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1.
PLoS One ; 18(1): e0280551, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36689413

RESUMO

BACKGROUND: The CC genotype of the IFNL4 gene is known to be associated with increased Hepatitis C (HCV) cure rates with interferon-based therapy and may contribute to cure with direct acting antivirals. The Genedrive® IFNL4 is a CE marked Point of Care (PoC) molecular diagnostic test, designed for in vitro diagnostic use to provide rapid, real-time detection of IFNL4 genotype status for SNP rs12979860. METHODS: 120 Participants were consented to a substudy comparing IFNL4 genotyping results from a buccal swab analysed on the Genedrive® platform with results generated using the Affymetix UK Biobank array considered to be the gold standard. RESULTS: Buccal swabs were taken from 120 participants for PoC IFNL4 testing and a whole blood sample for genetic sequencing. Whole blood genotyping vs. buccal swab PoC testing identified 40 (33%), 65 (54%), and 15 (13%) had CC, CT and TT IFNL4 genotype respectively. The Buccal swab PoC identified 38 (32%) CC, 64 (53%) CT and 18 (15%) TT IFNL4 genotype respectively. The sensitivity and specificity of the buccal swab test to detect CC vs non-CC was 90% (95% CI 76-97%) and 98% (95% CI 91-100%) respectively. CONCLUSIONS: The buccal swab test was better at correctly identifying non-CC genotypes than CC genotypes. The high specificity of the Genedrive® assay prevents CT/TT genotypes being mistaken for CC, and could avoid patients being identified as potentially 'good responders' to interferon-based therapy.


Assuntos
Antivirais , Hepatite C Crônica , Humanos , Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Interleucinas/genética , Genótipo , Interferons/uso terapêutico , Testes Imediatos
2.
Nat Cell Biol ; 25(1): 92-107, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36604592

RESUMO

RIPK3-ZBP1-MLKL-mediated necroptosis is a proinflammatory cell death process that is crucial for antiviral host defence. RIPK3 self-oligomerization and autophosphorylation are prerequisites for executing necroptosis, yet the underlying mechanism of virus-induced RIPK3 activation remains elusive. Interferon-inducible 2'-5' oligoadenylate synthetase-like (OASL) protein is devoid of enzymatic function but displays potent antiviral activity. Here we describe a role of OASL as a virus-induced necroptosis promoter that scaffolds the RIPK3-ZBP1 non-canonical necrosome via liquid-like phase condensation. This liquid-like platform of OASL recruits RIPK3 and ZBP1 via protein-protein interactions to provide spatial segregation for RIPK3 nucleation. This process facilitates the amyloid-like fibril formation and activation of RIPK3 and thereby MLKL phosphorylation for necroptosis. Mice deficient in Oasl1 exhibit severely impaired necroptosis and attenuated inflammation after viral infection, resulting in uncontrolled viral dissemination and lethality. Our study demonstrates an interferon-induced innate response whereby OASL scaffolds RIPK3-ZBP1 assembly via its phase-separated liquid droplets to facilitate necroptosis-mediated antiviral immunity.


Assuntos
Necroptose , Proteínas Quinases , Animais , Camundongos , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Morte Celular , Antivirais , Interferons/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Apoptose , Proteínas de Ligação a RNA/metabolismo
3.
Emerg Infect Dis ; 29(2): 268-277, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36692327

RESUMO

Crimean-Congo hemorrhagic fever (CCHF), endemic in certain regions of the world, is listed as a priority disease with pandemic potential. Since CCHF was first identified in Turkey, children have been known to experience milder disease than adults. However, during the COVID-19 pandemic, we observed an unusually severe disease course, including hemophagocytic lymphohistiocytosis (HLH). We examined cytokine/chemokine profiles of 9/12 case-patients compared with healthy controls at 3 time intervals. Interferon pathway-related cytokines/chemokines, including interleukin (IL) 18, macrophage inflammatory protein 3α, and IL-33, were elevated, but tumor necrosis factor-α, IL-6, CXCL8 (formerly IL-8), and cytokines acting through C-C chemokine receptor 2 and CCR5 were lower among case-patients than controls. Interferon pathway activation and cytokines/chemokines acting through CCR2 and CCR5 improved health results among children with severe CCHF. Children can experience severe CCHF, including HLH, and HLH secondary to CCHF can be successfully treated with intravenous immunoglobulin and steroid therapy.


