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2.
J Cell Biol ; 223(6)2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38587486

RESUMO

ß-Coronaviruses remodel host endomembranes to form double-membrane vesicles (DMVs) as replication organelles (ROs) that provide a shielded microenvironment for viral RNA synthesis in infected cells. DMVs are clustered, but the molecular underpinnings and pathophysiological functions remain unknown. Here, we reveal that host fragile X-related (FXR) family proteins (FXR1/FXR2/FMR1) are required for DMV clustering induced by expression of viral non-structural proteins (Nsps) Nsp3 and Nsp4. Depleting FXRs results in DMV dispersion in the cytoplasm. FXR1/2 and FMR1 are recruited to DMV sites via specific interaction with Nsp3. FXRs form condensates driven by liquid-liquid phase separation, which is required for DMV clustering. FXR1 liquid droplets concentrate Nsp3 and Nsp3-decorated liposomes in vitro. FXR droplets facilitate recruitment of translation machinery for efficient translation surrounding DMVs. In cells depleted of FXRs, SARS-CoV-2 replication is significantly attenuated. Thus, SARS-CoV-2 exploits host FXR proteins to cluster viral DMVs via phase separation for efficient viral replication.


Assuntos
COVID-19 , Proteína do X Frágil de Retardo Mental , Lipossomos , Proteínas de Ligação a RNA , SARS-CoV-2 , Humanos , Proliferação de Células , Análise por Conglomerados , COVID-19/metabolismo , COVID-19/virologia , Citoplasma , Proteína do X Frágil de Retardo Mental/metabolismo , Células HeLa , Lipossomos/metabolismo , Organelas , Proteínas de Ligação a RNA/metabolismo , Proteínas não Estruturais Virais/metabolismo
3.
Braz J Biol ; 84: e265550, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38451627

RESUMO

Despite of the global unity against COVID-19 pandemic, the threat of SARS-CoV-2 variants on the lives of human being is still not over. SARS-CoV-2 pandemic has urged the need of rapid viral detection at earliest. To cope with gradually expanding scenario of SARS-CoV-2, accurate diagnosis is extremely crucial factor which should be noticed by international health organizations. Limited research followed by sporadic marketing of SARS-CoV-2 rapid pharmaceutical detection kits raises critical questions against quality assurance and quality control measures. Herein we aimed to interrogate effectivity and specificity analysis of SARS-CoV-2 pharmaceutical rapid detection kits (nasopharyngeal swab based) using conventional gold standard triple target real-time polymerase chain reaction (USFDA approved). A cross-sectional study was conducted over 1500 suspected SARS-CoV-2 patients. 100 real time-PCR confirmed patients were evaluated for pharmaceutical RDT kits based upon nasopharyngeal swab based kits. The SARS-CoV-2 nasopharyngeal swab based rapid diagnostic kit (NSP RDTs) analysis showed 78% reactivity. Among real time PCR confirmed negative subjects, 49.3% represented false positivity. The positive predictive analysis revealed 67.82%, while negative predictive values were 64.40%. The NSP RDTs showed limited sensitivities and specificities as compared to gold standard real time PCR. Valid and authentic detection of SARS-CoV-2 is deemed necessary for accurate COVID-19 surveillance across the globe. Current study highlights the potential consequences of inadequate detection of SARS-CoV-2 and emerging novel mutants, compromising vaccine preventable diseases. Current study emphasizes need to wake higher authorities including strategic organizations for designing adequate measures to prevent future SARS-CoV-2 epidemics.


Assuntos
COVID-19 , Kit de Reagentes para Diagnóstico , SARS-CoV-2 , Humanos , COVID-19/diagnóstico , Estudos Transversais , Nasofaringe/virologia , Paquistão , Pandemias , SARS-CoV-2/genética , Sensibilidade e Especificidade
4.
Science ; 383(6687): 1111-1117, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38452081

RESUMO

The extent to which prophage proteins interact with eukaryotic macromolecules is largely unknown. In this work, we show that cytoplasmic incompatibility factor A (CifA) and B (CifB) proteins, encoded by prophage WO of the endosymbiont Wolbachia, alter long noncoding RNA (lncRNA) and DNA during Drosophila sperm development to establish a paternal-effect embryonic lethality known as cytoplasmic incompatibility (CI). CifA is a ribonuclease (RNase) that depletes a spermatocyte lncRNA important for the histone-to-protamine transition of spermiogenesis. Both CifA and CifB are deoxyribonucleases (DNases) that elevate DNA damage in late spermiogenesis. lncRNA knockdown enhances CI, and mutagenesis links lncRNA depletion and subsequent sperm chromatin integrity changes to embryonic DNA damage and CI. Hence, prophage proteins interact with eukaryotic macromolecules during gametogenesis to create a symbiosis that is fundamental to insect evolution and vector control.


