance and used for LASSO Cox-regression analysis. KEY FINDINGS: Samples from exclusive training and testing set that randomly generated from TCGA, and another independent validation set from the Gene Expression Omnibus (GEO) were divided into high- and low-risk groups according to the prognostic model. HNSCC samples within high-risk groups have significantly inferior overall survival (OS) compared with those within low-risk groups. Differences in genomic mutation landscape and tumor infiltration immune cells also exist between the two sample groups. What's more, risk score was proved to be an independent prognostic factor for HNSCC by stratification analysis. SIGNIFICANCE: IRGs are pivotal HNSCC prognostic signatures and should be helpful for its clinical decision-making.


Assuntos
Regulação Neoplásica da Expressão Gênica , Imunidade/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Prognóstico , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Adulto Jovem
8.
BMC Evol Biol ; 20(1): 69, 2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32564776

RESUMO

BACKGROUND: East African lake cichlids are one of the most impressive examples of an adaptive radiation. Independently in Lake Victoria, Tanganyika, and Malawi, several hundreds of species arose within the last 10 million to 100,000 years. Whereas most analyses in cichlids focused on nucleotide substitutions across species to investigate the genetic bases of this explosive radiation, to date, no study has investigated the contribution of structural variants (SVs) in the evolution of adaptive traits across the three Great Lakes of East Africa. RESULTS: Here, we annotate and characterize the repertoires and evolutionary potential of different SV classes (deletion, duplication, inversion, insertions and translocations) in four cichlid species: Haplochromis burtoni, Metriaclima zebra, Neolamprologus brichardi and Pundamilia nyererei. We investigate the patterns of gain and loss evolution for each SV type, enabling the identification of lineage specific events. Both deletions and inversions show a significant overlap with SINE elements, while inversions additionally show a limited, but significant association with DNA transposons. Inverted regions are enriched for genes regulating behaviour, or involved in skeletal and visual system development. We also find that duplicated regions show enrichment for genes associated with "antigen processing and presentation" and other immune related categories. Our pipeline and results were further tested by PCR validation of selected deletions and inversions, which confirmed respectively 7 out of 10 and 6 out of 9 events. CONCLUSIONS: Altogether, we provide the first comprehensive overview of rearrangement evolution in East African cichlids, and some important insights into their likely contribution to adaptation.


Assuntos
Ciclídeos/genética , Variação Genética , Crescimento e Desenvolvimento/genética , Imunidade/genética , Animais , Ciclídeos/crescimento & desenvolvimento , Ciclídeos/imunologia , Elementos de DNA Transponíveis/genética , Evolução Molecular , Fenótipo
9.
Inflamm Res ; 69(7): 635-640, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32350571

RESUMO

At the population level, the virus-host relationship is not set up to end with the complete elimination of either or both. Pathogen-resistant individuals will always remain in the host population. In turn, the virus can never completely eliminate the host population, because evolutionarily such an event is a dead end for the virus as an obligate intracellular parasite. A certain existential balance exists in the virus-host relationship. Against this backdrop, viral epidemics and pandemics only become manifest and egregious to human beings when tens and hundreds of thousands of people die and the question emerges what caused the high mortality peaks on the death chart. The answer seems clear; the emerging strain of the virus is new to the host population, and new mutations of the virus and natural selection will lead to a survival of only genetically resistant individuals in a host population. The dangers inherent to a novel virus are due to new features generally inthe molecular structure of proteins, which enable the virus to infect the cells of the host organism more intensively, dramatically challenging host immunity, and thus be transmitted more readily in the host population. In this article, we will concentrate on the facts currently available about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has caused COVID-19 (coronavirus disease 2019) pandemic and try to predict its development and consequences based on the virus-host relationship. In fact, only two scenarios will occur simultaneously in the very near future: people who are genetically resistant to the virus will get sick, recover, and develop immunity, while people who are sensitive to the virus will need drugs and vaccines, which will have to be researched and developed if they are to recover. If the pandemic does not stop, in a few decades it is anticipated that SARS-CoV-2 will become as safe as the four non-severe acute respiratory syndrome human coronaviruses (HCoV-NL63, HCoV-HKU1, HCoV-OC43, and HCoV-229E) currently circulating but causing low mortality in the human population.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno , Pneumonia Viral/virologia , Animais , Betacoronavirus/genética , Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Resistência à Doença/genética , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Imunidade/genética , Imunidade/imunologia , Pandemias/prevenção & controle , Peptidil Dipeptidase A , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/prevenção & controle , Seleção Genética/imunologia , Vacinas Virais , Replicação Viral
10.
PLoS Comput Biol ; 16(4): e1007837, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32339161

RESUMO

Immunoglobulin genes are formed through V(D)J recombination, which joins the variable (V), diversity (D), and joining (J) germline genes. Since variations in germline genes have been linked to various diseases, personalized immunogenomics focuses on finding alleles of germline genes across various patients. Although reconstruction of V and J genes is a well-studied problem, the more challenging task of reconstructing D genes remained open until the IgScout algorithm was developed in 2019. In this work, we address limitations of IgScout by developing a probabilistic MINING-D algorithm for D gene reconstruction, apply it to hundreds of immunosequencing datasets from multiple species, and validate the newly inferred D genes by analyzing diverse whole genome sequencing datasets and haplotyping heterozygous V genes.