Assuntos
COVID-19 , Vírus da Febre Hemorrágica da Crimeia-Congo , Febre Hemorrágica da Crimeia , Linfo-Histiocitose Hemofagocítica , Adulto , Humanos , Criança , Febre Hemorrágica da Crimeia/tratamento farmacológico , Febre Hemorrágica da Crimeia/epidemiologia , Febre Hemorrágica da Crimeia/patologia , Turquia/epidemiologia , Pandemias , COVID-19/epidemiologia , Citocinas , Progressão da Doença , Quimiocinas , Interferons , Linfo-Histiocitose Hemofagocítica/epidemiologia
4.
PLoS Pathog ; 19(1): e1011049, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36603036

RESUMO

The arenavirus nucleoprotein (NP) plays an important role in the virus' ability to block interferon (IFN) production, and its exonuclease function appears to contribute to this activity. However, efforts to analyze this contribution are complicated by the functional overlap between the exonuclease active site and a neighboring region involved in IKKε-binding and subsequent inhibition of IRF3 activation, which also plays an important role in IFN production. To circumvent this issue, we mutated a residue located away from the active site that is involved in binding of the dsRNA substrate being targeted for exonuclease digestion, i.e. H426A. We found that expression of Tacaribe virus (TCRV) NP containing this RNA-binding H426A mutation was still able to efficiently block IFN-ß promoter activity in response to Sendai virus infection, despite being strongly impaired in its exonuclease activity. This was in contrast to a conventional exonuclease active site mutant (E388A), which was impaired with respect to both exonuclease activity and IFN antagonism. Importantly, growth of a recombinant virus encoding the RNA-binding mutation (rTCRV-H426A) was similar to wild-type in IFN-deficient cells, unlike the active site mutant (rTCRV-E388A), which was already markedly impaired in these cells. Further, in IFN-competent cells, the TCRV-H426A RNA-binding mutant showed more robust growth and delayed IFN-ß mRNA upregulation compared to the TCRV-E388A active site mutant. Taken together, this novel mutational approach, which allows us to now dissect the different contributions of the NP exonuclease activity and IKKε-binding/IRF3 inhibition to IFN antagonism, clearly suggests that conventional exonuclease mutants targeting the active site overestimate the contribution of the exonuclease function, and that rather other IFN antagonistic functions of NP play the dominant role in IFN-antagonism.


Assuntos
Arenavirus , Arenavirus/genética , Interferons , Nucleoproteínas/genética , Nucleoproteínas/metabolismo , Quinase I-kappa B , Exonucleases/genética , RNA
5.
PLoS One ; 18(1): e0280392, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36649304

RESUMO

For coronavirus disease 2019 (COVID-19), a pandemic disease characterized by strong immune dysregulation in severe patients, convenient and efficient monitoring of the host immune response is critical. Human hosts respond to viral and bacterial infections in different ways, the former is characterized by the activation of interferon stimulated genes (ISGs) such as IFI27, while the latter is characterized by the activation of anti-bacterial associated genes (ABGs) such as S100A12. This two-tiered innate immune response has not been examined in COVID-19. In this study, the activation patterns of this two-tiered innate immune response represented by IFI27 and S100A12 were explored based on 1421 samples from 17 transcriptome datasets derived from the blood of COVID-19 patients and relevant controls. It was found that IFI27 activation occurred in most of the symptomatic patients and displayed no correlation with disease severity, while S100A12 activation was more restricted to patients under severe and critical conditions with a stepwise activation pattern. In addition, most of the S100A12 activation was accompanied by IFI27 activation. Furthermore, the activation of IFI27 was most pronounced within the first week of symptom onset, but generally waned after 2-3 weeks. On the other hand, the activation of S100A12 displayed no apparent correlation with disease duration and could last for several months in certain patients. These features of the two-tiered innate immune response can further our understanding on the disease mechanism of COVID-19 and may have implications to the clinical triage. Development of a convenient two-gene protocol for the routine serial monitoring of this two-tiered immune response will be a valuable addition to the existing laboratory tests.