Assuntos
Proteínas de Bactérias , Desoxirribonucleases , Drosophila melanogaster , Herança Paterna , Prófagos , RNA Longo não Codificante , Espermatozoides , Proteínas Virais , Wolbachia , Animais , Masculino , Citoplasma/metabolismo , DNA/metabolismo , Prófagos/genética , Prófagos/metabolismo , RNA Longo não Codificante/metabolismo , Espermatozoides/crescimento & desenvolvimento , Espermatozoides/metabolismo , Wolbachia/metabolismo , Wolbachia/virologia , Proteínas Virais/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/microbiologia , Proteínas de Bactérias/metabolismo , Desoxirribonucleases/metabolismo
5.
Front Public Health ; 12: 1356932, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38463163

RESUMO

Introduction: Rotavirus-associated diarrheal diseases significantly burden healthcare systems, particularly affecting infants under five years. Both Rotarix™ (RV1) and RotaTeq™ (RV5) vaccines have been effective but have distinct application schedules and limited interchangeability data. This study aims to provide evidence on the immunogenicity, reactogenicity, and safety of mixed RV1-RV5 schedules compared to their standard counterparts. Methods: This randomized, double-blind study evaluated the non-inferiority in terms of immunogenicity of mixed rotavirus vaccine schedules compared to standard RV1 and RV5 schedules in a cohort of 1,498 healthy infants aged 6 to 10 weeks. Participants were randomly assigned to one of seven groups receiving various combinations of RV1, and RV5. Standard RV1 and RV5 schedules served as controls of immunogenicity, reactogenicity, and safety analysis. IgA antibody levels were measured from blood samples collected before the first dose and one month after the third dose. Non-inferiority was concluded if the reduction in seroresponse rate in the mixed schemes, compared to the standard highest responding scheme, did not exceed the non-inferiority margin of -0.10. Reactogenicity traits and adverse events were monitored for 30 days after each vaccination and analyzed on the entire cohort. Results: Out of the initial cohort, 1,365 infants completed the study. Immunogenicity analysis included 1,014 infants, considering IgA antibody titers ≥20 U/mL as seropositive. Mixed vaccine schedules demonstrated non-inferiority to standard schedules, with no significant differences in immunogenic response. Safety profiles were comparable across all groups, with no increased incidence of serious adverse events or intussusception. Conclusion: The study confirms that mixed rotavirus vaccine schedules are non-inferior to standard RV1 and RV5 regimens in terms of immunogenicity and safety. This finding supports the flexibility of rotavirus vaccination strategies, particularly in contexts of vaccine shortage or logistic constraints. These results contribute to the global effort to optimize rotavirus vaccination programs for broader and more effective pediatric coverage.Clinical trial registration: ClinicalTrials.gov, NCT02193061.


Assuntos
Infecções por Rotavirus , Vacinas contra Rotavirus , Humanos , Lactente , Diarreia/virologia , Imunoglobulina A , Infecções por Rotavirus/complicações , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/efeitos adversos , Método Duplo-Cego
7.
Womens Health (Lond) ; 20: 17455057241235881, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38444072

