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1.
Nat Commun ; 15(1): 3882, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38719809

RESUMO

In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684.


Assuntos
Linfócitos T CD8-Positivos , Vacinas Anticâncer , Carboximetilcelulose Sódica/análogos & derivados , Células Dendríticas , Glioma , Interferons , Poli I-C , Polilisina/análogos & derivados , Humanos , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Glioma/imunologia , Glioma/terapia , Feminino , Masculino , Pessoa de Meia-Idade , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Poli I-C/administração & dosagem , Poli I-C/farmacologia , Adulto , Receptores Toll-Like/agonistas , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Idoso , Vacinação , Monócitos/imunologia , Monócitos/efeitos dos fármacos , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/tratamento farmacológico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Imunoterapia/métodos , Agonistas do Receptor Semelhante a Toll
2.
Nat Commun ; 15(1): 4177, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38755196

RESUMO

Plasma RNAemia, delayed antibody responses and inflammation predict COVID-19 outcomes, but the mechanisms underlying these immunovirological patterns are poorly understood. We profile 782 longitudinal plasma samples from 318 hospitalized patients with COVID-19. Integrated analysis using k-means reveals four patient clusters in a discovery cohort: mechanically ventilated critically-ill cases are subdivided into good prognosis and high-fatality clusters (reproduced in a validation cohort), while non-critical survivors segregate into high and low early antibody responders. Only the high-fatality cluster is enriched for transcriptomic signatures associated with COVID-19 severity, and each cluster has distinct RBD-specific antibody elicitation kinetics. Both critical and non-critical clusters with delayed antibody responses exhibit sustained IFN signatures, which negatively correlate with contemporaneous RBD-specific IgG levels and absolute SARS-CoV-2-specific B and CD4+ T cell frequencies. These data suggest that the "Interferon paradox" previously described in murine LCMV models is operative in COVID-19, with excessive IFN signaling delaying development of adaptive virus-specific immunity.


Assuntos
Anticorpos Antivirais , COVID-19 , Interferons , SARS-CoV-2 , Transdução de Sinais , Humanos , COVID-19/imunologia , SARS-CoV-2/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Transdução de Sinais/imunologia , Interferons/metabolismo , Interferons/imunologia , Feminino , Masculino , Pessoa de Meia-Idade , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Linfócitos T CD4-Positivos/imunologia , Idoso , Adulto , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/genética
3.
Proc Natl Acad Sci U S A ; 121(21): e2402540121, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38758698

RESUMO

All respiratory viruses establish primary infections in the nasal epithelium, where efficient innate immune induction may prevent dissemination to the lower airway and thus minimize pathogenesis. Human coronaviruses (HCoVs) cause a range of pathologies, but the host and viral determinants of disease during common cold versus lethal HCoV infections are poorly understood. We model the initial site of infection using primary nasal epithelial cells cultured at an air-liquid interface (ALI). HCoV-229E, HCoV-NL63, and human rhinovirus-16 are common cold-associated viruses that exhibit unique features in this model: early induction of antiviral interferon (IFN) signaling, IFN-mediated viral clearance, and preferential replication at nasal airway temperature (33 °C) which confers muted host IFN responses. In contrast, lethal SARS-CoV-2 and MERS-CoV encode antagonist proteins that prevent IFN-mediated clearance in nasal cultures. Our study identifies features shared among common cold-associated viruses, highlighting nasal innate immune responses as predictive of infection outcomes and nasally directed IFNs as potential therapeutics.


Assuntos
Resfriado Comum , Imunidade Inata , Interferons , Mucosa Nasal , SARS-CoV-2 , Transdução de Sinais , Humanos , Mucosa Nasal/virologia , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Interferons/metabolismo , Interferons/imunologia , Resfriado Comum/imunologia , Resfriado Comum/virologia , Transdução de Sinais/imunologia , SARS-CoV-2/imunologia , Replicação Viral , Rhinovirus/imunologia , Coronavirus Humano 229E/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Células Epiteliais/virologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavirus Humano NL63/imunologia
4.
Front Immunol ; 15: 1385473, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38720890

