RESUMEN
Human humoral immune responses to SARS-CoV-2 vaccines exhibit substantial inter-individual variability and have been linked to vaccine efficacy. To elucidate the underlying mechanism behind this variability, we conducted a genome-wide association study (GWAS) on the anti-spike IgG serostatus of UK Biobank participants who were previously uninfected by SARS-CoV-2 and had received either the first dose (n = 54,066) or the second dose (n = 46,232) of COVID-19 vaccines. Our analysis revealed significant genome-wide associations between the IgG antibody serostatus following the initial vaccine and human leukocyte antigen (HLA) class II alleles. Specifically, the HLA-DRB1∗13:02 allele (MAF = 4.0%, OR = 0.75, p = 2.34e-16) demonstrated the most statistically significant protective effect against IgG seronegativity. This protective effect was driven by an alteration from arginine (Arg) to glutamic acid (Glu) at position 71 on HLA-DRß1 (p = 1.88e-25), leading to a change in the electrostatic potential of pocket 4 of the peptide binding groove. Notably, the impact of HLA alleles on IgG responses was cell type specific, and we observed a shared genetic predisposition between IgG status and susceptibility/severity of COVID-19. These results were replicated within independent cohorts where IgG serostatus was assayed by two different antibody serology tests. Our findings provide insights into the biological mechanism underlying individual variation in responses to COVID-19 vaccines and highlight the need to consider the influence of constitutive genetics when designing vaccination strategies for optimizing protection and control of infectious disease across diverse populations.
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COVID-19 , Inmunoglobulina G , Humanos , Formación de Anticuerpos/genética , Vacunas contra la COVID-19 , Estudio de Asociación del Genoma Completo , COVID-19/genética , COVID-19/prevención & control , SARS-CoV-2 , VacunaciónRESUMEN
c-FLIP functions as a dual regulator of apoptosis and inflammation, yet its implications in Zika virus (ZIKV) infection remain partially understood, especially in the context of ZIKV-induced congenital Zika syndrome (CZS) where both apoptosis and inflammation play pivotal roles. Our findings demonstrate that c-FLIP promotes ZIKV infection in placental cells and myeloid-derived macrophages, involving inflammation and caspase-8/3-mediated apoptosis. Moreover, our observations reveal that c-FLIP augments ZIKV infection in multiple tissues, including blood cell, spleen, uterus, testis, and the brain of mice. Notably, the partial deficiency of c-FLIP provides protection to embryos against ZIKV-induced CZS, accompanied by a reduction in caspase-3-mediated apoptosis. Additionally, we have found a distinctive parental effect of c-FLIP influencing ZIKV replication in fetal heads. In summary, our study reveals the critical role of c-FLIP as a positive regulator in caspase-8/3-mediated apoptosis during ZIKV infection, significantly contributing to the development of CZS.
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Apoptosis , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Caspasa 3 , Caspasa 8 , Infección por el Virus Zika , Virus Zika , Infección por el Virus Zika/virología , Infección por el Virus Zika/metabolismo , Infección por el Virus Zika/patología , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Animales , Ratones , Caspasa 8/metabolismo , Femenino , Humanos , Caspasa 3/metabolismo , Embarazo , Placenta/virología , Placenta/metabolismo , Placenta/patología , Ratones Endogámicos C57BL , Replicación Viral , Ratones NoqueadosRESUMEN
Since 2020, clade 2.3.4.4b highly pathogenic avian influenza H5N8 and H5N1 viruses have swept through continents, posing serious threats to the world. Through comprehensive analyses of epidemiological, genetic, and bird migration data, we found that the dominant genotype replacement of the H5N8 viruses in 2020 contributed to the H5N1 outbreak in the 2021/2022 wave. The 2020 outbreak of the H5N8 G1 genotype instead of the G0 genotype produced reassortment opportunities and led to the emergence of a new H5N1 virus with G1's HA and MP genes. Despite extensive reassortments in the 2021/2022 wave, the H5N1 virus retained the HA and MP genes, causing a significant outbreak in Europe and North America. Furtherly, through the wild bird migration flyways investigation, we found that the temporal-spatial coincidence between the outbreak of the H5N8 G1 virus and the bird autumn migration may have expanded the H5 viral spread, which may be one of the main drivers of the emergence of the 2020-2022 H5 panzootic.IMPORTANCESince 2020, highly pathogenic avian influenza (HPAI) H5 subtype variants of clade 2.3.4.4b have spread across continents, posing unprecedented threats globally. However, the factors promoting the genesis and spread of H5 HPAI viruses remain unclear. Here, we found that the spatiotemporal genotype replacement of H5N8 HPAI viruses contributed to the emergence of the H5N1 variant that caused the 2021/2022 panzootic, and the viral evolution in poultry of Egypt and surrounding area and autumn bird migration from the Russia-Kazakhstan region to Europe are important drivers of the emergence of the 2020-2022 H5 panzootic. These findings provide important targets for early warning and could help control the current and future HPAI epidemics.
