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1.
Games Health J ; 13(1): 40-49, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38300525

RESUMO

Background: Children with attention-deficit hyperactivity disorder (ADHD) struggle with impaired attention, leading to impaired executive function and behavioral symptoms. In this study, we aimed to evaluate the effect of attention training on executive functions and behavioral symptoms in children with ADHD, in a tele-cognitive-rehabilitation setting. Methods: Thirty children (mean age: 9.93 ± 1.68 years, 21 boys) with ADHD were randomly assigned to 2 equal groups of attention training and active control group. Attentive Rehabilitation and Improvement of Attention (ARIA) and a class of storytelling were used for intervention in two groups, in an online platform. Continuous performance test, one-back test, Wisconsin card sorting test (WCST), Conner's parent rating scale, and behavioral rating inventory of executive function (BRIEF) were used for assessment in three-baseline, postintervention, and follow-up sessions. Repeated measures analysis of variances were used for analysis. Results: ARIA leads to significant improvement in omission error (P < 0.001), commission error (P = 0.006), and response time (P = 0.005) of continuous performance test, cluster (P = 0.001), but not preservation error (P = 0.110) of WCST, accuracy of NBT (P = 0.004) and the score of Conner's parent rating scale (P < 0.001) and BRIEF (P < 0.001). These results indicate improved attention and executive functions, amelioration of ADHD symptoms, and improved behavioral performance. Conclusion: This study suggests that attention can be trained through tele-cognitive rehabilitation using a remediation program in children with ADHD. The effectiveness of this training can be confirmed by examining the transfer of training effects to other untrained cognitive domains, executive functions, symptoms of ADHD, and behavioral performance.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Coronavirus , Masculino , Criança , Humanos , Função Executiva/fisiologia , Transtorno do Deficit de Atenção com Hiperatividade/terapia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Treino Cognitivo , Sintomas Comportamentais , Cognição
2.
Sci Rep ; 14(1): 4509, 2024 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-38402266

RESUMO

The 5'-mRNA-cap formation is a conserved process in protection of mRNA in eukaryotic cells, resulting in mRNA stability and efficient translation. In humans, two methyltransferases, RNA cap guanine-N7 methyltransferase (hRNMT) and cap-specific nucleoside-2'-O-methyltransferase 1 (hCMTr1) methylate the mRNA resulting in cap0 (N7mGpppN-RNA) and cap1 (N7mGpppN2'-Om-RNA) formation, respectively. Coronaviruses mimic this process by capping their RNA to evade human immune systems. The coronaviral nonstructural proteins, nsp14 and nsp10-nsp16, catalyze the same reactions as hRNMT and hCMTr1, respectively. These two viral enzymes are important targets for development of inhibitor-based antiviral therapeutics. However, assessing the selectivity of such inhibitors against human corresponding proteins is crucial. Human RNMTs have been implicated in proliferation of cancer cells and are also potential targets for development of anticancer therapeutics. Here, we report the development and optimization of a radiometric assay for hRNMT, full kinetic characterization of its activity, and optimization of the assay for high-throughput screening with a Z-factor of 0.79. This enables selectivity determination for a large number of hits from various screening of coronaviral methyltransferases, and also screening hRNMT for discovery of inhibitors and chemical probes that potentially could be used to further investigate the roles RNMTs play in cancers.


Assuntos
Infecções por Coronavirus , Coronavirus , Humanos , Coronavirus/genética , Guanina/metabolismo , Metiltransferases/metabolismo , Capuzes de RNA/metabolismo , RNA Mensageiro/genética , RNA Viral/genética , Proteínas não Estruturais Virais/genética
3.
Clin Cardiol ; 47(2): e24240, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38402574