RESUMO

Interferons (IFNs) are a family of cytokines that activate the JAK-STAT signaling pathway to induce an antiviral state in cells. Interleukin 27 (IL-27) is a member of the IL-6 and/or IL-12 family that elicits both pro- and anti-inflammatory responses. Recent studies have reported that IL-27 also induces a robust antiviral response against diverse viruses, both in vitro and in vivo, suggesting that IFNs and IL-27 share many similarities at the functional level. However, it is still unknown how similar or different IFN- and IL-27-dependent signaling pathways are. To address this question, we conducted a comparative analysis of the transcriptomic profiles of human monocyte-derived macrophages (MDMs) exposed to IL-27 and those exposed to recombinant human IFN-α, IFN-γ, and IFN-λ. We utilized bioinformatics approaches to identify common differentially expressed genes between the different transcriptomes. To verify the accuracy of this approach, we used RT-qPCR, ELISA, flow cytometry, and microarrays data. We found that IFNs and IL-27 induce transcriptional changes in several genes, including those involved in JAK-STAT signaling, and induce shared pro-inflammatory and antiviral pathways in MDMs, leading to the common and unique expression of inflammatory factors and IFN-stimulated genes (ISGs)Importantly, the ability of IL-27 to induce those responses is independent of IFN induction and cellular lineage. Additionally, functional analysis demonstrated that like IFNs, IL-27-mediated response reduced chikungunya and dengue viruses replication in MDMs. In summary, IL-27 exhibits properties similar to those of all three types of human IFN, including the ability to stimulate a protective antiviral response. Given this similarity, we propose that IL-27 could be classified as a distinct type of IFN, possibly categorized as IFN-pi (IFN-π), the type V IFN (IFN-V).


Assuntos
Vírus Chikungunya , Vírus da Dengue , Dengue , Interferons , Janus Quinases , Macrófagos , Fatores de Transcrição STAT , Transdução de Sinais , Replicação Viral , Humanos , Vírus Chikungunya/fisiologia , Vírus Chikungunya/imunologia , Vírus da Dengue/fisiologia , Vírus da Dengue/imunologia , Janus Quinases/metabolismo , Replicação Viral/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Macrófagos/imunologia , Macrófagos/virologia , Macrófagos/metabolismo , Interferons/metabolismo , Dengue/imunologia , Dengue/virologia , Febre de Chikungunya/imunologia , Febre de Chikungunya/virologia , Interleucina-27/metabolismo , Interleucinas/metabolismo , Interleucinas/farmacologia , Interleucinas/imunologia , Transcriptoma , Células Cultivadas
5.
Int Ophthalmol ; 44(1): 223, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38727788

RESUMO

PURPOSE: This review investigates the therapeutic benefits of interferons (IFNs) in vitreoretinal diseases, focusing on their regulatory roles in innate immunological reactions and angiogenesis. The study aims to categorize the clinical outcomes of IFN applications and proposes a molecular mechanism underlying their action. METHODS: A systematic review was conducted using MEDLINE/PubMed, Web of Science, EMBASE, and Google Scholar databases to identify randomized clinical trials, case series, and case-control studies related to IFNs' impact on vitreoretinal diseases (1990-2022). The data synthesis involved an in-depth analysis of the anti-inflammatory and anti-angiogenesis effects of IFNs across various studies. RESULTS: Our findings indicate that IFNs exhibit efficacy in treating inflammation-associated vitreoretinal disorders. However, a lack of sufficient evidence exists regarding the suitability of IFNs in angiogenesis-associated vitreoretinal diseases like choroidal neovascularization and diabetic retinopathies. The synthesis of data suggests that IFNs may not be optimal for managing advanced stages of angiogenesis-associated disorders. CONCLUSION: While IFNs emerge as promising therapeutic candidates for inflammation-related vitreoretinal diseases, caution is warranted in their application for angiogenesis-associated disorders, especially in advanced stages. Further research is needed to elucidate the nuanced molecular pathways of IFN action, guiding their targeted use in specific vitreoretinal conditions.


Assuntos
Interferons , Humanos , Interferons/uso terapêutico , Doenças Retinianas/tratamento farmacológico , Corpo Vítreo
6.
Front Immunol ; 15: 1374368, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38715616

RESUMO

NOD1 and NOD2 as two representative members of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family play important roles in antimicrobial immunity. However, transcription mechanism of nod1 and nod2 and their signal circle are less understood in teleost fish. In this study, with the cloning of card9 and ripk2 in Chinese perch, the interaction between NOD1, NOD2, and CARD9 and RIPK2 were revealed through coimmunoprecipitation and immunofluorescence assays. The overexpression of NOD1, NOD2, RIPK2 and CARD9 induced significantly the promoter activity of NF-κB, IFNh and IFNc. Furthermore, it was found that nod1 and nod2 were induced by poly(I:C), type I IFNs, RLR and even NOD1/NOD2 themselves through the ISRE site of their proximal promoters. It is thus indicated that nod1 and nod2 can be classified also as ISGs due to the presence of ISRE in their proximal promoter, and their expression can be mechanistically controlled through PRR pathway as well as through IFN signaling in antiviral immune response.


