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1.
Emerg Microbes Infect ; 13(1): 2302106, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38170506

RESUMO

The highly pathogenic avian influenza H5 2.3.4.4 and 2.3.2.1c subclades have distinct antigenic properties and are responsible for the majority of human infections. Therefore, it is essential to understand the processes by which antibodies inhibit these subclade viruses to develop effective therapies and vaccines to prevent their escape from neutralizing antibodies. Herein, we report the epitopes of two specific monoclonal antibodies (mAbs) targeting haemagglutinin (HA) of the H5 2.3.4.4b subclade and their neutralizing abilities. The results indicated that the two mAbs provided specific protection against the H5 2.3.4.4b clade viral challenge in MDCK cells and mouse models. Through epitope identification and docking studies, we showed that these novel sites (which are located near the 130-loop (S136, T143) and 190-helix (N199, N205) of HA receptor-binding sites that contribute to the binding affinity of neutralizing mAbs and six residues of the complementarity-determining regions) can be targeted to generate antibodies with enhanced cross-neutralization. This can also help in understanding escape mutations that differ among the H5 2.3.4.4b, h, and 2.3.2.1c subclades. These results provide specific information to facilitate future vaccine design and therapeutics for both subclade viruses, which are dominant and pose a serious threat to humans.


Assuntos
Virus da Influenza A Subtipo H5N1 , Vacinas contra Influenza , Influenza Aviária , Animais , Camundongos , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , Mapeamento de Epitopos/métodos , Virus da Influenza A Subtipo H5N1/genética , Epitopos , Anticorpos Monoclonais , Glicoproteínas de Hemaglutininação de Vírus da Influenza
2.
Emerg Infect Dis ; 29(10): 2130-2134, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37735771

RESUMO

We report on an outbreak of nongroupable Neisseria meningitidis-associated urethritis, primarily among men who have sex with men in southern Vietnam. Nearly 50% of N. meningitidis isolates were resistant to ciprofloxacin. This emerging pathogen should be considered in the differential diagnosis and management of urethritis.


Assuntos
Neisseria meningitidis , Minorias Sexuais e de Gênero , Uretrite , Masculino , Humanos , Uretrite/diagnóstico , Uretrite/epidemiologia , Vietnã/epidemiologia , Homossexualidade Masculina , Surtos de Doenças , Neisseria meningitidis/genética
3.
Psychol Res Behav Manag ; 16: 1987-2003, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37284555

RESUMO

Purpose: This study aims to reveal the relationship between personality characteristics and verbal or physical aggression in Vietnamese adolescents. Patients and Methods: We recruited 3003 participants [1498 boys (49.9%) and 1505 girls (50.1%); mean age ± SD = 13.50 ± 0.936] who we tested with the Eysenck Personality Questionnaire - Brief version (EPQ-BV), and Vietnamese Aggression Scale (VAS). A multivariate analysis of variance test, Pearson Correlation, and analyzing mediating variable interaction is used to analyze data. Results: The findings suggested a significant interaction between personality traits, specifically extraversion and neuroticism, and physical aggression, verbal aggression, and anger. Students with higher levels of personality had higher levels of verbal aggression, and students with higher levels of physical aggression and anger had stronger personality traits than others and lower levels of physical aggression and anger. Personality traits, specifically extraversion, and neuroticism, differed significantly by gender and school years in adolescence. Mediation analysis revealed a positive and statistically significant indirect correlation between personality traits and physically aggressive behavior, with anger as a mediator. Similarly, a positive and statistically significant indirect correlation between personality traits and verbally aggressive behavior through anger was found. The relationship between personality traits and physical aggression was also significant via verbal aggression and anger. Conclusion: This study improved our understanding of personality traits and verbal or physical aggression. Most crucially, physical and verbal aggression mediate personality traits and aggressive conduct. In secondary school, gender and school year affected extraversion and neuroticism. This discovery illuminates personality-based aggressiveness intervention.