Assuntos
COVID-19 , Imunidade Inata , Humanos , COVID-19/genética , COVID-19/imunologia , Marcadores Genéticos , Imunidade Inata/genética , Interferons , Proteína S100A12/genética
6.
Viruses ; 15(1)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36680267

RESUMO

Herpes simplex virus (HSV) has persisted within human populations due to its ability to establish both lytic and latent infection. Given this, human hosts have evolved numerous immune responses to protect against HSV infection. Critical in this defense against HSV, the host protein stimulator of interferon genes (STING) functions as a mediator of the antiviral response by inducing interferon (IFN) as well as IFN-stimulated genes. Emerging evidence suggests that during HSV infection, dsDNA derived from either the virus or the host itself ultimately activates STING signaling. While a complex regulatory circuit is in operation, HSV has evolved several mechanisms to neutralize the STING-mediated antiviral response. Within this review, we highlight recent progress involving HSV interactions with the STING pathway, with a focus on how STING influences HSV replication and pathogenesis.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Humanos , Herpesvirus Humano 1/fisiologia , Interferons/metabolismo , Transdução de Sinais , Antivirais/metabolismo , Imunidade Inata , Replicação Viral/genética
7.
Viruses ; 15(1)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36680268

RESUMO

The cessation of measles virus (MeV) vaccination in more than 40 countries as a consequence of the COVID-19 pandemic is expected to significantly increase deaths due to measles. MeV can infect the central nervous system (CNS) and lead to lethal encephalitis. Substantial part of virus sequences recovered from patients' brain were mutated in the matrix and/or the fusion protein (F). Mutations of the heptad repeat domain located in the C terminal (HRC) part of the F protein were often observed and were associated to hyperfusogenicity. These mutations promote brain invasion as a hallmark of neuroadaptation. Wild-type F allows entry into the brain, followed by limited spreading compared with the massive invasion observed for hyperfusogenic MeV. Taking advantage of our ex vivo models of hamster organotypic brain cultures, we investigated how the hyperfusogenic mutations in the F HRC domain modulate virus distribution in CNS cells. In this study, we also identified the dependence of neural cells susceptibility on both their activation state and destabilization of the virus F protein. Type I interferon (IFN-I) impaired mainly astrocytes and microglial cells permissiveness contrarily to neurons, opening a new way of consideration on the development of treatments against viral encephalitis.


Assuntos
Sistema Nervoso Central , Vírus do Sarampo , Sarampo , Animais , Cricetinae , Humanos , Encéfalo , Sistema Nervoso Central/virologia , Interferons/metabolismo , Vírus do Sarampo/fisiologia , Proteínas Virais de Fusão/genética
8.
Immunohorizons ; 7(1): 97-105, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36645852

RESUMO

Although the effectiveness of vaccination at preventing hospitalization and severe coronavirus disease (COVID-19) has been reported in numerous studies, the detailed mechanism of innate immunity occurring in host cells by breakthrough infection is unclear. One hundred forty-six patients were included in this study. To determine the effects of vaccination and past infection on innate immunity following SARS-CoV-2 infection, we analyzed the relationship between anti-SARS-CoV-2 S Abs and biomarkers associated with the deterioration of COVID-19 (IFN-λ3, C-reactive protein, lactate dehydrogenase, ferritin, procalcitonin, and D-dimer). Anti-S Abs were classified into two groups according to titer: high titer (≥250 U/ml) and low titer (<250 U/ml). A negative correlation was observed between anti-SARS-CoV-2 S Abs and IFN-λ3 levels (r = -0.437, p < 0.001). A low titer of anti-SARS-CoV-2 S Abs showed a significant association with oxygen demand in patients, excluding aspiration pneumonia. Finally, in a multivariate analysis, a low titer of anti-SARS-CoV-2 S Abs was an independent risk factor for oxygen demand, even after adjusting for age, sex, body mass index, aspiration pneumonia, and IFN-λ3 levels. In summary, measuring anti-SARS-CoV-2 S Abs and IFN-λ3 may have clinical significance for patients with COVID-19. To predict the oxygen demand of patients with COVID-19 after hospitalization, it is important to evaluate the computed tomography findings to determine whether the pneumonia is the result of COVID-19 or aspiration pneumonia.