Assuntos
Proteínas de Peixes , Proteína Adaptadora de Sinalização NOD1 , Proteína Adaptadora de Sinalização NOD2 , Proteína Serina-Treonina Quinase 2 de Interação com Receptor , Transdução de Sinais , Animais , Proteína Adaptadora de Sinalização NOD1/genética , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Proteínas de Peixes/imunologia , Percas/genética , Percas/imunologia , Percas/metabolismo , Interferons/metabolismo , Interferons/genética , Regiões Promotoras Genéticas , Transcrição Gênica , Imunidade Inata/genética , Ligação Proteica
7.
Biotechnol J ; 19(5): e2300672, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38719621

RESUMO

The production of recombinant adeno-associated virus (rAAV) for gene therapy applications relies on the use of various host cell lines, with suspension-grown HEK293 cells being the preferred expression system due to their satisfactory rAAV yields in transient transfections. As the field of gene therapy continues to expand, there is a growing demand for efficient rAAV production, which has prompted efforts to optimize HEK293 cell line productivity through engineering. In contrast to other cell lines like CHO cells, the transcriptome of HEK293 cells during rAAV production has remained largely unexplored in terms of identifying molecular components that can enhance yields. In our previous research, we analyzed global regulatory pathways and mRNA expression patterns associated with increased rAAV production in HEK293 cells. Our data revealed substantial variations in the expression patterns between cell lines with low (LP) and high-production (HP) rates. Moving to a deeper layer for a more detailed analysis of inflammation-related transcriptome data, we detected an increased expression of interferon-related genes in low-producing cell lines. Following upon these results, we investigated the use of Ruxolitinib, an interferon pathway inhibitor, during the transient production of rAAV in HEK293 cells as potential media additive to boost rAAV titers. Indeed, we find a two-fold increase in rAAV titers compared to the control when the interferon pathways were inhibited. In essence, this work offers a rational design approach for optimization of HEK293 cell line productivity and potential engineering targets, ultimately paving the way for more cost-efficient and readily available gene therapies for patients.


Assuntos
Dependovirus , Interferons , Transdução de Sinais , Humanos , Células HEK293 , Dependovirus/genética , Interferons/metabolismo , Interferons/genética , Nitrilas/farmacologia , Pirimidinas/farmacologia , Transfecção , Pirazóis/farmacologia
8.
New Microbiol ; 47(1): 60-67, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38700885

RESUMO

Acute respiratory tract infection (ARTI) is common in all age groups, especially in children and the elderly. About 85% of children who present with bronchiolitis are infected with respiratory syncytial virus (RSV); however, nearly one-third are coinfected with another respiratory virus, such as human rhinovirus (HRV). Therefore, it is necessary to explore the immune response to coinfection to better understand the molecular and cellular pathways involving virus-virus interactions that might be modulated by innate immunity and additional host cell response mechanisms. This study aims to investigate the host innate immune response against RSV-HRV coinfection compared with monoinfection. Human primary bronchial/tracheal epithelial cells (HPECs) were infected with RSV, HRV, or coinfected with both viruses, and the infected cells were collected at 48 and 72 hours. Gene expression profiles of IL-6, CCL5, TNF-α, IFN-ß, IFN-λ1, CXCL10, IL-10, IL-13, IRF3, and IRF7 were investigated using real-time quantitative PCR, which revealed that RSV-infected cells exhibited increased expression of IL-10, whereas HRV infection increased the expression of CXCL10, IL-10, and CCL5. IFN-λ1 and CXCL10 expression was significantly different between the coinfection and monoinfection groups. In conclusion, our study revealed that two important cytokines, IFN-λ1 and CXCL10, exhibited increased expression during coinfection.