RESUMO

BACKGROUND: Hepatitis B virus infection is a major public health problem among pregnant women worldwide. Hepatitis B virus is highly infectious and is the most common cause of morbidity and mortality among pregnant women, and evidence is scarce on the pooled seroprevalence of hepatitis B virus in Ethiopia. OBJECTIVES: This study aimed to investigate the pooled seroprevalence of hepatitis B virus infection and factors associated with pregnant women in Ethiopia. DESIGN: A systematic review and meta-analysis was employed in accordance with the Preferred Reporting Items for Systematic Reviews. DATA SOURCES: Searches were carried out in biomedical databases such as PubMed/Medline, Science Direct, Web of Science, Google Scholar, Hinari, and the Cochrane Library published in English until June 2023. METHODS: Observational study designs were selected. Endnote citation manager was used to collect and organize the search outcomes and remove duplicate articles. The data were extracted using a Microsoft Excel spreadsheet and exported to STATA 16.0 software for the analysis. RESULTS: A total of 48 research articles were included in the final analysis. The pooled estimated sero prevalence of hepatitis B virus infection among pregnant women in Ethiopia was 5.78% (95% confidence interval = 5.14, 6.43). History of abortion (odds ratio = 6.56, 95% confidence interval = 4.88, 8.90), history of blood transfusion (odds ratio = 5.74, 95% confidence interval = 4.04, 8.16), history of hospitalization (odds ratio = 5.40, 95% confidence interval = 3.68, 7.94), history of multiple sexual partner (odds ratio = 5.80, 95% confidence interval = 3.71, 9.05), history of surgical procedure (odds ratio = 7.39, 95% confidence interval = 4.16, 13.14), history of tattooing (odds ratio = 4.59, 95% confidence interval = 2.83, 7.43), and history of tooth extraction (odds ratio = 4.46, 95% confidence interval = 2.42, 8.22) were significantly associated with hepatitis B virus infection among pregnant women in Ethiopia. CONCLUSION: The overall pooled prevalence of hepatitis B virus infection among pregnant women in Ethiopia is relatively high. Having a history of abortion, blood transfusion, hospitalization, multiple sexual partners, surgical procedures, tattooing, and tooth extraction were found to be risk factors for hepatitis B virus. Therefore, extensive screening programs for hepatitis B virus in all pregnant women in Ethiopia are needed to prevent further infection and decrease the vertical transmission caused by the disease. REGISTRATION NUMBER: PROSPERO CRD: 42023438522.


Assuntos
Hepatite B , Complicações Infecciosas na Gravidez , Feminino , Humanos , Gravidez , Etiópia/epidemiologia , Hepatite B/epidemiologia , Vírus da Hepatite B , Estudos Observacionais como Assunto , Estudos Soroepidemiológicos , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/virologia
8.
Neurol India ; 72(1): 11-19, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38442994

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has strained global healthcare and financial infrastructures. Neurological manifestations of COVID-19 have gained recognition, emphasizing the need for comprehensive research in this area. This systematic review aims to comprehensively examine the neurological manifestations and complications associated with COVID-19 and assess their prevalence, impact on patient outcomes, and potential relationships with comorbidities, while emphasizing the significance of ongoing research in this field. We conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) 2020 guidelines. A comprehensive search of PubMed, Google Scholar, Science Direct, and ResearchGate databases was conducted to identify eligible studies focusing on COVID-19 patients, reporting neurological symptoms or complications, and published between 2020 and 2022 in English. The data extracted is performed in a Microsoft Excel spreadsheet. Two independent reviewers assessed study quality and bias using the AMSTAR 2 scale before inclusion. This systematic includes 12 systematic reviews and meta-analysis with 191,412 participants and average age of 60 years. Neurological symptoms included headaches, dizziness, anosmia, and ageusia. Complications ranged from cerebrovascular events to Guillain-Barré syndrome. Comorbidities, such as hypertension and diabetes, exacerbated severity. Mortality rates associated with neurological manifestations varied from 29.1% to 84.8%. The study underscores the complex neurological impact of COVID-19, affecting patients across age groups. Ongoing research is vital to understand mechanisms and develop targeted interventions, improving patient care and addressing pandemic consequences. This review provides a holistic view of COVID-19's neurological effects, emphasizing the need for sustained research efforts and collaborative endeavors to combat the neurological issues.


Assuntos
COVID-19 , Doenças do Sistema Nervoso , Humanos , COVID-19/complicações , Doenças do Sistema Nervoso/virologia
9.
N Engl J Med ; 390(11): 1009-1021, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38477988