4.
Front Psychol ; 13: 971711, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36518965

RESUMO

Vietnam, a middle-income country, has been suffering four waves of the Coronavirus disease 2019 (COVID-19) pandemic and a massive lockdown to suppress the spread of this infectious disease. Consequently, COVID-19 has caused psychological ramifications and affected humankind's life satisfaction. Because of the lockdown period, numerous people had plentiful time. Hence, they found solace in excessive watching of television and movies, which could lead to post-series depression. The purpose of this study is to investigate the relationship between life satisfaction (LS), post-series depression (PSD), and positive mental health (PMH) and inquire about the mediation effect of satisfaction of life and PSD. A total of 2,572 participants who were voluntarily recruited from various media platforms completed self-report questionnaires, including the Satisfaction with life scale, Post-series depression scale, and Positive Mental Health Scale. This study was assessed using the PLS-SEM approach. The findings of this research discovered (i) a significantly positive effect of LS on PMH; (ii) a significantly negative effect of PSD on PMH; (iii) a significantly negative effect of LS on PSD, and (iv) a significant indirect effect of LS on PMH through PSD. The study provided additional evidence to the relationship between life satisfaction and PMH of individuals. Besides, the negative effects of PSD, which is a non-clinical term for feeling down that frequently appears after individuals finish their much-loved film and TV series, on individuals' PMH is proved, especially in the COVID-19 pandemic context in which Vietnamese people must remain in their current location.

5.
Psychol Res Behav Manag ; 15: 3513-3530, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36505671

RESUMO

Purpose: The purpose of this study was to investigate the direct and indirect effects of expectations for marital relationships and premarital sexual permissiveness on intent to marry of Vietnamese emerging adults. Patients and Methods: Our cross-sectional study was focused on emerging adults including 344 participants, undergraduate students from universities in Viet Nam. This study was assessed by using the PLS-SEM approach. Results: The main findings demonstrated that (i) sexual orientation have a significant effect on marital intention; (ii) individuals' expectations for marital relationship have a direct effect on marital intention; and (iii) premarital sexuality permissiveness mediates the relationship between expectations for marital relationship and marital intention. Conclusion: Our results contribute important documents and clearer understanding of emerging adults' expectations and requirements in a relationship for the marriage decision-making process.

6.
Sensors (Basel) ; 22(15)2022 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-35957265

RESUMO

In recent years, due to the ubiquitous presence of WiFi access points in buildings, the WiFi fingerprinting method has become one of the most promising approaches for indoor positioning applications. However, the performance of this method is vulnerable to changes in indoor environments. To tackle this challenge, in this paper, we propose a novel WiFi fingerprinting method that uses the valued tolerance rough set theory-based classification method. In the offline phase, the conventional received signal strength (RSS) fingerprinting database is converted into a decision table. Then a new fingerprinting database with decision rules is constructed based on the decision table, which includes the credibility degrees and the support object set values for all decision rules. In the online phase, various classification levels are applied to find out the best match between the RSS values in the decision rules database and the measured RSS values at the unknown position. The experimental results compared the performance of the proposed method with those of the nearest-neighbor-based and the random statistical methods in two different test cases. The results show that the proposed method greatly outperforms the others in both cases, where it achieves high accuracy with 98.05% of right position classification, which is approximately 50.49% more accurate than the others. The mean positioning errors at wrong estimated positions for the two test cases are 1.71 m and 1.99 m, using the proposed method.


Assuntos
Algoritmos
7.
Int J Mol Sci ; 23(11)2022 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-35682982

RESUMO

Rapid diagnosis is essential for the control and prevention of H5 highly pathogenic avian influenza viruses (HPAIVs). However, highly sensitive and rapid diagnostic systems have shown limited performance due to specific antibody scarcity. In this study, two novel specific monoclonal antibodies (mAbs) for clade 2.3.4.4 H5Nx viruses were developed by using an immunogen from a reversed genetic influenza virus (RGV). These mAbs were combined with fluorescence europium nanoparticles and an optimized lysis buffer, which were further used for developing a fluorescent immunochromatographic rapid strip test (FICT) for early detection of H5Nx influenza viruses on chicken stool samples. The result indicates that the limit of detection (LoD) of the developed FICT was 40 HAU/mL for detection of HPAIV H5 clade 2.3.4.4b in spiked chicken stool samples, which corresponded to 4.78 × 104 RNA copies as obtained from real-time polymerase chain reaction (RT-PCR). An experimental challenge of chicken with H5N6 HPAIV is lethal for chicken three days post-infection (DPI). Interestingly, our FICT could detect H5N6 in stool samples at 2 DPI earlier, with 100% relative sensitivity in comparison with RT-PCR, and it showed 50% higher sensitivity than the traditional colloidal gold-based rapid diagnostic test using the same mAbs pair. In conclusion, our rapid diagnostic method can be utilized for the early detection of H5Nx 2.3.4.4 HPAIVs in avian fecal samples from poultry farms or for influenza surveillance in wild migratory birds.