Assuntos
Brônquios , Quimiocina CXCL10 , Coinfecção , Células Epiteliais , Interferon lambda , Interferons , Interleucinas , Infecções por Picornaviridae , Infecções por Vírus Respiratório Sincicial , Rhinovirus , Humanos , Rhinovirus/fisiologia , Coinfecção/virologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Células Epiteliais/virologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/virologia , Brônquios/virologia , Brônquios/citologia , Infecções por Picornaviridae/virologia , Infecções por Picornaviridae/imunologia , Interferons/genética , Interferons/metabolismo , Vírus Sincicial Respiratório Humano/fisiologia , Vírus Sincicial Respiratório Humano/genética , Células Cultivadas , Vírus Sinciciais Respiratórios/fisiologia
9.
Nat Commun ; 15(1): 4067, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38744958

RESUMO

The complexity of the tumor microenvironment poses significant challenges in cancer therapy. Here, to comprehensively investigate the tumor-normal ecosystems, we perform an integrative analysis of 4.9 million single-cell transcriptomes from 1070 tumor and 493 normal samples in combination with pan-cancer 137 spatial transcriptomics, 8887 TCGA, and 1261 checkpoint inhibitor-treated bulk tumors. We define a myriad of cell states constituting the tumor-normal ecosystems and also identify hallmark gene signatures across different cell types and organs. Our atlas characterizes distinctions between inflammatory fibroblasts marked by AKR1C1 or WNT5A in terms of cellular interactions and spatial co-localization patterns. Co-occurrence analysis reveals interferon-enriched community states including tertiary lymphoid structure (TLS) components, which exhibit differential rewiring between tumor, adjacent normal, and healthy normal tissues. The favorable response of interferon-enriched community states to immunotherapy is validated using immunotherapy-treated cancers (n = 1261) including our lung cancer cohort (n = 497). Deconvolution of spatial transcriptomes discriminates TLS-enriched from non-enriched cell types among immunotherapy-favorable components. Our systematic dissection of tumor-normal ecosystems provides a deeper understanding of inter- and intra-tumoral heterogeneity.


Assuntos
Neoplasias , Análise de Célula Única , Transcriptoma , Microambiente Tumoral , Humanos , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo , Regulação Neoplásica da Expressão Gênica , Imunoterapia/métodos , Perfilação da Expressão Gênica , Interferons/metabolismo
10.
Front Immunol ; 15: 1383358, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38779657

RESUMO

Introduction: Immune cells that contribute to the pathogenesis of systemic lupus erythematosus (SLE) derive from adult hematopoietic stem and progenitor cells (HSPCs) within the bone marrow (BM). For this reason, we reasoned that fundamental abnormalities in SLE can be traced to a BM-derived HSPC inflammatory signature. Methods: BM samples from four SLE patients, six healthy controls, and two umbilical cord blood (CB) samples were used. CD34+ cells were isolated from BM and CB samples, and single-cell RNA-sequencing was performed. Results: A total of 426 cells and 24,473 genes were used in the analysis. Clustering analysis resulted in seven distinct clusters of cell types. Mutually exclusive markers, which were characteristic of each cell type, were identified. We identified three HSPC subpopulations, one of which consisted of proliferating cells (MKI67 expressing cells), one T-like, one B-like, and two myeloid-like progenitor subpopulations. Differential expression analysis revealed i) cell cycle-associated signatures, in healthy BM of HSPC clusters 3 and 4 when compared with CB, and ii) interferon (IFN) signatures in SLE BM of HSPC clusters 3 and 4 and myeloid-like progenitor cluster 5 when compared with healthy controls. The IFN signature in SLE appeared to be deregulated following TF regulatory network analysis and differential alternative splicing analysis between SLE and healthy controls in HSPC subpopulations. Discussion: This study revealed both quantitative-as evidenced by decreased numbers of non-proliferating early progenitors-and qualitative differences-characterized by an IFN signature in SLE, which is known to drive loss of function and depletion of HSPCs. Chronic IFN exposure affects early hematopoietic progenitors in SLE, which may account for the immune aberrancies and the cytopenias in SLE.