RESUMO

BACKGROUND: Vaccination against respiratory syncytial virus (RSV) during pregnancy may protect infants from RSV disease. Efficacy and safety data on a candidate RSV prefusion F protein-based maternal vaccine (RSVPreF3-Mat) are needed. METHODS: We conducted a phase 3 trial involving pregnant women 18 to 49 years of age to assess the efficacy and safety of RSVPreF3-Mat. The women were randomly assigned in a 2:1 ratio to receive RSVPreF3-Mat or placebo between 24 weeks 0 days and 34 weeks 0 days of gestation. The primary outcomes were any or severe medically assessed RSV-associated lower respiratory tract disease in infants from birth to 6 months of age and safety in infants from birth to 12 months of age. After the observation of a higher risk of preterm birth in the vaccine group than in the placebo group, enrollment and vaccination were stopped early, and exploratory analyses of the safety signal of preterm birth were performed. RESULTS: The analyses included 5328 pregnant women and 5233 infants; the target enrollment of approximately 10,000 pregnant women and their infants was not reached because enrollment was stopped early. A total of 3426 infants in the vaccine group and 1711 infants in the placebo group were followed from birth to 6 months of age; 16 and 24 infants, respectively, had any medically assessed RSV-associated lower respiratory tract disease (vaccine efficacy, 65.5%; 95% credible interval, 37.5 to 82.0), and 8 and 14, respectively, had severe medically assessed RSV-associated lower respiratory tract disease (vaccine efficacy, 69.0%; 95% credible interval, 33.0 to 87.6). Preterm birth occurred in 6.8% of the infants (237 of 3494) in the vaccine group and in 4.9% of those (86 of 1739) in the placebo group (relative risk, 1.37; 95% confidence interval [CI], 1.08 to 1.74; P = 0.01); neonatal death occurred in 0.4% (13 of 3494) and 0.2% (3 of 1739), respectively (relative risk, 2.16; 95% CI, 0.62 to 7.56; P = 0.23), an imbalance probably attributable to the greater percentage of preterm births in the vaccine group. No other safety signal was observed. CONCLUSIONS: The results of this trial, in which enrollment was stopped early because of safety concerns, suggest that the risks of any and severe medically assessed RSV-associated lower respiratory tract disease among infants were lower with the candidate maternal RSV vaccine than with placebo but that the risk of preterm birth was higher with the candidate vaccine. (Funded by GlaxoSmithKline Biologicals; ClinicalTrials.gov number, NCT04605159.).


Assuntos
Nascimento Prematuro , Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Vírus Sincicial Respiratório Humano , Feminino , Humanos , Lactente , Recém-Nascido , Gravidez , Nascimento Prematuro/induzido quimicamente , Nascimento Prematuro/etiologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Vacinas contra Vírus Sincicial Respiratório/uso terapêutico , Doenças Respiratórias/prevenção & controle , Doenças Respiratórias/virologia , Eficácia de Vacinas , Resultado do Tratamento , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Risco
10.
Arch Virol ; 169(4): 85, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38546898

RESUMO

The fishing and aquaculture industry is vital for global food security, yet viral diseases can result in mass fish die-off events. Determining the viromes of traditionally understudied species, such as fish, enhances our understanding of the global virosphere and the factors that influence virome composition and disease emergence. Very little is known about the viruses present in New Zealand's native fish species, including the shortfin eel (Anguilla australis) and the longfin eel (Anguilla dieffenbachii), both of which are fished culturally by Maori (the indigenous population of New Zealand) and commercially. Through a total RNA metatranscriptomic analysis of longfin and shortfin eels across three different geographic locations in the South Island of New Zealand, we aimed to determine whether viruses had jumped between the two eel species and whether eel virome composition was impacted by life stage, species, and geographic location. We identified nine viral species spanning eight different families, thereby enhancing our understanding of eel virus diversity in New Zealand and the host range of these viral families. Viruses of the family Flaviviridae (genus Hepacivirus) were widespread and found in both longfin and shortfin eels, indicative of cross-species transmission or virus-host co-divergence. Notably, both host specificity and geographic location appeared to influence eel virome composition, highlighting the complex interaction between viruses, hosts, and their ecosystems. This study broadens our understanding of viromes in aquatic hosts and highlights the importance of gaining baseline knowledge of fish viral abundance and diversity, particularly in aquatic species that are facing population declines.