Assuntos
Anticorpos Antivirais , COVID-19 , Interferons , Oxigênio , Humanos , COVID-19/imunologia , COVID-19/terapia , Oxigênio/administração & dosagem , Pneumonia Aspirativa , SARS-CoV-2 , Anticorpos Antivirais/sangue , Interferons/imunologia
9.
Sci Rep ; 13(1): 690, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639424

RESUMO

HIV infection damages the gut mucosa leading to chronic immune activation, increased morbidities and mortality, and antiretroviral therapies, do not completely ameliorate mucosal dysfunction. Understanding early molecular changes in acute infection may identify new biomarkers underlying gut dysfunction. Here we utilized a proteomics approach, coupled with flow cytometry, to characterize early molecular and immunological alterations during acute SIV infection in gut tissue of rhesus macaques. Gut tissue biopsies were obtained at 2 times pre-infection and 4 times post-infection from 6 macaques. The tissue proteome was analyzed by mass spectrometry, and immune cell populations in tissue and blood by flow cytometry. Significant proteome changes (p < 0.05) occurred at 3 days post-infection (dpi) (13.0%), 14 dpi (13.7%), 28 dpi (16.9%) and 63 dpi (14.8%). At 3 dpi, proteome changes included cellular structural activity, barrier integrity, and activation of epithelial to mesenchymal transition (EMT) (FDR < 0.0001) prior to the antiviral response at 14 dpi (IFNa/g pathways, p < 0.001). Novel EMT proteomic biomarkers (keratins 2, 6A and 20, collagen 12A1, desmoplakin) and inflammatory biomarkers (PSMB9, FGL2) were associated with early infection and barrier dysfunction. These findings identify new biomarkers preceding inflammation in SIV infection involved with EMT activation. This warrants further investigation of the role of these biomarkers in chronic infection, mucosal inflammation, and disease pathogenesis of HIV.


Assuntos
Infecções por HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Macaca mulatta , Interferons , Proteoma , Transição Epitelial-Mesenquimal , Proteômica , Inflamação/patologia
10.
Indian Pediatr ; 60(1): 55-62, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36639971

RESUMO

INTRODUCTION: With the advent of direct-acting antivirals (DAAs), the past decade has seen a paradigm shift in the management of hepatitis C (HCV) infection in children. In this review, we summarize the various treatment options for pediatric HCV infection, highlighting the recent changes in the management. METHODS: A literature search was performed using the PubMed database with the relevant keywords. Filters included were human, ages 0-18 years, and the English language. RESULTS: Initial phase of HCV treatment using conventional or pegylated interferon and ribavirin combination regimens yielded poor outcomes in children, especially in genotypes 1 and 4, with an overall sustained virologic response of 58%. Also, treatment with interferon and ribavirin combination was associated with significant side effects in up to 52% of those treated. Presently, various combinations of direct-acting antivirals (DAAs) have been approved in children above three years of age with documented evidence of high efficacy (SVR12 of 92% to 100%) and excellent safety, and the current standard of care. CONCLUSION: With various DAA regimens now being approved for children above three years of age, the treatment of active HCV infection (HCV-RNA positive) in children has become simple. Besides the effectiveness of DAA therapy, public awareness about HCV transmission, better screening, and making the DAAs available at a subsidized price in the public sectors are necessary to eliminate HCV infection in India.


Assuntos
Hepatite C Crônica , Hepatite C , Humanos , Criança , Recém-Nascido , Lactente , Pré-Escolar , Adolescente , Ribavirina/uso terapêutico , Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Quimioterapia Combinada , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Hepatite C/induzido quimicamente , Interferons/uso terapêutico , Genótipo , Resultado do Tratamento
11.
J Interferon Cytokine Res ; 43(1): 35-42, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36651846