RESUMO

BACKGROUND: Since 2019, Coronavirus disease-2019 (COVID-19) has raised unprecedented global health crisis. The incidence and impact of atrial fibrillation (AF) on patients with COVID-19 remain unclearly defined. METHODS: We conducted a retrospective cohort study using ICD-10 codes to identify patients with a primary diagnosis of COVID-19 with or without AF in National Inpatient Sample Database 2020. We compared the outcome of COVID-19 patients with a concurrent diagnosis of AF with those without. HYPOTHESIS: AF will adversely affect the prognosis of hospitalized COVID-19 patients. RESULTS: A total of 211 619 patients with a primary diagnosis of COVID-19 were identified. Among these patients, 31 923 (15.08%) had a secondary diagnosis of AF. Before propensity score matching, COVID-AF cohort was older (75.8 vs. 62.2-year-old, p < .001) and had more men (57.5% vs. 52.0%, p < .001). It is associated with more comorbidities, mainly including diabetes mellitus (43.7% vs. 39.9%, p < .001), hyperlipidemia (54.6% vs. 39.8%, p < .001), chronic kidney disease (34.5% vs. 17.0%, p < .001), coronary artery disease (35.3% vs. 14.4%, p < .001), anemia (27.8% vs. 18.6%, p < .001), and cancer (4.8% vs. 3.4%, p < .001). After performing propensity score match, a total of 31 862 patients were matched within each group. COVID-AF cohort had higher inpatient mortality (22.2% vs. 15.3%, p < .001) and more complications, mainly including cardiac arrest (3.9% vs. 2.3%, p < .001), cardiogenic shock (0.9% vs. 0.3%, p < .001), hemorrhagic stroke (0.4% vs. 0.3%, p = .025), and ischemic stroke (1.3% vs. 0.7%, p < .001). COVID-AF cohort was more costly, with a longer length of stay, and a higher total charge. CONCLUSION: AF is common in patients hospitalized for COVID-19, and is associated with poorer in-hospital mortality, immediate complications and increased healthcare resource utilization.


Assuntos
Fibrilação Atrial , COVID-19 , Coronavirus , Masculino , Humanos , Pessoa de Meia-Idade , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Incidência , Estudos Retrospectivos , COVID-19/complicações , COVID-19/epidemiologia
4.
Alzheimer Dis Assoc Disord ; 38(1): 65-69, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38372646

RESUMO

OBJECTIVE: In New York City in 2020 the pandemic shut down in-person research. Icahn School of Medicine's Alzheimer's Disease Research Center transitioned longitudinal evaluations from in-person to telephone to enhance equity of access. We assessed diverse research participants' and clinical research coordinators' (CRC) satisfaction with remote evaluation and examined sociodemographic, cognitive, and behavioral factors that might impact satisfaction. METHODS: Data collected: 241 participants with Clinical Dementia Rating (CDR) = 0/0.5 (3/2020 to 6/2021). A Telehealth Satisfaction Questionnaire for CRCs and participants was administered at the end of remote evaluations. We compared Telehealth Satisfaction Questionnaire items by CDR and Geriatric Depression Scale. RESULTS: Participants' mean age was 78.4, 61.4% were females, 16.2% were Hispanic, 17.1% Asian, 15.8% were non-Hispanic black, and 72.6% CDR = 0. Participant satisfaction was high [14.1 ± 1.4 (out of 15)] but was lower among those with depression. CRC satisfaction was high [16.9 ± 1.8 (out of 18)] but was lower concerning the ability to explain the test battery and interact with participants with CDR = 0.5. CONCLUSION: Telephone research assessments provide flexibility in a hybrid model. They offer equitable access to research participation for those who do not use computer technology and may promote the retention of diverse elderly research participants.


Assuntos
Doença de Alzheimer , Coronavirus , Feminino , Humanos , Idoso , Masculino , Doença de Alzheimer/psicologia , Inquéritos e Questionários , Cognição , Satisfação Pessoal
5.
Nat Commun ; 15(1): 1048, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316817

RESUMO

We recently detected a HKU4-related coronavirus in subgenus Merbecovirus (named pangolin-CoV-HKU4-P251T) from a Malayan pangolin1. Here we report isolation and characterization of pangolin-CoV-HKU4-P251T, the genome sequence of which is closest to that of a coronavirus from the greater bamboo bat (Tylonycteris robustula) in Yunnan Province, China, with a 94.3% nucleotide identity. Pangolin-CoV-HKU4-P251T is able to infect human cell lines, and replicates more efficiently in cells that express human-dipeptidyl-peptidase-4 (hDPP4)-expressing and pangolin-DPP4-expressing cells than in bat-DPP4-expressing cells. After intranasal inoculation with pangolin-CoV-HKU4-P251, hDPP4-transgenic female mice are likely infected, showing persistent viral RNA copy numbers in the lungs. Progressive interstitial pneumonia developed in the infected mice, characterized by the accumulation of macrophages, and increase of antiviral cytokines, proinflammatory cytokines, and chemokines in lung tissues. These findings suggest that the pangolin-borne HKU4-related coronavirus has a potential for emerging as a human pathogen by using hDPP4.