Assuntos
Anguilla , Rhabdoviridae , Animais , Anguilla/virologia , Ecossistema , Geografia , Nova Zelândia
11.
JAMA ; 331(12): 1025-1034, 2024 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-38446792

RESUMO

Importance: Despite the widespread availability of antiretroviral therapy (ART), people with HIV still experience high mortality after hospital admission. Objective: To determine whether a linkage case management intervention (named "Daraja" ["bridge" in Kiswahili]) that was designed to address barriers to HIV care engagement could improve posthospital outcomes. Design, Setting, and Participants: Single-blind, individually randomized clinical trial to evaluate the effectiveness of the Daraja intervention. The study was conducted in 20 hospitals in Northwestern Tanzania. Five hundred people with HIV who were either not treated (ART-naive) or had discontinued ART and were hospitalized for any reason were enrolled between March 2019 and February 2022. Participants were randomly assigned 1:1 to receive either the Daraja intervention or enhanced standard care and were followed up for 12 months through March 2023. Intervention: The Daraja intervention group (n = 250) received up to 5 sessions conducted by a social worker at the hospital, in the home, and in the HIV clinic over a 3-month period. The enhanced standard care group (n = 250) received predischarge HIV counseling and assistance in scheduling an HIV clinic appointment. Main Outcomes and Measures: The primary outcome was all-cause mortality at 12 months after enrollment. Secondary outcomes related to HIV clinic attendance, ART use, and viral load suppression were extracted from HIV medical records. Antiretroviral therapy adherence was self-reported and pharmacy records confirmed perfect adherence. Results: The mean age was 37 (SD, 12) years, 76.8% were female, 35.0% had CD4 cell counts of less than 100/µL, and 80.4% were ART-naive. Intervention fidelity and uptake were high. A total of 85 participants (17.0%) died (43 in the intervention group; 42 in the enhanced standard care group); mortality did not differ by trial group (17.2% with intervention vs 16.8% with standard care; hazard ratio [HR], 1.01; 95% CI, 0.66-1.55; P = .96). The intervention, compared with enhanced standard care, reduced time to HIV clinic linkage (HR, 1.50; 95% CI, 1.24-1.82; P < .001) and ART initiation (HR, 1.56; 95% CI, 1.28-1.89; P < .001). Intervention participants also achieved higher rates of HIV clinic retention (87.4% vs 76.3%; P = .005), ART adherence (81.1% vs 67.6%; P = .002), and HIV viral load suppression (78.6% vs 67.1%; P = .01) at 12 months. The mean cost of the Daraja intervention was about US $22 per participant including startup costs. Conclusions and Relevance: Among hospitalized people with HIV, a linkage case management intervention did not reduce 12-month mortality outcomes. These findings may help inform decisions about the potential role of linkage case management among hospitalized people with HIV. Trial Registration: ClinicalTrials.gov Identifier: NCT03858998.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Humanos , Feminino , Adulto , Masculino , Administração de Caso , Método Simples-Cego , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Antirretrovirais/uso terapêutico
12.
Int J Mol Sci ; 25(6)2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38542099

RESUMO

Bacteriophages associated with thermophiles are gaining increased attention due to their pivotal roles in various biogeochemical and ecological processes, as well as their applications in biotechnology and bionanotechnology. Although thermophages are not suitable for controlling bacterial infections in humans or animals, their individual components, such as enzymes and capsid proteins, can be employed in molecular biology and significantly contribute to the enhancement of human and animal health. Despite their significance, thermophages still remain underrepresented in the known prokaryotic virosphere, primarily due to limited in-depth investigations. However, due to their unique properties, thermophages are currently attracting increasing interest, as evidenced by several newly discovered phages belonging to this group. This review offers an updated compilation of thermophages characterized to date, focusing on species infecting the thermophilic bacilli. Moreover, it presents experimental findings, including novel proteomic data (39 proteins) concerning the model TP-84 bacteriophage, along with the first announcement of 6 recently discovered thermophages infecting Geobacillus thermodenitrificans: PK5.2, PK2.1, NIIg10.1, NIIg2.1, NIIg2.2, and NIIg2.3. This review serves as an update to our previous publication in 2021.