RESUMO

The human beta-coronavirus strain, OC43, provides a useful model for testing the antiviral activity of various agents. We compared the activity of several antiviral drugs against OC43, including remdesivir, chloroquine, interferon (IFN)-ß, IFN-λ1, and IFN-λ4, in two distinct cell types: human colorectal carcinoma cell line (HCT-8 cells) and normal human bronchial epithelial (NHBE) cells. We also tested whether these agents mediate additive, synergistic, or antagonistic activity against OC43 infection when used in combination. When used as single agents, remdesivir exhibited stronger antiviral activity than chloroquine, and IFN-ß exhibited stronger activity than IFN-λ1 or IFN-λ4 against OC43 in both HCT-8 and NHBE cells. Anakinra (IL-1 inhibitor) and tocilizumab (IL-6 inhibitor) did not mediate any antiviral activity. The combination of IFN-ß plus chloroquine or remdesivir resulted in higher synergy scores and higher expression of IFN-stimulated genes than did IFN-ß alone. In contrast, the combination of remdesivir plus chloroquine resulted in an antagonistic interaction in NHBE cells. Our findings indicate that the combined use of IFN-ß plus remdesivir or chloroquine induces maximal antiviral activity against human coronavirus strain OC43 in primary human respiratory epithelial cells. Furthermore, our experimental OC43 virus infection model provides an excellent method for evaluating the biological activity of antiviral drugs.


Assuntos
Infecções por Coronavirus , Coronavirus Humano OC43 , Humanos , Antivirais/farmacologia , Antivirais/uso terapêutico , Interferon beta/farmacologia , Interferon beta/uso terapêutico , Coronavirus Humano OC43/genética , Coronavirus Humano OC43/metabolismo , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Interferons/metabolismo
12.
Vet Microbiol ; 277: 109622, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36543089

RESUMO

Interferon-induced transmembrane proteins (IFITMs) play an important role in the innate immune response triggered by viral infection. Transmissible gastroenteritis virus (TGEV) causes severe diarrhea, vomiting and dehydration in piglets, resulting in huge economic losses to the swine industry. In this study, we showed that IFITM3 inhibits the replication of TGEV and interferes with the binding of TGEV to PK15 cells. Moreover, the inhibitory effect of IFITM3 on TGEV circumvents the upregulation of inflammatory cytokines. Subsequently, we found that the M22A mutant loses part of the antiviral effect of IFITM3 on TGEV; in contrast, the K24A mutant enhances the antiviral effect of IFITM3. Notably, our data shows a synergistic effect between IFITM3 and CQ, which further amplifies the antiviral effect against TGEV.


Assuntos
Gastroenterite Suína Transmissível , Doenças dos Suínos , Vírus da Gastroenterite Transmissível , Animais , Suínos , Vírus da Gastroenterite Transmissível/genética , Interferons , Antivirais , Imunidade Inata
13.
Mol Immunol ; 153: 212-225, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36563641

RESUMO

The last two decades have seen the emergence of three highly pathogenic coronaviruses with zoonotic origins, which prompted immediate attention to the underlying cause and prevention of future outbreaks. Intensification of camel husbandry in the Middle East has resulted in increased human-camel interactions, which has led to the spread of potentially zoonotic viruses with human spillover risks like MERS-coronavirus, camelpox virus, etc. Type-I interferons function as the first line of defense against invading viruses and are pivotal for limiting viral replication and immune-mediated pathologies. Seven novel dromedary camel interferon delta genes were identified and cloned. Functional characterization of this novel class of IFNs from the mammalian suborder tylopoda is reported for the first time. The camel interferon-delta proteins resemble the reported mammalian counterparts in sequence similarity, conservation of cysteines, and phylogenetic proximity. Prokaryotically expressed recombinant camel interferon-δ1 induced IFN-stimulated gene expression and also exerted antiviral action against camelpox virus, an endemic zoonotic virus. The pre-treatment of camel kidney cells with recombinant camel IFN-δ1 increased cell survival and reduced camelpox virus in a dose-dependent manner. The identification of novel IFNs from species with zoonotic spillover risk such as camels, and evaluating their antiviral effects in-vitro will play a key role in improving immunotherapies against viruses and expanding the arsenal to combat emerging zoonotic pathogens.