Assuntos
Quirópteros , Infecções por Coronavirus , Coronavirus , Coronavírus da Síndrome Respiratória do Oriente Médio , Humanos , Feminino , Animais , Camundongos , Pangolins , Camundongos Transgênicos , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , China , Citocinas , Coronavírus da Síndrome Respiratória do Oriente Médio/genética
6.
Sheng Wu Gong Cheng Xue Bao ; 40(2): 419-433, 2024 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-38369830

RESUMO

Coronaviruses pose significant threats to animal and human health, leading to the development of various infectious diseases. It is critical to develop effective vaccines and antiviral medicines to prevent and treat these diseases. The coronavirus genome encodes several types of proteins, including structural, nonstructural, and accessory proteins. Among them, nonstructural protein 13 (NSP13) helicase plays a crucial role in regulating viral replication and the innate immune response of the host. Therefore, it serves as a vital target for the development of anti-coronavirus drugs. This paper presents a comprehensive review of NSP13 research, covering its source, structure, sequence conservation, unwinding mechanism, enzyme inhibitors, protein interaction, and immune regulation. Additionally, the paper analyzes the current challenges in NSP13 research and aims to provide a theoretical foundation for the development of broad-spectrum antiviral drugs targeting NSP13.


Assuntos
Infecções por Coronavirus , Coronavirus , Animais , Humanos , DNA Helicases/metabolismo , Proteínas não Estruturais Virais/genética , Replicação Viral , RNA Helicases/genética , RNA Helicases/metabolismo
7.
Int J Geriatr Psychiatry ; 39(1): e6045, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38161288

RESUMO

OBJECTIVES: We examined the impact of the social network before the coronavirus pandemic on loneliness and depressed mood during the pandemic in older European individuals, and how these relationships differ between different European countries. METHODS: Data of N = 19,999 persons (age: M = 69.18 years; 51% female) from the pan-European longitudinal survey of health, ageing and retirement in Europe, interviewed between October 2019 and March 2020 (Wave 8) and between June and August 2020 (Corona Questionnaire 1), were used. To test the models we employed path analyses, controlling for age, gender, education, and occupational status. Models were also run separately in collectivistic (Romania, Slovenia, Croatia, and Greece) and individualistic (Netherlands, Belgium, Denmark, and France) country groups. RESULTS: A larger social network before the pandemic reduced the probability of an increase in loneliness and depression. The negative association between social network size and increase in loneliness was stronger in collectivist countries than in individualist ones. Moreover, an increase in loneliness increased the probability of feeling depressed. CONCLUSIONS: It appears that pre-pandemic social networks served as a buffer to negative mental health consequences of the pandemic in older Europeans. In fact, this association was stronger in collectivist than for individualist countries. While this underscores the importance of social connectedness, it also stresses the vulnerability of socially isolated individuals regarding loneliness and depression. Future work should thus focus on supporting social networks in older adults.


Assuntos
Coronavirus , Solidão , Humanos , Feminino , Idoso , Masculino , Solidão/psicologia , Depressão/epidemiologia , Pandemias , Rede Social
8.
Appl Microbiol Biotechnol ; 108(1): 137, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38229331

RESUMO

Porcine epidemic diarrhea virus (PEDV), an enteric coronavirus, induces severe vomiting and acute watery diarrhea in unweaned piglets. The pig industry has suffered tremendous financial losses due to the high mortality rate of piglets caused by PEDV. Consequently, a simple and rapid on-site diagnostic technology is crucial for preventing and controlling PEDV. This study established a detection method for PEDV using recombinase-aided amplification (RAA) and Pyrococcus furiosus Argonaute (PfAgo), which can detect 100 copies of PEDV without cross-reactivity with other pathogens. The entire reaction of RAA and PfAgo to detect PEDV does not require sophisticated instruments, and the reaction results can be observed with the naked eye. Overall, this integrated RAA-PfAgo cleavage assay is a practical tool for accurately and quickly detecting PEDV. KEY POINTS: • PfAgo has the potential to serve as a viable molecular diagnostic tool for the detection and diagnosis of viral genomes • The RAA-PfAgo detection technique has a remarkable level of sensitivity and specificity • The RAA-PfAgo detection system can identify PEDV without needing advanced equipment.


Assuntos
Infecções por Coronavirus , Coronavirus , Vírus da Diarreia Epidêmica Suína , Pyrococcus furiosus , Doenças dos Suínos , Animais , Suínos , Vírus da Diarreia Epidêmica Suína/genética , Pyrococcus furiosus/genética , Doenças dos Suínos/diagnóstico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/veterinária , Diarreia , Recombinases
9.
EMBO J ; 43(2): 151-167, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38200146

RESUMO

Coronaviruses are a group of related RNA viruses that cause respiratory diseases in humans and animals. Understanding the mechanisms of translation regulation during coronaviral infections is critical for developing antiviral therapies and preventing viral spread. Translation of the viral single-stranded RNA genome in the host cell cytoplasm is an essential step in the life cycle of coronaviruses, which affects the cellular mRNA translation landscape in many ways. Here we discuss various viral strategies of translation control, including how members of the Betacoronavirus genus shut down host cell translation and suppress host innate immune functions, as well as the role of the viral non-structural protein 1 (Nsp1) in the process. We also outline the fate of viral RNA, considering stress response mechanisms triggered in infected cells, and describe how unique viral RNA features contribute to programmed ribosomal -1 frameshifting, RNA editing, and translation shutdown evasion.