Assuntos
Bacillus , Bacteriófagos , Bacillus/virologia , Bacteriófagos/genética , Proteômica
13.
Viruses ; 16(3)2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38543794

RESUMO

During the COVID-19 pandemic, nonpharmaceutical interventions (NPIs) were implemented in order to control the transmission of SARS-CoV-2, potentially affecting the prevalence of respiratory syncytial virus (RSV). This review evaluated the impact of NPIs on RSV-related hospitalizations in children during the lockdown (2020-2021) compared to the pre-pandemic (2015-2020) and post-lockdown (2021-2022) periods. In this systematic review and meta-analysis, we searched through PubMed, Scopus, and Web of Science for studies published in English between 1 January 2015 and 31 December 2022. Additionally, we conducted hand searches of other records published between 1 January 2023 and 22 January 2024. Our target population was hospitalized children aged 0-18 years with RSV-related lower respiratory tract infections confirmed through immunofluorescence, antigen testing, or molecular assays. We focused on peer-reviewed observational studies, analyzing the primary outcome of pooled RSV prevalence. A generalized linear mixed model with a random-effects model was utilized to pool each RSV prevalence. Heterogeneity was assessed using Cochran's Q and I2 statistics, while publication bias was evaluated through funnel plots and Egger's tests. We identified and analyzed 5815 publications and included 112 studies with 308,985 participants. Notably, RSV prevalence was significantly lower during the lockdown period (5.03% [95% CI: 2.67; 9.28]) than during the pre-pandemic period (25.60% [95% CI: 22.57; 28.88], p < 0.0001). However, RSV prevalence increased notably in the post-lockdown period after the relaxation of COVID-19 prevention measures (42.02% [95% CI: 31.49; 53.33] vs. 5.03% [95% CI: 2.67; 9.28], p < 0.0001). Most pooled effect estimates exhibited significant heterogeneity (I2: 91.2% to 99.3%). Our findings emphasize the effectiveness of NPIs in reducing RSV transmission. NPIs should be considered significant public health measures to address RSV outbreaks.


Assuntos
COVID-19 , Infecções por Vírus Respiratório Sincicial , Infecções Respiratórias , Criança , Humanos , Criança Hospitalizada , Controle de Doenças Transmissíveis , COVID-19/epidemiologia , COVID-19/prevenção & controle , Pandemias , Prevalência , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/prevenção & controle , Infecções Respiratórias/virologia , Recém-Nascido , Lactente , Pré-Escolar , Adolescente
16.
Neurol Neuroimmunol Neuroinflamm ; 11(3): e200217, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38547427

RESUMO

BACKGROUND AND OBJECTIVES: Epstein-Barr virus (EBV) has been strongly implicated in the pathogenesis of multiple sclerosis (MS). Despite this, there are no routinely used tests to measure cellular response to EBV. In this study, we analyzed the cellular response to EBV nuclear antigen-1 (EBNA-1) in people with MS (pwMS) using a whole blood assay. METHODS: This cross-sectional study took place in a dedicated MS clinic in a university hospital. We recruited healthy controls, people with epilepsy (PWE), and pwMS taking a range of disease-modifying treatments (DMTs) including natalizumab, anti-CD20 monoclonal antibodies (mAbs), dimethyl fumarate (DMF), and also treatment naïve. Whole blood samples were stimulated with commercially available PepTivator EBNA1 peptides and a control virus-cytomegalovirus (CMV) peptide. We recorded the cellular response to stimulation with both interferon gamma (IFN-γ) and interleukin-2 (IL-2). We also compared the cellular responses to EBNA1 with IgG responses to EBNA1, viral capsid antigen (VCA), and EBV viral load. RESULTS: We recruited 86 pwMS, with relapsing remitting MS, in this group, and we observed a higher level of cellular response recorded with IFN-γ (0.79 IU/mL ± 1.36) vs healthy controls (0.29 IU/mL ± 0.90, p = 0.0048) and PWE (0.17 IU/mL ± 0.33, p = 0.0088). Treatment with either anti-CD20 mAbs (0.28 IU/mL ± 0.57) or DMF (0.07 IU/mL ± 0.15) resulted in a cellular response equivalent to control levels or in PWE (p = 0.26). The results of recording IL-2 response were concordant with IFN-γ: with suppression also seen with anti-CD20 mAbs and DMF. By contrast, we did not record any differential effect of DMTs on the levels of IgG to either EBNA-1 or VCA. Nor did we observe differences in cellular response to cytomegalovirus between groups. DISCUSSION: This study demonstrates how testing and recording the cellular response to EBNA-1 in pwMS may be beneficial. EBNA-1 stimulation of whole blood samples produced higher levels of IFN-γ and IL-2 in pwMS compared with controls and PWE. In addition, we show a differential effect of currently available DMTs on this response. The functional assay deployed uses whole blood samples with minimal preprocessing suggesting that employment as a treatment response measure in clinical trials targeting EBV may be possible.