Assuntos
Interferon Tipo I , Coronavírus da Síndrome Respiratória do Oriente Médio , Animais , Humanos , Interferons/genética , Interferon Tipo I/genética , Camelus , Filogenia , Antivirais , Coronavírus da Síndrome Respiratória do Oriente Médio/genética
14.
Emerg Microbes Infect ; 12(1): 2164217, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36583373

RESUMO

CSFV (classical swine fever virus) is currently endemic in developing countries in Asia and has recently re-emerged in Japan. Under the pressure of natural selection pressure, CSFV keeps evolving to maintain its ecological niche in nature. CSFV has evolved mechanisms that induce immune depression, but its pathogenic mechanism is still unclear. In this study, using transcriptomics and metabolomics methods, we found that CSFV infection alters innate host immunity by activating the interferon pathway, inhibiting host inflammation, apoptosis, and remodelling host metabolism in porcine alveolar macrophages. Moreover, we revealed that autophagy could alter innate immunity and metabolism induced by CSFV infection. Enhanced autophagy further inhibited CSFV-induced RIG-I-IRF3 signal transduction axis and JAK-STAT signalling pathway and blocked type I interferon production while reducing autophagy inhibition of the NF-κB signalling pathway and apoptosis in CSFV infection cells. Furthermore, the level of CSFV infection-induced glycolysis and the content of lactate and pyruvate, as well as 3-phosphoglyceraldehyde, a derivative of glycolysis converted to serine, was altered by autophagy. We also found that silencing HK2 (hexokinase 2), the rate-limiting enzyme of glycolytic metabolism, could induce autophagy but reduce the interferon signalling pathway, NF-κB signalling pathway, and inhibition of apoptosis induced by CSFV infection. In addition, inhibited cellular autophagy by silencing ATG5 or using 3-Methyladenine, could backfill the inhibitory effect of silencing HK2 on the cellular interferon signalling pathway, NF-κB signalling pathway, and apoptosis.


Assuntos
Vírus da Febre Suína Clássica , Peste Suína Clássica , Imunidade Inata , Animais , Autofagia , Vírus da Febre Suína Clássica/fisiologia , Homeostase , Interferons , NF-kappa B/metabolismo , Suínos , Replicação Viral , Peste Suína Clássica/imunologia
15.
Dev Comp Immunol ; 140: 104614, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36502963

RESUMO

From mammals to fish, interferons (IFNs) play vital roles in the immune response. In this study, a newly identified type IV interferon (bcIFN-υ) from black carp (Mylopharyngodon piceus) has been cloned and characterized. The CDS of bcIFN-υ consists of 489 nucleotides, encoding 163 amino acids, with the first 20 amino acids predicted to be the signal peptide region. The immunoblot and immunofluorescence assays verified that bcIFN-υ was a secreted cytokine. qPCR analysis and reporter assay demonstrated that bcIFN-υ participated in innate immune defense and activated the transcription of fish ISRE promoter under spring viremia of carp virus (SVCV) stimulation. Additionally, compared with control group, EPC cells transfected with bcIFN-υ or incubated with the bcIFN-υ-containing conditioned media before SVCV infection showed greatly enhanced antiviral activity, and the transcription levels of MX1, PKR, ISG15 and Viperin genes were significantly increased. The subsequential co-immunoprecipitation assay identified the interaction between bcIFN-υ proteins. Collectively, our data conclude that bcIFN-υ is a kind of secretory protein with self-interaction and triggering the expression of downstream ISGs to enhance the antiviral activity of host cells.


Assuntos
Carpas , Doenças dos Peixes , Infecções por Reoviridae , Reoviridae , Infecções por Rhabdoviridae , Animais , Interferons/genética , Carpas/genética , Carpas/metabolismo , Reoviridae/fisiologia , Imunidade Inata/genética , Sequência de Aminoácidos , Clonagem Molecular , Antivirais , Proteínas de Peixes/metabolismo , Mamíferos/genética
16.
Dev Comp Immunol ; 140: 104624, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36586430