Assuntos
Infecções por Coronavirus , Coronavirus , Animais , Humanos , Coronavirus/genética , Infecções por Coronavirus/genética , Betacoronavirus/fisiologia , Antivirais/farmacologia , RNA Viral/genética
10.
West J Emerg Med ; 25(1): 101-110, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38205991

RESUMO

Introduction: People without reliable access to healthcare are more likely to be diagnosed with late-stage cancer that could have been treated more effectively if diagnosed earlier. Emergency departments (ED) may be a novel place for cancer screening education for underserved patients. In this study we sought to determine patient characteristics and barriers to cancer screening for those patients who presented to a large, academic safety-net ED and were overdue for breast, cervical, and colorectal cancer screening since the coronavirus 2019 (COVID-19) pandemic. Methods: Adult ED patients eligible for at least one cancer screening based on US Preventive Serivces Task Force guidelines completed a web-based survey. We examined the association of demographic characteristics and having a personal physician with being overdue on screening using chi-square or the Fisher exact test for categorical variables and t-tests for continuous variables. Results: Of 221 participants, 144 were eligible for colorectal, 96 for cervical, and 55 for breast cancer screening. Of eligible patients, 46% (25/55) were overdue for breast cancer screening, 43% (62/144) for colorectal, and 40% (38/96) for cervical cancer screening. There were no significant characteristics associated with breast cancer screening. Being overdue for cervical cancer screening was significantly more likely for patients who were of Asian race (P = 0.02), had less than a high school diploma (P = 0.01), and were without a routine checkup within the prior five years (P = 0.01). Overdue for colorectal cancer screening was associated with patients not having insurance (P = 0.04), being in their 40s (P = 0.03), being Hispanic (P = 0.01), and not having a primary care physician (P=0.01). Of 97 patients overdue for at least one screening, the most common barriers were cost (37%), lack of time (37%), and lack of knowledge of screening recommendations (34%). Only 8.3% reported that the COVID-19 pandemic delayed their screening. Conclusion: The ED may be a novel setting to target patients for cancer screening education. Future work that refers patients to free screening programs and primary care physicians may help improve disparities in cancer screening and cancer mortality rates for underserved populations.


Assuntos
Neoplasias da Mama , Neoplasias Colorretais , Infecções por Coronavirus , Coronavirus , Neoplasias do Colo do Útero , Adulto , Feminino , Humanos , Detecção Precoce de Câncer , Pandemias , Neoplasias do Colo do Útero/diagnóstico , Serviço Hospitalar de Emergência , Neoplasias da Mama/diagnóstico , Neoplasias Colorretais/diagnóstico
12.
J Anal Psychol ; 69(1): 6-26, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38197543

RESUMO

The "health emergency" forced analysts to seek new ways of continuing with analysis. The article focuses, in particular, on the changes brought about in the setting by the presence of the sanitary mask, following a line that begins with the theme of the "mask" in the collective uses of human cultures, and develops through the Jungian concept of persona, as opposed to the "face" that may convey an authentic image of oneself. A clinical vignette illustrates the issues that the mask raises in the setting by obstructing the communication of emotions. When there is no transformative processing of concrete data, "unmasking" can also lead to an uncanny encounter and to moments of darkness and confusion in analysis, when the analyst experiences the kind of "unconscious identity" between therapist and patient that Jung defined as nigredo. The article is intended as a contribution to the analytic community's current reflections on the new and unforeseen challenges encountered in analysis at the time of the Coronavirus. It is possible to learn from these experiences with a view to integrating new elements and thus modify one's own internal setting, the compass with which each analyst orientates himself.


'L'urgence sanitaire' a forcé les analystes à rechercher de nouvelles manières de poursuivre le travail analytique. Cet article met l'accent en particulier sur les changements survenus dans le cadre du fait du port du masque sanitaire; l'article suit un fil conducteur qui commence avec le thème du 'masque' dans les usages collectifs des cultures humaines et se poursuit avec le concept Jungien de persona, en opposition avec le 'visage' qui peut communiquer une image authentique de soi. Une vignette clinique illustre les problèmes que le masque soulève dans la situation analytique en entravant la communication d'émotions. Quand il n'y a pas de processus de transformation des données concrètes, 'démasquer' peut également mener à une rencontre étrange et à des moments de ténèbres et de confusion dans l'analyse, quand l'analyste fait l'expérience du type 'd'identité inconsciente' entre le thérapeute et le patient que Jung a défini comme nigredo. Cet article a pour but de contribuer aux réflexions actuelles de la communauté analytique en ce qui concerne les défis nouveaux et inattendus rencontrés dans l'analyse dans la période du Coronavirus. Il est possible de tirer des leçons de ces expériences afin d'intégrer de nouveaux éléments et ainsi de modifier notre propre cadre interne, la boussole avec laquelle chaque analyste s'oriente.