Assuntos
Biologia Computacional/métodos , Genes de Imunoglobulinas/genética , Imunoglobulina D/genética , Algoritmos , Animais , Bases de Dados Genéticas , Humanos , Imunidade/genética
12.
PLoS Genet ; 16(3): e1008686, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32168362

RESUMO

Identifying the factors that shape protein expression variability in complex multi-cellular organisms has primarily focused on promoter architecture and regulation of single-cell expression in cis. However, this targeted approach has to date been unable to identify major regulators of cell-to-cell gene expression variability in humans. To address this, we have combined single-cell protein expression measurements in the human immune system using flow cytometry with a quantitative genetics analysis. For the majority of proteins whose variability in expression has a heritable component, we find that genetic variants act in trans, with notably fewer variants acting in cis. Furthermore, we highlight using Mendelian Randomization that these variability-Quantitative Trait Loci might be driven by the cis regulation of upstream genes. This indicates that natural selection may balance the impact of gene regulation in cis with downstream impacts on expression variability in trans.


Assuntos
Regulação da Expressão Gênica/genética , Expressão Gênica/genética , Alelos , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica/métodos , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla/métodos , Humanos , Sistema Imunitário/metabolismo , Imunidade/genética , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Seleção Genética/genética
13.
Nat Commun ; 11(1): 1562, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32218434

RESUMO

CCL5 is a unique chemokine with distinct stage and cell-type specificities for regulating inflammation, but how these specificities are achieved and how CCL5 modulates immune responses is not well understood. Here we identify two stage-specific enhancers: the proximal enhancer mediates the constitutive CCL5 expression during the steady state, while the distal enhancer located 1.35 Mb from the promoter induces CCL5 expression in activated cells. Both enhancers are antagonized by RUNX/CBFß complexes, and SATB1 further mediates the long-distance interaction of the distal enhancer with the promoter. Deletion of the proximal enhancer decreases CCL5 expression and augments the cytotoxic activity of tissue-resident T and NK cells, which coincides with reduced melanoma metastasis in mouse models. By contrast, increased CCL5 expression resulting from RUNX3 mutation is associated with more tumor metastasis in the lung. Collectively, our results suggest that RUNX3-mediated CCL5 repression is critical for modulating anti-tumor immunity.


Assuntos
Quimiocina CCL5/genética , Subunidades alfa de Fatores de Ligação ao Core/metabolismo , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica , Imunidade , Animais , Antígenos CD/metabolismo , Subunidade beta de Fator de Ligação ao Core/metabolismo , Homeostase/genética , Imunidade/genética , Ativação Linfocitária/imunologia , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
14.
J Immunol Res ; 2020: 5494858, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32211443

RESUMO

Immune-related genes (IRGs) have been identified as critical drivers of the initiation and progression of hepatocellular carcinoma (HCC). This study is aimed at constructing an IRG signature for HCC and validating its prognostic value in clinical application. The prognostic signature was developed by integrating multiple IRG expression data sets from TCGA and GEO databases. The IRGs were then combined with clinical features to validate the robustness of the prognostic signature through bioinformatics tools. A total of 1039 IRGs were identified in the 657 HCC samples. Subsequently, the IRGs were subjected to univariate Cox regression and LASSO Cox regression analyses in the training set to construct an IRG signature comprising nine immune-related gene pairs (IRGPs). Functional analyses revealed that the nine IRGPs were associated with tumor immune mechanisms, including cell proliferation, cell-mediated immunity, and tumorigenesis signal pathway. Concerning the overall survival rate, the IRGPs distinctly grouped the HCC samples into the high- and low-risk groups. Also, we found that the risk score based on nine IRGPs was related to clinical and pathologic factors and remained a valid independent prognostic signature after adjusting for tumor TNM, grade, and grade in multivariate Cox regression analyses. The prognostic value of the nine IRGPs was further validated by forest and nomogram plots, which revealed that it was superior to the tumor TNM, grade, and stage. Our findings suggest that the nine-IRGP signature can be effective in determining the disease outcomes of HCC patients.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/diagnóstico , Imunidade/genética , Neoplasias Hepáticas/diagnóstico , Carcinogênese/genética , Carcinoma Hepatocelular/mortalidade , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/mortalidade , Estadiamento de Neoplasias , Nomogramas , Prognóstico , Risco , Análise de Sobrevida , Transcriptoma
15.
DNA Repair (Amst) ; 88: 102785, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32007736