RESUMO

Cross-species comparison of vertebrate genomes has unraveled previously unknown complexities of interferon (IFN) systems in amphibian species. Recent genomic curation revealed that amphibian species have evolved expanded repertoires of four types of intron-containing IFN genes akin to those seen in jawed fish, intronless type I IFNs and intron-containing type III IFNs akin to those seen in amniotes, as well as uniquely intronless type III IFNs. This appears to be the case with at least ten analyzed amphibian species; with distinct species encoding diverse repertoires of these respective IFN gene subsets. Amphibians represent a key stage in vertebrate evolution, and in this context offer a unique perspective into the divergent and converged pathways leading to the emergence of distinct IFN families and groups. Recent studies have begun to unravel the roles of amphibian IFNs during these animals' immune responses in general and during their antiviral responses, in particular. However, the pleiotropic potentials of these highly expanded amphibian IFN repertoires warrant further studies. Based on recent reports and our omics analyses using Xenopus models, we posit that amphibian IFN complex may have evolved novel functions, as indicated by their extensive molecular diversity. Here, we provide an overview and an update of the present understanding of the amphibian IFN complex in the context of the evolution of vertebrate immune systems. A greater understanding of the amphibian IFN complex will grant new perspectives on the evolution of vertebrate immunity and may yield new measures by which to counteract the global amphibian declines.


Assuntos
Interferon Tipo I , Interferons , Animais , Interferons/genética , Evolução Molecular , Interferon Tipo I/genética , Íntrons , Xenopus laevis
17.
Vaccine ; 41(3): 724-734, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36564274

RESUMO

The candidate Adjuvant System AS37 contains a synthetic toll-like receptor agonist (TLR7a) adsorbed to alum. In a phase I study (NCT02639351), healthy adults were randomised to receive one dose of licensed alum-adjuvanted meningococcal serogroup C (MenC-CRM197) conjugate vaccine (control) or MenC-CRM197 conjugate vaccine adjuvanted with AS37 (TLR7a dose 12.5, 25, 50 or 100 µg). A subset of 66 participants consented to characterisation of peripheral whole blood transcriptomic responses, systemic cytokine/chemokine responses and multiple myeloid and lymphoid cell responses as exploratory study endpoints. Blood samples were collected pre-vaccination, 6 and 24 h post-vaccination, and 3, 7, 28 and 180 days post-vaccination. The gene expression profile in whole blood showed an early, AS37-specific transcriptome response that peaked at 24 h, increased with TLR7a dose up to 50 µg and generally resolved within one week. Five clusters of differentially expressed genes were identified, including those involved in the interferon-mediated antiviral response. Evaluation of 30 cytokines/chemokines by multiplex assay showed an increased level of interferon-induced chemokine CXCL10 (IP-10) at 24 h and 3 days post-vaccination in the AS37-adjuvanted vaccine groups. Increases in activated plasmacytoid dendritic cells (pDC) and intermediate monocytes were detected 3 days post-vaccination in the AS37-adjuvanted vaccine groups. T follicular helper (Tfh) cells increased 7 days post-vaccination and were maintained at 28 days post-vaccination, particularly in the AS37-adjuvanted vaccine groups. Moreover, most of the subjects that received vaccine containing 25, 50 and 100 µg TLR7a showed an increased MenC-specific memory B cell responses versus baseline. These data show that the adsorption of TLR7a to alum promotes an immune signature consistent with TLR7 engagement, with up-regulation of interferon-inducible genes, cytokines and frequency of activated pDC, intermediate monocytes, MenC-specific memory B cells and Tfh cells. TLR7a 25-50 µg can be considered the optimal dose for AS37, particularly for the adjuvanted MenC-CRM197 conjugate vaccine.


Assuntos
Hidróxido de Alumínio , Vacinas Meningocócicas , Adulto , Humanos , Interferons , Receptor 7 Toll-Like , Antivirais , Vacinas Conjugadas , Adjuvantes Imunológicos , Citocinas , Análise de Sistemas
18.
Viral Immunol ; 36(1): 48-54, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36493365

RESUMO

To study the clinical significance of manganese (Mn) in the serum of children with infectious mononucleosis (IM) caused by Epstein-Barr virus (EBV) infection, we analyzed the correlation between Mn and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and explored the immune pathogenesis of EBV infection. Children diagnosed with IM comprised the IM group, and healthy children during the same period were selected as the normal control group. Real-time reverse transcription-polymerase chain reaction was used to detect the mRNA expression levels of cGAS, STING, Tank-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), and related inflammatory factors, and Mn in serum was detected by inductively coupled plasma mass spectrometry. Interferon (IFN)-α and IFN-ß expression levels in serum were detected by enzyme-linked immunosorbent assay, and the correlation between Mn levels and clinical manifestations and laboratory tests was analyzed. Mn levels and the expression levels of cGAS, STING, and related inflammatory factors were significantly higher in children with IM than in healthy children. Furthermore, Mn levels in children with IM were positively correlated with the expression levels of cGAS and related inflammatory factors. Thus, Mn, cGAS, STING, and inflammatory cytokines may be involved in the immune mechanism of IM caused by EBV infection.