La "emergencia sanitaria" obligó a los analistas a buscar nuevas formas de continuar con el análisis. El artículo se centra, en particular, en los cambios provocados en el encuadre analítico por la presencia de la mascarilla sanitaria. Presenta un desarrollo a partir del tema de la "máscara" en los usos colectivos de las culturas humanas, y continúa a través del concepto junguiano de persona, en contraposición al de "rostro", el cual puede transmitir una imagen auténtica de uno mismo. Una viñeta clínica ilustra los problemas que plantea la máscara en el entorno al obstruir la comunicación de las emociones. Cuando no hay un procesamiento transformador de los datos concretos, el "desenmascaramiento" también puede conducir a un encuentro misterioso y a momentos de oscuridad y confusión en el análisis, cuando el analista experimenta una forma de "identidad inconsciente" entre terapeuta y paciente que Jung definió como nigredo. El artículo pretende ser una contribución a las reflexiones actuales de la comunidad analítica sobre los nuevos e imprevistos desafíos encontrados en el análisis en la época del Coronavirus. Es posible aprender de estas experiencias con vistas a integrar nuevos elementos y así modificar la propia configuración interna, la brújula con la que cada analista se orienta.


Assuntos
Coronavirus , Humanos , Máscaras , Emoções , Comunicação
13.
Virol J ; 21(1): 30, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38273382

RESUMO

Viruses have developed many mechanisms by which they can stimulate or inhibit inflammation and cause various diseases, including viral respiratory diseases that kill many people every year. One of the mechanisms that viruses use to induce or inhibit inflammation is exosomes. Exosomes are small membrane nanovesicles (30-150 nm) released from cells that contain proteins, DNA, and coding and non-coding RNA species. They are a group of extracellular vesicles that cells can take up to produce and mediate communication. Intercellular effect exosomes can deliver a broad confine of biological molecules, containing nucleic acids, proteins, and lipids, to the target cell, where they can convey therapeutic or pathogenic consequences through the modulation of inflammation and immune processes. Recent research has shown that exosomes can deliver entire virus genomes or virions to distant target cells, then the delivered viruses can escape the immune system and infect cells. Adenoviruses, orthomyxoviruses, paramyxoviruses, respiratory syncytial viruses, picornaviruses, coronaviruses, and rhinoviruses are mostly related to respiratory diseases. In this article, we will first discuss the current knowledge of exosomes. We will learn about the relationship between exosomes and viral infections, and We mention the inflammations caused by viruses in the airways, the role of exosomes in them, and finally, we examine the relationship between the viruses as mentioned earlier, and the regulation of inflammatory pathways that play a role in causing the disease.


Assuntos
Coronavirus , Exossomos , Doenças Respiratórias , Viroses , Humanos , Inflamação
14.
Rev Assoc Med Bras (1992) ; 70(1): e20231004, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38294125

RESUMO

OBJECTIVE: The objective of the present study was to verify the indication of common mental disorder and changes in healthy lifestyle among individuals affected by coronavirus disease, as well as to evaluate if changes in healthy lifestyle are predictors of common mental disorder. METHODS: This descriptive, cross-sectional study employed an exploratory approach and quantitative methodology, using the Self-Reporting Questionnaire to assess the indication of common mental disorder and questions regarding healthy lifestyle during the pandemic. RESULTS: A total of 280 individuals affected by coronavirus disease, aged 18 years and above, participated in the study. The average indication for common mental disorder was 5.0±5.34. The average age was characterized by adults (41.24±14.03 years), with the majority being women (57.9%), White (51.4%), and those in stable relationships (55.7%). Worsening sleep quality (ß==6.327; p<0.001) was the main predictor of common mental disorder, followed by female gender (ß==2.814; p<0.001) and worsening dietary habits (ß==2.227; p<0.012). CONCLUSION: These factors should be considered in the assessment of individuals affected by coronavirus disease to provide comprehensive care.