Assuntos
Vírus da Influenza A , Influenza Aviária , Nanopartículas Metálicas , Animais , Animais Selvagens , Galinhas , Európio , Vírus da Influenza A/genética , Influenza Aviária/epidemiologia , Filogenia
8.
Emerg Microbes Infect ; 11(1): 1425-1434, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35451353

RESUMO

Several novel highly pathogenic avian influenza (HPAIVs) A(H5N6) viruses were reported in Mongolia in 2020, some of which included host-specific markers associated with mammalian infection. However, their pathogenicity has not yet been investigated. Here, we isolated and evaluate two novel genotypes of A(H5N6) subtype in Mongolia during 2018-2019 (A/wildDuck/MN/H5N6/2018-19). Their evolution pattern and molecular characteristics were evaluated using gene sequencing and their pathogenicity was determined using a mouse model. We also compared their antigenicity with previous H5 Clade 2.3.4.4 human isolates by cross-hemagglutination inhibition (HI). Our data suggests that A/wildDuck/MN/H5N6/2018-19 belongs to clade 2.3.4.4h, and maintains several residues associated with mammal adaptation. In addition, our evaluations revealed that their isolates are less virulent in mice than the previously identified H5 human isolates. However, their antigenicity is distinct from other HPAIVs H5 clade 2.3.4.4, thus supporting their continued evaluation as potential infection risks and the preparation of novel candidate vaccines for their neutralization.


Assuntos
Vírus da Influenza A , Influenza Aviária , Animais , Galinhas , Patos , Fezes , Vírus da Influenza A/genética , Mamíferos , Filogenia , Virulência
9.
Artigo em Inglês | MEDLINE | ID: mdl-35457468

RESUMO

Genetic variants of severe acute respiratory syndrome coronavirus (SARS-CoV-2) have been globally surging and devastating many countries around the world. There are at least eleven reported variants dedicated with inevitably catastrophic consequences. In 2021, the most dominant Delta and Omicron variants were estimated to lead to more severity and deaths than other variants. Furthermore, these variants have some contagious characteristics involving high transmissibility, more severe illness, and an increased mortality rate. All outbreaks caused by the Delta variant have been rapidly skyrocketing in infection cases in communities despite tough restrictions in 2021. Apart from it, the United States, the United Kingdom and other high-rate vaccination rollout countries are still wrestling with this trend because the Delta variant can result in a significant number of breakthrough infections. However, the pandemic has changed since the latest SARS-CoV-2 variant in late 2021 in South Africa, Omicron. The preliminary data suggest that the Omicron variant possesses 100-fold greater than the Delta variant in transmissibility. Therefore, this paper aims to review these characteristics based on the available meta-data and information from the first emergence to recent days. Australia and the five most affected countries, including the United States, India, Brazil, France, as well as the United Kingdom, are selected in order to review the transmissibility, severity and fatality due to Delta and Omicron variants. Finally, the vaccination programs for each country are also reviewed as the main factor in prevention.


Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/epidemiologia , Surtos de Doenças , Humanos , Pandemias , SARS-CoV-2/genética , Estados Unidos/epidemiologia
10.
Emerg Infect Dis ; 28(2): 432-435, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35076010

RESUMO

Among 114 clinical Neisseria gonorrhoeae isolates collected in Vietnam during 2019-2020, we detected 15 of subclone sequence type 13871 of the FC428 clonal complex. Fourteen sequence type 13871 isolates with mosaic penA allele 60.001 were ceftriaxone or cefixime nonsusceptible, and 3/14 were azithromycin nonsusceptible. Emergence of this subclone threatens treatment effectiveness.