Assuntos
Infecções por Vírus Epstein-Barr , Mononucleose Infecciosa , Criança , Humanos , Herpesvirus Humano 4 , Manganês , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Interferons
19.
J Agric Food Chem ; 71(1): 569-579, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36583613

RESUMO

Di(2-ethylhexyl) phthalate (DEHP) is a highly harmful and persistent environmental pollutant. Due to its unique chemical composition, it frequently dissolves and enters the environment to endanger human and animal health. Lycopene is a natural bioactive component that can potentially reduce the risk of environmental factor-induced chronic diseases. The present study sought to explore the role and underlying mechanism of lycopene (LYC) on DEHP-induced renal inflammatory response and apoptosis. In this study, mice were orally treated with LYC (5 mg/kg BW/day) and/or DEHP (500 or 1000 mg/kg BW/day) for 28 days. Our results indicated that LYC prevented DEHP-induced histopathological alterations and ultrastructural injuries, including decreased mitochondrial membrane potential (ΔΨm), PINK1/Parkin pathway-mediated mitophagy, and mitochondrial energetic deficit. When damaged mitochondria release mitochondrial DNA (mtDNA) into cytosol, LYC can alleviate inflammation and apoptosis caused by DEHP exposure by activating the cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signal pathway. Collectively, our data demonstrate that LYC can reduce mitophagy caused by DEHP exposure by activating the PINK1/Parkin pathway and then reduce renal inflammation and apoptosis through the cGAS-STING pathway.


Assuntos
Dietilexilftalato , Animais , Camundongos , Dietilexilftalato/toxicidade , DNA Mitocondrial/metabolismo , Inflamação/genética , Interferons , Rim/metabolismo , Licopeno , Nucleotidiltransferases/metabolismo , Proteínas Quinases/metabolismo , Transdução de Sinais , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
20.
Fish Shellfish Immunol ; 132: 108481, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36566833

RESUMO

Interferon (IFN)-stimulated gene product 15 (ISG15) is a ubiquitin-like protein critical for the control of microbial infections. Golden pompano, Trachinotus ovatus is one of the precious marine economic fish in the southern coast of China, always suffering from viruses, bacteria, and parasite infections. To date, the roles of golden pompano genes involved in viral and bacterial infections, especially IFN-related genes remained largely unknown. To identify the interferon system genes of golden pompano and explore their function, in this study, the ISG15 homolog (ToISG15) was cloned from golden pompano, and its role in response to grouper iridovirus (SGIV), nervous necrosis virus (NNV), and Aeromonas hydrophila infection was investigated. The whole ORF of ToISG15 was composed of 465 bp and encoded a polypeptide of 154 amino acids with different identity with the known ISG15 homologs from other fish species. Two conserved ubiquitin-like (UBL) domains and an Ub-conjugation domain (LRGG) were found in ToISG15 sequence. Expression analysis showed that ToISG15 was located mainly in the cytoplasm of golden pompano cells, and dramatically induced following SGIV, Aeromonas hydrophila, or poly I:C treatment, but little change was observed when NNV infection. Overexpression of ToISG15 in vitro significantly inhibited the replication of SGIV and NNV. Interestingly, ToISG15 possessed the ability to restrain the growth of Aeromonas hydrophila. Furthermore, To-ISG15 overexpression enhanced the expression of IFNc, IFNh, IRF3, IRF7, and viperin genes as well as, to a lesser extent, the IL-6 gene. Taken together, our results demonstrated the antiviral and antibacterial effect of To-ISG15, shedding light on the evolutionary conservation of ISG15 in the immune response to microbial infection.


Assuntos
Infecções Bacterianas , Doenças dos Peixes , Iridovirus , Animais , Proteínas de Peixes/química , Imunidade Inata/genética , Peixes/genética , Peixes/metabolismo , Interferons , Filogenia
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