RESUMO

Many studies have shown that TP53 mutations play a negative role in antitumor immunity. However, a few studies reported that TP53 mutations could promote antitumor immunity. To explain these contradictory findings, we analyzed five cancer cohorts from The Cancer Genome Atlas (TCGA) project. We found that TP53-mutated cancers had significantly higher levels of antitumor immune signatures than TP53-wildtype cancers in breast invasive carcinoma (BRCA) and lung adenocarcinoma (LUAD). In contrast, TP53-mutated cancers had significantly lower antitumor immune signature levels than TP53-wildtype cancers in stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), and head and neck squamous cell carcinoma (HNSC). Moreover, TP53-mutated cancers were more likely to have a higher tumor mutation burden (TMB) and tumor aneuploidy level (TAL) than TP53-wildtype cancers. However, the TMB differences were more marked between TP53-mutated and TP53-wildtype cancers than the TAL differences in BRCA and LUAD, and the TAL differences were more significant in STAD and COAD. Furthermore, we showed that TMB and TAL had a positive and a negative correlation with antitumor immunity and that TMB affected antitumor immunity more than TAL did in BRCA and LUAD while TAL affected antitumor immunity more strongly than TMB in STAD and HNSC. These findings indicate that the distinct correlations between TP53 mutations and antitumor immunity in different cancer types are a consequence of the joint effect of the altered TMB and TAL caused by TP53 mutations on tumor immunity. In addition, the deregulation of p53-mediated pathways, including cell cycle and apoptosis, may also contribute to the different correlations of TP53 mutations with antitumor immunity between different cancer cohorts. Furthermore, we demonstrated the different correlations of TP53 mutations with the response to immune checkpoint inhibitors between different cancer cohorts, suggesting that the TP53 mutation status could be a useful biomarker for predicting the response to cancer immunotherapy in different cancer types.


Assuntos
Imunidade/genética , Mutação , Neoplasias/genética , Neoplasias/imunologia , Proteína Supressora de Tumor p53/genética , Perfilação da Expressão Gênica , Genômica , Humanos , Imunoterapia , Neoplasias/classificação , Neoplasias/terapia , Prognóstico , Resultado do Tratamento
16.
Sci Rep ; 10(1): 1852, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024876

RESUMO

While cancer cells gain aggressiveness by mutations, abundant mutations release neoantigens, attracting anti-cancer immune cells. We hypothesized that in breast cancer (BC), where mutation is less common, tumors with high mutation rates demonstrate aggressive phenotypes and attract immune cells simultaneously. High mutation rates were defined as the top 10% of the mutation rate, utilizing TCGA and METABRIC transcriptomic data. Mutation rate did not impact survival although high mutation BCs were associated with aggressive clinical features, such as more frequent in ER-negative tumors (p < 0.01), in triple-negative subtype (p = 0.03), and increased MKI-67 mRNA expression (p < 0.01) in both cohorts. Tumors with high mutation rates were associated with APOBEC3B and homologous recombination deficiency, increasing neoantigen loads (all p < 0.01). Cell proliferation and immune activity pathways were enriched in BCs with high mutation rates. Furthermore, there were higher lymphocytes and M1 macrophage infiltration in high mutation BCs. Additionally, T-cell receptor diversity, cytolytic activity score (CYT), and T-cell exhaustion marker expression were significantly elevated in BCs with high mutation rates (all p < 0.01), indicating strong immunogenicity. In conclusion, enhanced immunity due to neoantigens can be one of possible forces to counterbalance aggressiveness of a high mutation rate, resulting in similar survival rates to low mutation BCs.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Imunidade/imunologia , Mutação/genética , Proliferação de Células/genética , Citidina Desaminase/genética , Citidina Desaminase/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunidade/genética , Linfócitos/imunologia , Macrófagos/imunologia , Pessoa de Meia-Idade , Mutação/imunologia , Taxa de Mutação , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Taxa de Sobrevida
17.
Proc Natl Acad Sci U S A ; 117(9): 4601-4608, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32041883