Assuntos
Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas , Interferons , Lúpus Eritematoso Sistêmico , Análise de Célula Única , Transcriptoma , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Interferons/metabolismo , Interferons/genética , Feminino , Adulto , Reprogramação Celular/genética , Masculino
11.
Cell Rep Med ; 5(5): 101569, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38744279

RESUMO

Systemic lupus erythematosus (SLE) displays a hallmark interferon (IFN) signature. Yet, clinical trials targeting type I IFN (IFN-I) have shown variable efficacy, and blocking IFN-II failed to treat SLE. Here, we show that IFN type levels in SLE vary significantly across clinical and transcriptional endotypes. Whereas skin involvement correlated with IFN-I alone, systemic features like nephritis associated with co-elevation of IFN-I, IFN-II, and IFN-III, indicating additive IFN effects in severe SLE. Notably, while high IFN-II/-III levels without IFN-I had a limited effect on disease activity, IFN-II was linked to IFN-I-independent transcriptional profiles (e.g., OXPHOS and CD8+GZMH+ cells), and IFN-III enhanced IFN-induced gene expression when co-elevated with IFN-I. Moreover, dysregulated IFNs do not explain the IFN signature in 64% of patients or clinical manifestations including cytopenia, serositis, and anti-phospholipid syndrome, implying IFN-independent endotypes in SLE. This study sheds light on mechanisms underlying SLE heterogeneity and the variable response to IFN-targeted therapies in clinical trials.


Assuntos
Interferons , Lúpus Eritematoso Sistêmico , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Interferons/metabolismo , Interferons/genética , Feminino , Adulto , Masculino , Transcriptoma/genética , Interferon Tipo I/metabolismo , Interferon Tipo I/genética , Pessoa de Meia-Idade , Transcrição Gênica , Regulação da Expressão Gênica
12.
PLoS Pathog ; 20(5): e1011961, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38701091

RESUMO

Noroviruses (NoVs) are a leading cause of viral gastroenteritis. Despite global clinical relevance, our understanding of how host factors, such as antiviral cytokines interferons (IFNs), modulate NoV population dynamics is limited. Murine NoV (MNoV) is a tractable in vivo model for the study of host regulation of NoV. A persistent strain of MNoV, CR6, establishes a reservoir in intestinal tuft cells for chronic viral shedding in stool. However, the influence of host innate immunity and permissive cell numbers on viral population dynamics is an open question. We generated a pool of 20 different barcoded viruses (CR6BC) by inserting 6-nucleotide barcodes at the 3' position of the NS4 gene and used this pool as our viral inoculum for in vivo infections of different mouse lines. We found that over the course of persistent CR6 infection, shed virus was predominantly colon-derived, and viral barcode richness decreased over time irrespective of host immune status, suggesting that persistent infection involves a series of reinfection events. In mice lacking the IFN-λ receptor, intestinal barcode richness was enhanced, correlating with increased viral intestinal replication. IL-4 treatment, which increases tuft cell numbers, also increased barcode richness, indicating the abundance of permissive tuft cells to be a bottleneck during CR6 infection. In mice lacking type I IFN signaling (Ifnar1-/-) or all IFN signaling (Stat1-/-), barcode diversity at extraintestinal sites was dramatically increased, implicating different IFNs as critical bottlenecks at specific tissue sites. Of interest, extraintestinal barcodes were overlapping but distinct from intestinal barcodes, indicating that disseminated virus represents a distinct viral population than that replicating in the intestine. Barcoded viruses are a valuable tool to explore the influence of host factors on viral diversity in the context of establishment and maintenance of infection as well as dissemination and have provided important insights into how NoV infection proceeds in immunocompetent and immunocompromised hosts.


Assuntos
Infecções por Caliciviridae , Interferons , Norovirus , Animais , Norovirus/fisiologia , Infecções por Caliciviridae/virologia , Infecções por Caliciviridae/imunologia , Camundongos , Interferons/metabolismo , Infecção Persistente/virologia , Infecção Persistente/imunologia , Camundongos Endogâmicos C57BL , Mucosa Intestinal/virologia , Mucosa Intestinal/imunologia , Gastroenterite/virologia , Replicação Viral , Camundongos Knockout , Imunidade Inata , Eliminação de Partículas Virais
13.
Zhonghua Gan Zang Bing Za Zhi ; 32(4): 375-379, 2024 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-38733195

RESUMO

Hepatitis B virus (HBV) DNA integration occurs during the reverse transcription process of HBV replication, which develops in the early stages of HBV infection and accompanies the entire disease course. The integration of HBV DNA is detrimental to the attainment of clinical cure goals and also raises the risk of developing liver cancer. Theoretically, nucleos(t)ide analogs can reduce the synthesis of new double-stranded linear DNA, but there is no clearance function for hepatocytes that have already integrated HBV. Therefore, patients with serum HBV DNA-negative conversions still have the risk of developing liver cancer. As an immunomodulatory drug, interferon can not only inhibit viral replication but also inhibit or even eliminate existing clonally amplified hepatocytes carrying integrated HBV DNA fragments. However, there are currently few studies on the effects of nucleos(t)ide analogues and interferon therapy on HBV DNA integration. Thus, large-scale clinical studies are urgently needed for further clarification.