Assuntos
Gonorreia , Neisseria gonorrhoeae , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Ceftriaxona/farmacologia , Ceftriaxona/uso terapêutico , Farmacorresistência Bacteriana , Gonorreia/tratamento farmacológico , Gonorreia/epidemiologia , Humanos , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae/genética , Vietnã/epidemiologia
11.
Biosens Bioelectron ; 197: 113768, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34763153

RESUMO

A rapid diagnostic system employing an antigen detection biosensing method is needed to discriminate between Zika virus (ZIKV) and Dengue virus (DENV) due to their close antigenic homology. We developed a novel peptide pair-based flow immunochromatographic test strip (FICT) assay to detect ZIKV. Peptide aptamers, P6.1 (KQERNNWPLTWT), P29.1 (KYTTSTLKSGV), and B2.33 (KRHVWVSLSYSCAEA) were designed by paratopes and modified against the ZIKV envelope protein based on the binding affinity. An antibody-free lateral FICT was developed using a pair of peptide aptamers. In the rapid diagnostic strip, the limit of detection (LOD) for the B2.33-P6.1 peptide pair for ZIKV was 2 × 104 tissue culture infective dose TCID50/mL. Significantly, FICT could discriminate ZIKV from DENV. The stability and performance of FICT were confirmed using human sera and urine, showing a comparable LOD value. Our study demonstrated that in silico modeling could be used to develop a novel peptide pair-based FICT assay for detecting ZIKV by a rapid diagnostic test.


Assuntos
Aptâmeros de Peptídeos , Técnicas Biossensoriais , Dengue , Infecção por Zika virus , Zika virus , Anticorpos Antivirais , Reações Cruzadas , Humanos , Peptídeos , Infecção por Zika virus/diagnóstico
12.
Viruses ; 13(11)2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34835066

RESUMO

Avian influenza virus (AIV) subtypes H5 and H7, possessing the ability to mutate spontaneously from low pathogenic (LP) to highly pathogenic (HP) variants, are major concerns for enormous socio-economic losses in the poultry industry, as well as for fatal human infections. Through antigenic drift and shift, genetic reassortments of the genotypes pose serious threats of increased virulence and pathogenicity leading to potential pandemics. In this study, we isolated the H7-subtype AIVs circulating in the Republic of Korea during 2018-2019, and perform detailed molecular analysis to study their circulation, evolution, and possible emergence as a zoonotic threat. Phylogenetic and nucleotide sequence analyses of these isolates revealed their distribution into two distinct clusters, with the HA gene sharing the highest nucleotide identity with either the A/common teal/Shanghai/CM1216/2017, isolated from wild birds in Shanghai, China, or the A/duck/Shimane/2014, isolated from Japan. Mutations were found in HA (S138A (H3 numbering)), M1 (N30D and T215A), NS1 (P42S), PB2 (L89V), and PA (H266R and F277S) proteins-the mutations had previously been reported to be related to mammalian adaptation and changes in the virulence of AIVs. Taken together, the results firmly put forth the demand for routine surveillance of AIVs in wild birds to prevent possible pandemics arising from reassortant AIVs.


Assuntos
Evolução Molecular , Vírus da Influenza A/genética , Influenza Aviária/virologia , Zoonoses Virais/virologia , Animais , Animais Selvagens/virologia , Antígenos Virais/genética , Aves/virologia , Genoma Viral/genética , Vírus da Influenza A/isolamento & purificação , Vírus da Influenza A/patogenicidade , Influenza Aviária/epidemiologia , Influenza Aviária/transmissão , Mutação , Filogenia , RNA Viral/genética , Vírus Reordenados/genética , Vírus Reordenados/isolamento & purificação , Vírus Reordenados/patogenicidade , República da Coreia/epidemiologia , Zoonoses Virais/epidemiologia , Zoonoses Virais/transmissão , Virulência/genética
13.
Viruses ; 13(5)2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067187