Assuntos
Antígenos Nucleares do Vírus Epstein-Barr , Herpesvirus Humano 4 , Esclerose Múltipla , Humanos , Anticorpos Antivirais , Antígenos Virais , Proteínas do Capsídeo , Estudos Transversais , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Imunidade Celular , Imunoglobulina G , Interferon gama , Interleucina-2 , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/virologia
17.
Nature ; 627(8003): 399-406, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38448581

RESUMO

Immune cells rely on transient physical interactions with other immune and non-immune populations to regulate their function1. To study these 'kiss-and-run' interactions directly in vivo, we previously developed LIPSTIC (labelling immune partnerships by SorTagging intercellular contacts)2, an approach that uses enzymatic transfer of a labelled substrate between the molecular partners CD40L and CD40 to label interacting cells. Reliance on this pathway limited the use of LIPSTIC to measuring interactions between CD4+ T helper cells and antigen-presenting cells, however. Here we report the development of a universal version of LIPSTIC (uLIPSTIC), which can record physical interactions both among immune cells and between immune and non-immune populations irrespective of the receptors and ligands involved. We show that uLIPSTIC can be used, among other things, to monitor the priming of CD8+ T cells by dendritic cells, reveal the steady-state cellular partners of regulatory T cells and identify germinal centre-resident T follicular helper cells on the basis of their ability to interact cognately with germinal centre B cells. By coupling uLIPSTIC with single-cell transcriptomics, we build a catalogue of the immune populations that physically interact with intestinal epithelial cells at the steady state and profile the evolution of the interactome of lymphocytic choriomeningitis virus-specific CD8+ T cells in multiple organs following systemic infection. Thus, uLIPSTIC provides a broadly useful technology for measuring and understanding cell-cell interactions across multiple biological systems.


Assuntos
Linfócitos B , Linfócitos T CD8-Positivos , Comunicação Celular , Células Dendríticas , Células Epiteliais , Células T Auxiliares Foliculares , Linfócitos T Reguladores , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Comunicação Celular/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Ligantes , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Células T Auxiliares Foliculares/citologia , Células T Auxiliares Foliculares/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Centro Germinativo/citologia , Análise da Expressão Gênica de Célula Única , Células Epiteliais/citologia , Células Epiteliais/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Especificidade de Órgãos
18.
Zhonghua Gan Zang Bing Za Zhi ; 32(2): 148-154, 2024 Feb 20.
Artigo em Chinês | MEDLINE | ID: mdl-38514264

RESUMO

Objective: To analyze and evaluate the expressions and clinical value of tuftelin (TUFT1) and Krüppel-like factor 5 (KLF5) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) tissues. Method: KLF5 mRNA and TUFT1 mRNA transcriptional status in cancer and non-cancer groups were compared according to the Cancer Genome Atlas (TCGA) database. The differences and prognostic value between the groups were analyzed. Postoperative liver cancer and its paired pericancerous tissues, with the approval of the ethics committee, were collected to build tissue chips. The expression of KLF5 and TUFT1 and their intracellular localization were verified by immunohistochemistry. Tissue expression and clinicopathological characteristics were analyzed by immunoblotting. SPSS software was used to analyze the relationship between SPSS and patient prognosis. Results: The transcription level of TUFT1 or KLF5 mRNA was significantly higher in the HCC group than the non-cancer group (P < 0.001), according to TCGA data. Immunohistochemistry and Western blotting examination confirmed the overexpression of TUFT1 and KLF5 in human HCC tissues, which were mainly localized in the cytoplasm and cell membrane. The positivity rates of TUFT1 and KLF5 were 87.1% ( χ(2) = 18.563, P < 0.001) and 95.2% ( χ(2) = 96.435, P < 0.001) in HCC tissues, and both were significantly higher than those in the adjacent group. The expression intensity was higher in stage III-IV than stage I-II of the International Union Against Cancer standard (P < 0.01). The clinicopathological features showed that the abnormalities of the two were significantly related to HBV infection, tumor size, extrahepatic metastasis, TNM stage, and ascites. Univariate analysis was related to tumor size, HBV infection, and survival. Multivariate analysis was an independent prognostic factor for patients with HCC. Conclusion: TUFT1 and KLF5 may both be novel markers possessing clinical value in the diagnosis and prognosis of HBV-related HCC.