Assuntos
Antivirais , DNA Viral , Vírus da Hepatite B , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Humanos , Antivirais/uso terapêutico , Antivirais/farmacologia , Integração Viral , Hepatite B/tratamento farmacológico , Hepatite B/virologia , Replicação Viral/efeitos dos fármacos , Interferons/uso terapêutico
14.
Front Cell Infect Microbiol ; 14: 1365221, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38711929

RESUMO

Bunyaviruses are a large group of important viral pathogens that cause significant diseases in humans and animals worldwide. Bunyaviruses are enveloped, single-stranded, negative-sense RNA viruses that infect a wide range of hosts. Upon entry into host cells, the components of viruses are recognized by host innate immune system, leading to the activation of downstream signaling cascades to induce interferons (IFNs) and other proinflammatory cytokines. IFNs bind to their receptors and upregulate the expression of hundreds of interferon-stimulated genes (ISGs). Many ISGs have antiviral activities and confer an antiviral state to host cells. For efficient replication and spread, viruses have evolved different strategies to antagonize IFN-mediated restriction. Here, we discuss recent advances in our understanding of the interactions between bunyaviruses and host innate immune response.


Assuntos
Infecções por Bunyaviridae , Imunidade Inata , Orthobunyavirus , Infecções por Bunyaviridae/imunologia , Infecções por Bunyaviridae/virologia , Humanos , Animais , Orthobunyavirus/imunologia , Interações Hospedeiro-Patógeno/imunologia , Interferons/imunologia , Interferons/metabolismo , Transdução de Sinais , Citocinas/metabolismo , Citocinas/imunologia , Doenças Transmitidas por Vetores/imunologia , Doenças Transmitidas por Vetores/virologia , Doenças Transmitidas por Vetores/prevenção & controle , Replicação Viral
15.
Mol Immunol ; 170: 156-169, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38692097

RESUMO

Type-I and -III interferons play a central role in immune rejection of pathogens and tumors, thus promoting immunogenicity and suppressing tumor recurrence. Double strand RNA is an important ligand that stimulates tumor immunity via interferon responses. Differentiation of embryonic stem cells to pluripotent epithelial cells activates the interferon response during development, raising the question of whether epithelial vs. mesenchymal gene signatures in cancer potentially regulate the interferon pathway as well. Here, using genomics and signaling approaches, we show that Grainyhead-like-2 (GRHL2), a master programmer of epithelial cell identity, promotes type-I and -III interferon responses to double-strand RNA. GRHL2 enhanced the activation of IRF3 and relA/NF-kB and the expression of IRF1; a functional GRHL2 binding site in the IFNL1 promoter was also identified. Moreover, time to recurrence in breast cancer correlated positively with GRHL2 protein expression, indicating that GRHL2 is a tumor recurrence suppressor, consistent with its enhancement of interferon responses. These observations demonstrate that epithelial cell identity supports interferon responses in the context of cancer.


Assuntos
Neoplasias da Mama , Proteínas de Ligação a DNA , Fatores de Transcrição , Humanos , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Feminino , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Fator Regulador 3 de Interferon/genética , Recidiva Local de Neoplasia/imunologia , Interferons/metabolismo , Interferons/imunologia , Interferons/genética , Linhagem Celular Tumoral , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Animais , RNA de Cadeia Dupla/imunologia , Fator de Transcrição RelA/metabolismo , Camundongos , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais/imunologia , Fator Regulador 1 de Interferon/metabolismo , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/imunologia
16.
Wiad Lek ; 77(3): 491-496, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38691791

RESUMO

OBJECTIVE: Aim: To showcase a rare retinal lesion and the results of contemporary diagnostic and treatment of interferon-induced retinopathy. PATIENTS AND METHODS: Materials and Methods: We describe a case of a 36-year-old patient with interferon-induced retinopathy, with hepatitis C, that received prolonged interferon treatment. Clinical signs, examination and combined laser and pharmacologic treatment were showcased in the study. RESULTS: Results: As a result of pharmacologic and laser treatment, the patient's visual acuity increased from 0.1 to 1.0 through the duration of 3 months after treatment. The patients` condition remained stable under dynamic observation. CONCLUSION: Conclusions: Because interferon-induced retinopathy is a rare occurrence in routine ophthalmologic practice, combined laser therapy can be used for treatment of preretinal hemorrhage, which leads to improvement of visual functions and stabilization of the retinal processes. This case is an addition to the few described cases of interferon-induced retinopathy.