RESUMO

Low-pathogenicity avian influenza viruses (LPAIV) introduced by migratory birds circulate in wild birds and can be transmitted to poultry. These viruses can mutate to become highly pathogenic avian influenza viruses causing severe disease and death in poultry. In March 2019, an H7N3 avian influenza virus-A/Spot-billed duck/South Korea/WKU2019-1/2019 (H7N3)-was isolated from spot-billed ducks in South Korea. This study aimed to evaluate the phylogenetic and mutational analysis of this isolate. Molecular analysis revealed that the genes for HA (hemagglutinin) and NA (neuraminidase) of this strain belonged to the Central Asian lineage, whereas genes for other internal proteins such as polymerase basic protein 1 (PB1), PB2, nucleoprotein, polymerase acidic protein, matrix protein, and non-structural protein belonged to that of the Korean lineage. In addition, a monobasic amino acid (PQIEPR/GLF) at the HA cleavage site, and the non-deletion of the stalk region in the NA gene indicated that this isolate was a typical LPAIV. Nucleotide sequence similarity analysis of HA revealed that the highest homology (99.51%) of this isolate is to that of A/common teal/Shanghai/CM1216/2017 (H7N7), and amino acid sequence of NA (99.48%) was closely related to that of A/teal/Egypt/MB-D-487OP/2016 (H7N3). An in vitro propagation of the A/Spot-billed duck/South Korea/WKU2019-1/2019 (H7N3) virus showed highest (7.38 Log10 TCID50/mL) virus titer at 60 h post-infection, and in experimental mouse lungs, the virus was detected at six days' post-infection. Our study characterizes genetic mutations, as well as pathogenesis in both in vitro and in vivo model of a new Korea H7N3 viruses in 2019, carrying multiple potential mutations to become highly pathogenic and develop an ability to infect humans; thus, emphasizing the need for routine surveillance of avian influenza viruses in wild birds.


Assuntos
Patos/virologia , Vírus da Influenza A Subtipo H7N3/classificação , Vírus da Influenza A Subtipo H7N3/genética , Influenza Aviária/epidemiologia , Influenza Aviária/virologia , Animais , Animais Selvagens/virologia , Células Cultivadas , Feminino , Genes Virais , Genoma Viral , Genômica/métodos , História do Século XXI , Especificidade de Hospedeiro , Vírus da Influenza A Subtipo H7N3/isolamento & purificação , Influenza Aviária/história , Camundongos , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Filogenia , Vigilância em Saúde Pública , Vírus Reordenados , República da Coreia/epidemiologia , Replicação Viral
14.
Viruses ; 13(1)2020 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-33375376

RESUMO

Influenza A virus subtype H1N1 has caused global pandemics like the "Spanish flu" in 1918 and the 2009 H1N1 pandemic several times. H1N1 remains in circulation and survives in multiple animal sources, including wild birds. Surveillance during the winter of 2018-2019 in Korea revealed two H1N1 isolates in samples collected from wild bird feces: KNU18-64 (A/Greater white-fronted goose/South Korea/KNU18-64/2018(H1N1) and WKU19-4 (A/wild bird/South Korea/WKU19-4/2019(H1N1). Phylogenetic analysis indicated that M gene of KNU18-64(H1N1) isolate resembles that of the Alaskan avian influenza virus, whereas WKU19-4(H1N1) appears to be closer to the Mongolian virus. Molecular characterization revealed that they harbor the amino acid sequence PSIQRSGLF and are low-pathogenicity influenza viruses. In particular, the two isolates harbored three different mutation sites, indicating that they have different virulence characteristics. The mutations in the PB1-F2 and PA protein of WKU19-4(H1N1) indicate increasing polymerase activity. These results corroborate the kinetic growth data for WKU19-4 in MDCK cells: a dramatic increase in the viral titer after 12 h post-inoculation compared with that in the control group H1N1 (CA/04/09(pdm09)). The KNU18-64(H1N1) isolate carries mutations indicating an increase in mammal adaptation; this characterization was confirmed by the animal study in mice. The KNU18-64(H1N1) group showed the presence of viruses in the lungs at days 3 and 6 post-infection, with titers of 2.71 ± 0.16 and 3.71 ± 0.25 log10(TCID50/mL), respectively, whereas the virus was only detected in the WKU19-4(H1N1) group at day 6 post-infection, with a lower titer of 2.75 ± 0.51 log10(TCID50/mL). The present study supports the theory that there is a relationship between Korea and America with regard to reassortment to produce novel viral strains. Therefore, there is a need for increased surveillance of influenza virus circulation in free-flying and wild land-based birds in Korea, particularly with regard to Alaskan and Asian strains.