Assuntos
Carcinoma Hepatocelular , Proteínas do Esmalte Dentário , Hepatite B , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Proteínas do Esmalte Dentário/genética , Proteínas do Esmalte Dentário/metabolismo , Regulação Neoplásica da Expressão Gênica , Hepatite B/complicações , Hepatite B/genética , Vírus da Hepatite B/genética , Neoplasias Hepáticas/patologia , Prognóstico , RNA Mensageiro , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo
19.
J Med Virol ; 96(3): e29531, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38515377

RESUMO

The Nucleocapsid Protein (NP) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not only the core structural protein required for viral packaging, but also participates in the regulation of viral replication, and its post-translational modifications such as phosphorylation have been shown to be an important strategy for regulating virus proliferation. Our previous work identified NP could be ubiquitinated, as confirmed by two independent studies. But the function of NP ubiquitination is currently unknown. In this study, we first pinpointed TRIM6 as the E3 ubiquitin ligase responsible for NP ubiquitination, binding to NP's CTD via its RING and B-box-CCD domains. TRIM6 promotes the K29-typed polyubiquitination of NP at K102, K347, and K361 residues, increasing its binding to viral genomic RNA. Consistently, functional experiments such as the use of the reverse genetic tool trVLP model and gene knockout of TRIM6 further confirmed that blocking the ubiquitination of NP by TRIM6 significantly inhibited the proliferation of SARS-CoV-2. Notably, the NP of coronavirus is relatively conserved, and the NP of SARS-CoV can also be ubiquitinated by TRIM6, indicating that NP could be a broad-spectrum anti-coronavirus target. These findings shed light on the intricate interaction between SARS-CoV-2 and the host, potentially opening new opportunities for COVID-19 therapeutic development.


Assuntos
COVID-19 , Genoma Viral , SARS-CoV-2 , Ubiquitina-Proteína Ligases , Humanos , Proliferação de Células , COVID-19/genética , COVID-19/virologia , Proteínas do Nucleocapsídeo/genética , RNA Viral/genética , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Proteínas do Nucleocapsídeo de Coronavírus/genética , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo
20.
J Med Virol ; 96(3): e29546, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38516804

RESUMO

Tapasin, a crucial molecular chaperone involved viral antigen processing and presentation, plays an important role in antivirus immunity. However, its impact on T cell differentiation in the context of virus clearance remains unclear. In this study, we employed induced pluripotent stem cells to differentiate into hepatocyte-like cell, which were subsequently inserted to the inverted colloidal crystal scaffolds, thus establishing a hepatocyte organoid (HO). By inoculating hepatitis B virus (HBV) particles in the system, we successfully engineered a robust in vitro HBV infection model for at least 3 weeks. Furthermore, we aimed to explore the effects of lentivirus-mediated short hairpin RNA (shRNA) targeting human Tapasin on the differentiation and antiviral function of CD8+ T cells. Specifically, we transfected dendritic cells (DCs) with Tapasin-shRNA and cocultured with T cells. The results demonstrated that Tapasin-shRNA transfected DCs effectively suppressed T cell proliferation and impeded HBV-specific cytotoxic T lymphocyte responses. Our investigation also revealed the role of mTOR pathway activation in reducing autophagy activity within CD8+ T cells. Expressions of autophagy-related proteins, beclin-1, LC3II/LC3I were decreased and PI3K/AKT/mTOR activity was increased in Tapasin-shRNA group. Collectively, our findings elucidate that shRNA targeting the Tapasin gene within DCs inhibits T cell differentiation by reducing autophagy activity to hamper viral clearance in the HBV-infected HO.


Assuntos
Células Dendríticas , Hepatite B , Proteínas de Membrana Transportadoras , Humanos , Autofagia/genética , Linfócitos T CD8-Positivos/metabolismo , Células Dendríticas/metabolismo , Regulação para Baixo , Hepatite B/metabolismo , Antígenos do Núcleo do Vírus da Hepatite B/genética , Vírus da Hepatite B , Hepatócitos/metabolismo , Células-Tronco Pluripotentes Induzidas , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , RNA Interferente Pequeno/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Organoides/metabolismo , Organoides/virologia
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