Assuntos
Doenças Retinianas , Humanos , Adulto , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/tratamento farmacológico , Masculino , Acuidade Visual , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Interferons/efeitos adversos , Interferons/uso terapêutico , Resultado do Tratamento , Hepatite C/tratamento farmacológico , Hepatite C/complicações
17.
Immunol Rev ; 323(1): 257-275, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38567833

RESUMO

Training and priming of innate immune cells involve preconditioning by PAMPs, DAMPs, and/or cytokines that elicits stronger induction of inflammatory genes upon secondary challenge. Previous models distinguish training and priming based upon whether immune activation returns to baseline prior to secondary challenge. Tolerance is a protective mechanism whereby potent stimuli induce refractoriness to secondary challenge. Training and priming are important for innate memory responses that protect against infection, efficacy of vaccines, and maintaining innate immune cells in a state of readiness; tolerance prevents toxicity from excessive immune activation. Dysregulation of these processes can contribute to pathogenesis of autoimmune/inflammatory conditions, post-COVID-19 hyperinflammatory states, or sepsis-associated immunoparalysis. Training, priming, and tolerance regulate similar "signature" inflammatory genes such as TNF, IL6, and IL1B and utilize overlapping epigenetic mechanisms. We review how interferons (IFNs), best known for activating JAK-STAT signaling and interferon-stimulated genes, also play a key role in regulating training, priming, and tolerance via chromatin-mediated mechanisms. We present new data on how monocyte-to-macrophage differentiation modulates IFN-γ-mediated priming, affects regulation of AP-1 and CEBP activity, and attenuates superinduction of inflammatory genes. We present a "training-priming continuum" model that integrates IFN-mediated priming into current concepts about training and tolerance and proposes a central role for STAT1 and IRF1.


Assuntos
Epigênese Genética , Células-Tronco Hematopoéticas , Tolerância Imunológica , Interferons , Monócitos , Humanos , Monócitos/imunologia , Monócitos/metabolismo , Interferons/metabolismo , Animais , Células-Tronco Hematopoéticas/metabolismo , Imunidade Inata , Transdução de Sinais , COVID-19/imunologia , SARS-CoV-2/imunologia , Diferenciação Celular , Memória Imunológica
18.
Fish Shellfish Immunol ; 149: 109559, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38636737

RESUMO

USP14 regulates the immune related pathways by deubiquitinating the signaling molecules in mammals. In teleost, USP14 is also reported to inhibit the antiviral immune response through TBK1, but its regulatory mechanism remains obscure. To elucidate the role of USP14 in the RLR/IFN antiviral pathway in teleost, the homolog USP14 (bcUSP14) of black carp (Mylopharyngodon piceus) has been cloned and characterize in this paper. bcUSP14 contains 490 amino acids (aa), and the sequence is well conserved among in vertebrates. Over-expression of bcUSP14 in EPC cells attenuated SVCV-induced transcription activity of IFN promoters and enhanced SVCV replication. Knockdown of bcUSP14 in MPK cells led to the increased transcription of IFNs and decreased SVCV replication, suggesting the improved antiviral activity of the host cells. The interaction between bcUSP14 and bcTBK1 was identified by both co-immunoprecipitation and immunofluorescent staining. Co-expressed bcUSP14 obviously inhibited bcTBK1-induced IFN production and antiviral activity in EPC cells. K63-linked polyubiquitination of bcTBK1 was dampened by co-expressed bcUSP14, and bcTBK1-mediated phosphorylation and nuclear translocation of IRF3 were also inhibited by this deubiquitinase. Thus, all the data demonstrated that USP14 interacts with and inhibits TBK1 through deubiquitinating TBK1 in black carp.