Assuntos
Animais Selvagens , Patos/virologia , Vírus da Influenza A Subtipo H1N1/classificação , Vírus da Influenza A Subtipo H1N1/genética , Influenza Aviária/epidemiologia , Influenza Aviária/virologia , Vírus Reordenados , Animais , Cães , Feminino , Genoma Viral , Genômica/métodos , História do Século XXI , Especificidade de Hospedeiro , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Influenza Aviária/história , Influenza Aviária/patologia , Células Madin Darby de Rim Canino , Camundongos , Filogenia , Vigilância em Saúde Pública , República da Coreia/epidemiologia
15.
Int J Mol Sci ; 20(14)2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31311082

RESUMO

Dengue, one of the most prevalent illnesses caused by dengue viruses that are members of the genus Flavivirus, is a significant global health problem. However, similar clinical symptoms and high antigenic homologies with other Flaviviruses in the endemic area pose difficulties for differential diagnosis of dengue from other arbovirus infections. Here, we investigated four types of recombinant envelope protein domain III (DV-rED III) derived from four dengue virus (DENV) serotypes for diagnostic potential in detecting IgM in acute phase (mainly 2-3 days after onset of fever). Each independent DV-1, -3, and -4-rED III-ELISA showed less than 60% sensitivity, but the combined results of DV-1, -3, and -4-rED III-ELISA led to sensitivity of 81.82% (18/22) (95% CI, 59.72 to 94.81) and 100% specificity (46/46) (95% CI, 92.29 to 100.00) as each antigen compensated the other antigen-derived negative result. In conclusion, the independent combination of data derived from each recombinant antigen (DV1-, DV3-, and DV4-rED III) showed comparable efficacy for the detection of IgM in patients with acute-phase dengue infection.


Assuntos
Vírus da Dengue/imunologia , Dengue/diagnóstico , Testes Sorológicos/métodos , Proteínas do Envelope Viral/imunologia , Adulto , Anticorpos Antivirais/imunologia , Dengue/imunologia , Dengue/virologia , Vírus da Dengue/genética , Epitopos/genética , Epitopos/imunologia , Feminino , Humanos , Imunoglobulina M/imunologia , Masculino , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Sensibilidade e Especificidade , Testes Sorológicos/normas , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética
16.
J Exp Med ; 215(7): 1839-1852, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29930103

RESUMO

A20 (TNFAIP3) and ABIN-1 (TNIP1) are candidate susceptibility genes for inflammatory bowel disease and other autoimmune or inflammatory diseases, but it is unclear how these proteins interact in vivo to prevent disease. Here we show that intestinal epithelial cell (IEC)-specific deletion of either A20 or ABIN-1 alone leads to negligible IEC loss, whereas simultaneous deletion of both A20 and ABIN-1 leads to rapid IEC death and mouse lethality. Deletion of both A20 and ABIN-1 from enteroids causes spontaneous cell death in the absence of microbes or hematopoietic cells. Studies with enteroids reveal that A20 and ABIN-1 synergistically restrict death by inhibiting TNF-induced caspase 8 activation and RIPK1 kinase activity. Inhibition of RIPK1 kinase activity alone, or caspase inhibition combined with RIPK3 deletion, abrogates IEC death by blocking both apoptosis and necroptosis in A20 and ABIN-1 double-deficient cells. These data show that the disease susceptibility proteins A20 and ABIN-1 synergistically prevent intestinal inflammation by restricting IEC death and preserving tissue integrity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Intestinos/citologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Animais , Apoptose , Caspases/metabolismo , Sobrevivência Celular , Enterocolite/patologia , Deleção de Genes , Camundongos , Organoides/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
17.
PLoS One ; 13(5): e0195893, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29718933