Assuntos
Infecções por Coronavirus , Coronavirus , Transtornos Mentais , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Estudos Transversais , Infecções por Coronavirus/epidemiologia , Estilo de Vida Saudável , Transtornos Mentais/epidemiologia
15.
J Virol ; 98(2): e0137723, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38197629

RESUMO

Gut microbiota-derived metabolites are important for the replication and pathogenesis of many viruses. However, the roles of bacterial metabolites in swine enteric coronavirus (SECoV) infection remain poorly understood. Recent studies show that SECoVs infection in vivo significantly alters the composition of short-chain fatty acids (SCFAs)-producing gut microbiota. This prompted us to investigate whether and how SCFAs impact SECoV infection. Employing alphacoronavirus transmissible gastroenteritis virus (TGEV), a major cause of diarrhea in piglets, as a model, we found that SCFAs, particularly butyrate, enhanced TGEV infection both in porcine intestinal epithelial cells and swine testicular (ST) cells at the late stage of viral infection. This effect depended on the inhibited productions of virus-induced type I interferon (IFN) and downstream antiviral IFN-stimulated genes (ISGs) by butyrate. Mechanistically, butyrate suppressed the expression of retinoic acid-inducible gene I (RIG-I), a key viral RNA sensor, and downstream mitochondrial antiviral-signaling (MAVS) aggregation, thereby impairing type I IFN responses and increasing TGEV replication. Using pharmacological and genetic approaches, we showed that butyrate inhibited RIG-I-induced type I IFN signaling by suppressing class I histone deacetylase (HDAC). In summary, we identified a novel mechanism where butyrate enhances TGEV infection by suppressing RIG-I-mediated type I IFN responses. Our findings highlight that gut microbiota-derived metabolites like butyrate can be exploited by SECoV to dampen innate antiviral immunity and establish infection in the intestine.IMPORTANCESwine enteric coronaviruses (SECoVs) infection in vivo alters the composition of short-chain fatty acids (SCFAs)-producing gut microbiota, but whether microbiota-derived SCFAs impact coronavirus gastrointestinal infection is largely unknown. Here, we demonstrated that SCFAs, particularly butyrate, substantially increased alphacoronavirus TGEV infection at the late stage of infection, without affecting viral attachment or internalization. Furthermore, enhancement of TGEV by butyrate depended on impeding virus-induced type I interferon (IFN) responses. Mechanistically, butyrate suppressed the cytoplasmic viral RNA sensor RIG-I expression and downstream type I IFN signaling activation by inhibiting class I HDAC, thereby promoting TGEV infection. Our work reveals novel functions of gut microbiota-derived SCFAs in enhancing enteric coronavirus infection by impairing RIG-I-dependent type I IFN responses. This implies that bacterial metabolites could be therapeutic targets against SECoV infection by modulating antiviral immunity in the intestine.


Assuntos
Infecções por Coronavirus , Coronavirus , Microbioma Gastrointestinal , Interferon Tipo I , Vírus da Gastroenterite Transmissível , Animais , Suínos , Vírus da Gastroenterite Transmissível/genética , Coronavirus/genética , Butiratos/farmacologia , RNA Viral
16.
J Virol ; 98(2): e0181423, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38289103

RESUMO

HDAC6, a structurally and functionally unique member of the histone deacetylase (HDAC) family, is an important host factor that restricts viral infection. The broad-spectrum antiviral activity of HDAC6 makes it a potent antiviral agent. Previously, we found that HDAC6 functions to antagonize porcine deltacoronavirus (PDCoV), an emerging enteropathogenic coronavirus with zoonotic potential. However, the final outcome is typically a productive infection that materializes as cells succumb to viral infection, indicating that the virus has evolved sophisticated mechanisms to combat the antiviral effect of HDAC6. Here, we demonstrate that PDCoV nonstructural protein 5 (nsp5) can cleave HDAC6 at glutamine 519 (Q519), and cleavage of HDAC6 was also detected in the context of PDCoV infection. More importantly, the anti-PDCoV activity of HDAC6 was damaged by nsp5 cleavage. Mechanistically, the cleaved HDAC6 fragments (amino acids 1-519 and 520-1159) lost the ability to degrade PDCoV nsp8 due to their impaired deacetylase activity. Furthermore, nsp5-mediated cleavage impaired the ability of HDAC6 to activate RIG-I-mediated interferon responses. We also tested three other swine enteric coronaviruses (transmissible gastroenteritis virus, porcine epidemic diarrhea virus, and swine acute diarrhea syndrome-coronavirus) and found that all these coronaviruses have adopted similar mechanisms to cleave HDAC6 in both an overexpression system and virus-infected cells, suggesting that cleavage of HDAC6 is a common strategy utilized by swine enteric coronaviruses to antagonize the host's antiviral capacity. Together, these data illustrate how swine enteric coronaviruses antagonize the antiviral function of HDAC6 to maintain their infection, providing new insights to the interaction between virus and host.IMPORTANCEViral infections and host defenses are in constant opposition. Once viruses combat or evade host restriction, productive infection is achieved. HDAC6 is a broad-spectrum antiviral protein that has been demonstrated to inhibit many viruses, including porcine deltacoronavirus (PDCoV). However, whether HDAC6 is reciprocally targeted and disabled by viruses remains unclear. In this study, we used PDCoV as a model and found that HDAC6 is targeted and cleaved by nsp5, a viral 3C-like protease. The cleaved HDAC6 loses its deacetylase activity as well as its ability to degrade viral proteins and activate interferon responses. Furthermore, this cleavage mechanism is shared among other swine enteric coronaviruses. These findings shed light on the intricate interplay between viruses and HDAC6, highlighting the strategies employed by viruses to evade host antiviral defenses.