RESUMO

Health in later life varies significantly by individual demographic characteristics such as age, sex, and race/ethnicity, as well as by social factors including socioeconomic status and geographic region. This study examined whether sociodemographic variations in the immune and inflammatory molecular underpinnings of chronic disease might emerge decades earlier in young adulthood. Using data from 1,069 young adults from the National Longitudinal Study of Adolescent to Adult Health (Add Health)-the largest nationally representative and ethnically diverse sample with peripheral blood transcriptome profiles-we analyzed variation in the expression of genes involved in inflammation and type I interferon (IFN) response as a function of individual demographic factors, sociodemographic conditions, and biobehavioral factors (smoking, drinking, and body mass index). Differential gene expression was most pronounced by sex, race/ethnicity, and body mass index (BMI), but transcriptome correlates were identified for every demographic dimension analyzed. Inflammation-related gene expression showed the most pronounced variation as a function of biobehavioral factors (BMI and smoking) whereas type I IFN-related transcripts varied most strongly as a function of individual demographic characteristics (sex and race/ethnicity). Bioinformatic analyses of transcription factor and immune-cell activation based on transcriptome-wide empirical differences identified additional effects of family poverty and geographic region. These results identify pervasive sociodemographic differences in immune-cell gene regulation that emerge by young adulthood and may help explain social disparities in the development of chronic illness and premature mortality at older ages.


Assuntos
Status Econômico , Disparidades nos Níveis de Saúde , Classe Social , Transcriptoma , Adolescente , Adulto , Fatores Etários , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Imunidade/genética , Inflamação/genética , Interferons/genética , Longevidade , Masculino
18.
Nat Microbiol ; 5(5): 706-714, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32094588

RESUMO

The arms race among microorganisms is a key driver in the evolution of not only the weapons but also defence mechanisms. Many Gram-negative bacteria use the type six secretion system (T6SS) to deliver toxic effectors directly into neighbouring cells. Defence against effectors requires cognate immunity proteins. However, here we show immunity-independent protection mediated by envelope stress responses in Escherichia coli and Vibrio cholerae against a V. cholerae T6SS effector, TseH. We demonstrate that TseH is a PAAR-dependent species-specific effector highly potent against Aeromonas species but not against its V. cholerae immunity mutant or E. coli. A structural analysis reveals TseH is probably a NlpC/P60-family cysteine endopeptidase. We determine that two envelope stress-response pathways, Rcs and BaeSR, protect E. coli from TseH toxicity by mechanisms including capsule synthesis. The two-component system WigKR (VxrAB) is critical for protecting V. cholerae from its own T6SS despite expressing immunity genes. WigR also regulates T6SS expression, suggesting a dual role in attack and defence. This deepens our understanding of how bacteria survive T6SS attacks and suggests that defence against the T6SS represents a major selective pressure driving the evolution of species-specific effectors and protective mechanisms mediated by envelope stress responses and capsule synthesis.


Assuntos
Imunidade , Sistemas de Secreção Tipo VI/imunologia , Sistemas de Secreção Tipo VI/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Regulação Bacteriana da Expressão Gênica , Imunidade/genética , Modelos Moleculares , Conformação Proteica , Sistemas de Secreção Tipo VI/química , Sistemas de Secreção Tipo VI/genética , Vibrio cholerae/genética , Vibrio cholerae/metabolismo , Virulência/genética
19.
PLoS One ; 15(2): e0229577, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32101576

RESUMO

MicroRNAs (miRNAs) inhibit protein function by silencing the translation of target mRNAs. However, in primary central nervous system lymphoma (PCNSL), the expression and functions of miRNAs are inadequately known. Here, we examined the expression of 847 miRNAs in 40 PCNSL patients with a microarray and investigated for the miRNA predictors associated with cancer immunity-related genes such as T helper cell type 1/2 (Th-1/Th-2) and regulatory T cell (T-reg) status, and stimulatory and inhibitory checkpoint genes, for prognosis prediction in PCNSL. The aim of this study is to find promising prognosis markers based on the miRNA expression in PCNSL. We detected 334 miRNAs related to 66 cancer immunity-related genes in the microarray profiling. Variable importance measured by the random survival forest analysis and Cox proportional hazards regression model elucidated that 11 miRNAs successfully constitute the survival formulae dividing the Kaplan-Meier curve of the respective PCNSL subgroups. On the other hand, univariate analysis shortlisted 23 miRNAs for overall survival times, with four miRNAs clearly dividing the survival curves-miR-101/548b/554/1202. These miRNAs regulated Th-1/Th-2 status, T-reg cell status, and immune checkpoints. The miRNAs were also associated with gene ontology terms as Ras/MAP-kinase, ubiquitin ligase, PRC2 and acetylation, CDK, and phosphorylation, and several diseases including acquired immunodeficiency syndrome, glioma, and those related to blood and hippocampus with statistical significance. In conclusion, the results demonstrated that the four miRNAs comprising miR-101/548b/554/1202 associated with cancer immunity can be a useful prognostic marker in PCNSL and would help us understand target pathways for PCNSL treatments.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Linfoma/genética , MicroRNAs/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias do Sistema Nervoso Central/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Imunidade/genética , Estimativa de Kaplan-Meier , Linfoma/patologia , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Análise de Sobrevida
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