RESUMO

A20 is a ubiquitin-editing enzyme that is known to regulate inflammatory signaling and cell death. However, A20 mutations are also frequently found in multiple malignancies suggesting a potential role as a tumor suppressor as well. We recently described a novel role for A20 in regulating the wnt-beta-catenin signaling pathway and suppressing colonic tumor development in mice. The underlying mechanisms for this phenomenon are unclear. To study this, we first generated A20 knockout cell lines by genome-editing techniques. Using these cells, we show that loss of A20 causes dysregulation of wnt-dependent gene expression by RNAseq. Mechanistically, A20 interacts with a proximal signaling component of the wnt-signaling pathway, receptor interacting protein kinase 4 (RIPK4), and regulation of wnt-signaling by A20 occurs through RIPK4. Finally, similar to the mechanism by which A20 regulates other members of the receptor interacting protein kinase family, A20 modifies ubiquitin chains on RIPK4 suggesting a possible molecular mechanism for A20's control over the wnt-signaling pathway.


Assuntos
Proteínas Serina-Treonina Quinases/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Via de Sinalização Wnt , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Ligação Proteica , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/deficiência , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitinação
19.
Nat Immunol ; 16(6): 618-27, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25939025

RESUMO

A20 is an anti-inflammatory protein linked to multiple human diseases; however, the mechanisms by which A20 prevents inflammatory disease are incompletely defined. We found that A20-deficient T cells and fibroblasts were susceptible to caspase-independent and kinase RIPK3-dependent necroptosis. Global deficiency in RIPK3 significantly restored the survival of A20-deficient mice. A20-deficient cells exhibited exaggerated formation of RIPK1-RIPK3 complexes. RIPK3 underwent physiological ubiquitination at Lys5 (K5), and this ubiquitination event supported the formation of RIPK1-RIPK3 complexes. Both the ubiquitination of RIPK3 and formation of the RIPK1-RIPK3 complex required the catalytic cysteine of A20's deubiquitinating motif. Our studies link A20 and the ubiquitination of RIPK3 to necroptotic cell death and suggest additional mechanisms by which A20 might prevent inflammatory disease.


Assuntos
Cisteína Endopeptidases/metabolismo , Fibroblastos/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Linfócitos T/fisiologia , Animais , Apoptose/genética , Domínio Catalítico/genética , Cisteína Endopeptidases/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Células Jurkat , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexos Multiproteicos/genética , Necrose/genética , Ligação Proteica , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Ubiquitinação/genética , Ubiquitinas/metabolismo
20.
Immunity ; 42(1): 55-67, 2015 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-25607459

RESUMO

Inappropriate inflammasome activation contributes to multiple human diseases, but the mechanisms by which inflammasomes are suppressed are poorly understood. The NF-κB inhibitor A20 is a ubiquitin-modifying enzyme that might be critical in preventing human inflammatory diseases. Here, we report that A20-deficient macrophages, unlike normal cells, exhibit spontaneous NLRP3 inflammasome activity to LPS alone. The kinase RIPK3, but not the adaptor MyD88, is required for this response. In normal cells, A20 constitutively associates with caspase-1 and pro-IL-1ß, and NLRP3 activation further promotes A20 recruitment to the inflammasome. Pro-IL-1ß also co-immunoprecipitates with RIPK1, RIPK3, caspase-1, and caspase-8 in a complex that is modified with K63-linked and unanchored polyubiquitin. In A20-deficient macrophages, this pro-IL-1ß-associated ubiquitination is markedly increased in a RIPK3-dependent manner. Mass spectrometric and mutational analyses reveal that K133 of pro-IL-1ß is a physiological ubiquitination site that supports processing. Our study reveals a mechanism by which A20 prevents inflammatory diseases.


Assuntos
Proteínas de Transporte/metabolismo , Cisteína Endopeptidases/metabolismo , Inflamassomos/imunologia , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/fisiologia , Animais , Linhagem Celular , Cisteína Endopeptidases/genética , Análise Mutacional de DNA , Tolerância Imunológica , Interleucina-1beta/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Complexos Multiproteicos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Ubiquitinação/genética
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