Assuntos
Infecções por Coronavirus , Coronavirus , Doenças dos Suínos , Animais , Coronavirus/fisiologia , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/virologia , Deltacoronavirus , Interferons/metabolismo , Suínos , Doenças dos Suínos/virologia
17.
J Virol ; 98(2): e0168223, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38289117

RESUMO

Porcine deltacoronavirus (PDCoV) has caused enormous economic losses to the global pig industry. However, the immune escape mechanism of PDCoV remains to be fully clarified. Transcriptomic analysis revealed a high abundance of interferon (IFN)-induced protein with tetratricopeptide repeats 3 (IFIT3) transcripts after PDCoV infection, which initially implied a correlation between IFIT3 and PDCoV. Further studies showed that PDCoV nsp5 could antagonize the host type I interferon signaling pathway by cleaving IFIT3. We demonstrated that PDCoV nsp5 cleaved porcine IFIT3 (pIFIT3) at Gln-406. Similar cleavage of endogenous IFIT3 has also been observed in PDCoV-infected cells. The pIFIT3-Q406A mutant was resistant to nsp5-mediated cleavage and exhibited a greater ability to inhibit PDCoV infection than wild-type pIFIT3. Furthermore, we found that cleavage of IFIT3 is a common characteristic of nsp5 proteins of human coronaviruses, albeit not alphacoronavirus. This finding suggests that the cleavage of IFIT3 is an important mechanism by which PDCoV nsp5 antagonizes IFN signaling. Our study provides new insights into the mechanisms by which PDCoV antagonizes the host innate immune response.IMPORTANCEPorcine deltacoronavirus (PDCoV) is a potential emerging zoonotic pathogen, and studies on the prevalence and pathogenesis of PDCoV are ongoing. The main protease (nsp5) of PDCoV provides an excellent target for antivirals due to its essential and conserved function in the viral replication cycle. Previous studies have revealed that nsp5 of PDCoV antagonizes type I interferon (IFN) production by targeting the interferon-stimulated genes. Here, we provide the first demonstration that nsp5 of PDCoV antagonizes IFN signaling by cleaving IFIT3, which affects the IFN response after PDCoV infection. Our findings reveal that PDCoV nsp5 is an important interferon antagonist and enhance the understanding of immune evasion by deltacoronaviruses.


Assuntos
Infecções por Coronavirus , Coronavirus , Interferon Tipo I , Doenças dos Suínos , Animais , Suínos , Humanos , Deltacoronavirus/metabolismo , Coronavirus/fisiologia , Interferon beta/metabolismo , Transdução de Sinais , Imunidade Inata , Interferon Tipo I/metabolismo , Fatores de Transcrição/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
18.
Vet Microbiol ; 290: 109956, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38217919

RESUMO

Swine enteric coronaviruses, such as porcine epidemic diarrhea virus (PEDV) or transmissible gastroenteritis virus (TGEV), have risen concern for the porcine industry and research community due to the increase in their virulence, their potential recombination capacity and the emergence of new variants. This in vivo study aims to compare the impact of three different strains of swine enteric coronaviruses [(two G1b (S-INDEL) PEDV strains and a recombinant TGEV-PEDV or Swine enteric coronavirus (SeCoV)] in the intestine of 3-weeks-old infected piglets, focusing on the pathology and main components of the intestinal barrier, including the number of goblet cells, and the expression of IgA as well as FoxP3, a regulatory T cell marker. Severity of lesions was evidenced in the three infected groups and was highly correlated with the viral load in feces and the frequency of viral antigen-positive cells. Furthermore, higher cellular death together with an increase in the expression of the FoxP3 marker was detected in the duodenum and jejunum of infected animals at 3 days post-infection. Our results highlight a recruitment of FoxP3+ cells in the small intestine of infected animals which may represent a response to the tissue damage caused by viral replication and cell death. Further studies should be addressed to determine the potential role of these cells during swine enteric coronavirus infections.