Assuntos
Carpas , Doenças dos Peixes , Proteínas de Peixes , Imunidade Inata , Interferons , Proteínas Serina-Treonina Quinases , Infecções por Rhabdoviridae , Rhabdoviridae , Transdução de Sinais , Ubiquitinação , Animais , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Infecções por Rhabdoviridae/imunologia , Infecções por Rhabdoviridae/veterinária , Carpas/imunologia , Carpas/genética , Doenças dos Peixes/imunologia , Rhabdoviridae/fisiologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/imunologia , Interferons/genética , Interferons/imunologia , Interferons/metabolismo , Imunidade Inata/genética , Ubiquitina Tiolesterase/genética , Regulação da Expressão Gênica/imunologia , Sequência de Aminoácidos , Alinhamento de Sequência/veterinária , Filogenia , Perfilação da Expressão Gênica/veterinária
19.
Mol Biol Rep ; 51(1): 487, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578532

RESUMO

The stimulator of the interferon genes (STING) signaling pathway plays a crucial role in innate immunity by detecting cytoplasmic DNA and initiating antiviral host defense mechanisms. The STING cascade is triggered when the enzyme cyclic GMP-AMP synthase (cGAS) binds cytosolic DNA and synthesizes the secondary messenger cGAMP. cGAMP activates the endoplasmic reticulum adaptor STING, leading to the activation of kinases TBK1 and IRF3 that induce interferon production. Secreted interferons establish an antiviral state in infected and adjacent cells. Beyond infections, aberrant DNA in cancer cells can also activate the STING pathway. Preclinical studies have shown that pharmacological STING agonists like cyclic dinucleotides elicit antitumor immunity when administered intratumorally by provoking innate and adaptive immunity. Combining STING agonists with immune checkpoint inhibitors may improve outcomes by overcoming tumor immunosuppression. First-generation STING agonists encountered challenges like poor pharmacokinetics, limited tumor specificity, and systemic toxicity. The development of the next-generation STING-targeted drugs to realize the full potential of engaging this pathway for cancer treatment can be a solution to overcome the current challenges, but further studies are required to determine optimal applications and combination regimens for the clinic. Notably, the controlled activation of STING is needed to preclude adverse effects. This review explores the mechanisms and effects of STING activation, its role in cancer immunotherapy, and current challenges.


Assuntos
Imunoterapia , Neoplasias , Nucleotidiltransferases , Humanos , Antivirais , DNA/genética , Imunidade Inata , Interferons , Neoplasias/terapia , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo
20.
Front Cell Infect Microbiol ; 14: 1358967, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38572318

RESUMO

Introduction: The aim of this study is to investigate changes in TNF-related apoptosis-inducing ligand (TRAIL) and gamma interferon-induced protein 10 (IP-10) after COVID-19 vaccination in pregnant women and to explore their association with neutralizing antibody (Nab) inhibition. Methods: The study evaluated 93 pregnant women who had previously received two (n=21), three (n=55) or four (n=17) doses of COVID-19 vaccine. Also we evaluated maternal blood samples that were collected during childbirth. The levels of TRAIL, IP-10 and Nab inhibition were measured using enzyme-linked immunosorbent assays (ELISA). Results and discussion: Our study revealed four-dose group resulted in lower TRAIL levels when compared to the two-dose and three-dose groups (4.78 vs. 16.07 vs. 21.61 pg/ml, p = 0.014). The two-dose group had reduced IP-10 levels than the three-dose cohort (111.49 vs. 147.89 pg/ml, p=0.013), with no significant variation compared to the four-dose group. In addition, the four-dose group showed stronger Nab inhibition against specific strains (BA.2 and BA.5) than the three-dose group. A positive correlation was observed between TRAIL and IP-10 in the two-dose group, while this relationship was not found in other dose groups or between TRAIL/IP-10 and Nab inhibition. As the doses of the COVID-19 vaccine increase, the levels of TRAIL and IP-10 generally increase, only by the fourth dose, the group previously vaccinated with AZD1222 showed lower TRAIL but higher IP-10. Despite these changes, more doses of the vaccine consistently reinforced Nab inhibition, apparently without any relation to TRAIL and IP-10 levels. The variation may indicate the induction of immunological memory in vaccinated mothers, which justifies further research in the future.


Assuntos
COVID-19 , Interferons , Gravidez , Humanos , Feminino , Vacinas contra COVID-19 , Quimiocina CXCL10 , Ligante Indutor de Apoptose Relacionado a TNF , Gestantes , ChAdOx1 nCoV-19 , COVID-19/prevenção & controle , Vacinação , Anticorpos Neutralizantes , Anticorpos Antivirais
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