Assuntos
Infecções por Coronavirus , Coronavirus , Vírus da Diarreia Epidêmica Suína , Doenças dos Suínos , Vírus da Gastroenterite Transmissível , Suínos , Animais , Coronavirus/genética , Infecções por Coronavirus/veterinária , Intestino Delgado , Vírus da Diarreia Epidêmica Suína/genética , Fatores de Transcrição Forkhead/genética
19.
J Virol ; 98(2): e0177723, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38289106

RESUMO

Rubella virus encodes a nonstructural polyprotein with RNA polymerase, methyltransferase, and papain-like cysteine protease activities, along with a putative macrodomain of unknown function. Macrodomains bind ADP-ribose adducts, a post-translational modification that plays a key role in host-virus conflicts. Some macrodomains can also remove the mono-ADP-ribose adduct or degrade poly-ADP-ribose chains. Here, we report high-resolution crystal structures of the macrodomain from rubella virus nonstructural protein p150, with and without ADP-ribose binding. The overall fold is most similar to macroD-type macrodomains from various nonviral species. The specific composition and structure of the residues that coordinate ADP-ribose in the rubella virus macrodomain are most similar to those of macrodomains from alphaviruses. Isothermal calorimetry shows that the rubella virus macrodomain binds ADP-ribose in solution. Enzyme assays show that the rubella virus macrodomain can hydrolyze both mono- and poly-ADP-ribose adducts. Site-directed mutagenesis identifies Asn39 and Cys49 required for mono-ADP-ribosylhydrolase (de-MARylation) activity.IMPORTANCERubella virus remains a global health threat. Rubella infections during pregnancy can cause serious congenital pathology, for which no antiviral treatments are available. Our work demonstrates that, like alpha- and coronaviruses, rubiviruses encode a mono-ADP-ribosylhydrolase with a structurally conserved macrodomain fold to counteract MARylation by poly (ADP-ribose) polymerases (PARPs) in the host innate immune response. Our structural data will guide future efforts to develop novel antiviral therapeutics against rubella or infections with related viruses.


Assuntos
Coronavirus , Rubéola (Sarampo Alemão) , Humanos , Vírus da Rubéola/genética , Vírus da Rubéola/metabolismo , Ribose , Poli(ADP-Ribose) Polimerases/genética , Poli Adenosina Difosfato Ribose , Coronavirus/metabolismo , Adenosina Difosfato Ribose/genética , Adenosina Difosfato Ribose/metabolismo
20.
Virus Res ; 340: 199303, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38145807

RESUMO

Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus (CoV) that mainly causes acute diarrhea/vomiting, dehydration, and mortality in piglets, possessing economic losses and public health concerns. However, there are currently no proven effective antiviral agents against PDCoV. Cepharanthine (CEP) is a naturally occurring alkaloid used as a traditional remedy for radiation-induced symptoms, but its underlying mechanism of CEP against PDCoV has remained elusive. The aim of this study was to investigate the anti-PDCoV effects and mechanisms of CEP in LLC-PK1 cells. The results showed that the antiviral activity of CEP was based on direct action on cells, preventing the virus from attaching to host cells and virus replication. Importantly, Surface Plasmon Resonance (SPR) results showed that CEP has a moderate affinity to PDCoV receptor, porcine aminopeptidase N (pAPN) protein. AutoDock predicted that CEP can form hydrogen bonds with amino acid residues (R740, N783, and R790) in the binding regions of PDCoV and pAPN. In addition, RT-PCR results showed that CEP treatment could significantly reduce the transcription of ZBP1, cytokine (IL-1ß and IFN-α) and chemokine genes (CCL-2, CCL-4, CCL-5, CXCL-2, CXCL-8, and CXCL-10) induced by PDCoV. Western blot analysis revealed that CEP could inhibit viral replication by inducing autophagy. In conclusion, our results suggest that the anti-PDCoV activity of CEP is not only relies on competing the virus binding with pAPN, but also affects the proliferation of the virus in vitro by downregulating the excessive immune response caused by the virus and inducing autophagy. CEP emerges as a promising candidate for potential anti-PDCoV therapeutic development.


Assuntos
Benzodioxóis , Benzilisoquinolinas , Infecções por Coronavirus , Coronavirus , Deltacoronavirus , Doenças dos Suínos , Animais , Suínos , Coronavirus/genética , Antígenos CD13/metabolismo
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