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Subtipo H5N1 del Virus de la Influenza A , Subtipo H5N8 del Virus de la Influenza A , Gripe Aviar , Animales , Aves , Genotipo , Virus de la Influenza A/fisiología , Subtipo H5N1 del Virus de la Influenza A/genética , Subtipo H5N1 del Virus de la Influenza A/fisiología , Subtipo H5N8 del Virus de la Influenza A/genética , Subtipo H5N8 del Virus de la Influenza A/fisiología , Gripe Aviar/epidemiología , Gripe Aviar/virología , Filogenia , Aves de CorralRESUMEN
Exploring the relative role of different indoor environments in respiratory infections transmission remains unclear, which is crucial for developing targeted nonpharmaceutical interventions. In this study, a total of 2,583,441 influenza-like illness cases tested from 2010 to 2017 in China were identified. An agent-based model was built and calibrated with the surveillance data, to assess the roles of 3 age groups (children <19 years, younger adults 19-60 years, older adults >60 years) and 4 types of indoor environments (home, schools, workplaces, and community areas) in influenza transmission by province with varying urbanization rates. When the urbanization rates increased from 35% to 90%, the proportion of children aged <19 years among influenza cases decreased from 76% to 45%. Additionally, we estimated that infections originating from children decreased from 95.1% (95% confidence interval (CI): 92.7, 97.5) to 59.3% (95% CI: 49.8, 68.7). Influenza transmission in schools decreased from 80.4% (95% CI: 76.5, 84.3) to 36.6% (95% CI: 20.6, 52.5), while transmission in the community increased from 2.4% (95% CI: 1.9, 2.8) to 45.4% (95% CI: 35.9, 54.8). With increasing urbanization rates, community areas and younger adults contributed more to infection transmission. These findings could help the development of targeted public health policies. This article is part of a Special Collection on Environmental Epidemiology. This article is part of a Special Collection on Environmental Epidemiology.
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Gripe Humana , Infecciones del Sistema Respiratorio , Virosis , Niño , Humanos , Anciano , Gripe Humana/epidemiología , Urbanización , China/epidemiologíaRESUMEN
Circulation of seasonal influenza is the product of complex interplay among multiple drivers, yet characterizing the underlying mechanism remains challenging. Leveraging the diverse seasonality of A(H3N2) virus and abundant climatic space across regions in China, we quantitatively investigated the relative importance of population susceptibility, climatic factors, and antigenic change on the dynamics of influenza A(H3N2) through an integrative modelling framework. Specifically, an absolute humidity driven multiscale transmission model was constructed for the 2013/2014, 2014/2015 and 2016/2017 influenza seasons that were dominated by influenza A(H3N2). We revealed the variable impact of absolute humidity on influenza transmission and differences in the occurring timing and magnitude of antigenic change for those three seasons. Overall, the initial population susceptibility, climatic factors, and antigenic change explained nearly 55% of variations in the dynamics of influenza A(H3N2). Specifically, the additional variation explained by the initial population susceptibility, climatic factors, and antigenic change were at 33%, 26%, and 48%, respectively. The vaccination program alone failed to fully eliminate the summer epidemics of influenza A(H3N2) and non-pharmacological interventions were needed to suppress the summer circulation. The quantitative understanding of the interplay among driving factors on the circulation of influenza A(H3N2) highlights the importance of simultaneous monitoring of fluctuations for related factors, which is crucial for precise and targeted prevention and control of seasonal influenza.
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Epidemias , Gripe Humana , Humanos , Gripe Humana/epidemiología , Subtipo H3N2 del Virus de la Influenza A , Estaciones del Año , China/epidemiologíaRESUMEN
Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is well known to play a critical function in cancer, autoimmune and neurodegenerative diseases. However, its role in host-pathogen interactions has not been characterized yet. Herein, we identified that kynurenine-3-monooxygenase (KMO), a key rate-limiting enzyme in the KP, and quinolinic acid (QUIN), a key enzymatic product of KMO enzyme, exerted a novel antiviral function against a broad range of viruses. Mechanistically, QUIN induced the production of type I interferon (IFN-I) via activating the N-methyl-d-aspartate receptor (NMDAR) and Ca2+ influx to activate Calcium/calmodulin-dependent protein kinase II (CaMKII)/interferon regulatory factor 3 (IRF3). Importantly, QUIN treatment effectively inhibited viral infections and alleviated disease progression in mice. Furthermore, kmo-/- mice were vulnerable to pathogenic viral challenge with severe clinical symptoms. Collectively, our results demonstrated that KMO and its enzymatic product QUIN were potential therapeutics against emerging pathogenic viruses.
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Quinurenina 3-Monooxigenasa , Virosis , Animales , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Factor 3 Regulador del Interferón/metabolismo , Quinurenina/metabolismo , Quinurenina 3-Monooxigenasa/metabolismo , Ratones , Ácido Quinolínico/metabolismo , Ácido Quinolínico/farmacología , Virosis/tratamiento farmacológicoRESUMEN
Although a range of blood traits have been reported to be associated with influenza A(H1N1)pdm09 (H1N1pdm09) disease severity, their underlying causal relationships and biological mechanisms have remained unclear. This study aimed to investigate the causal relationship between blood traits and H1N1pdm09 using a two-sample Mendelian randomization analysis. Based on the data from our in-house genome-wide association study (GWAS) on H1N1pdm09 disease severity (Ncase [severe] = 70, Ncontrol [mild] = 95) and GWAS summaries of 44 blood traits from Biobank Japan (N = 12 303-143 658), we identified the potential causal effect of blood traits on severe H1N1pdm09. The inverse variance weighted method analysis revealed significant causal effects of lower aspartate aminotransferase (AST, ß = -3.212, p = 0.019), low-density-lipoprotein cholesterol (LDL-C, ß = -1.372, p = 0.045), and basophil counts (Baso, ß = -1.638, p = 0.047) on severe H1N1pdm09 disease. Additionally, polygenic risk score analysis further confirmed genetic overlap between these blood traits and severe H1N1pdm09 disease. This study provided evidence linking the lower level of AST, LDL-C, and lower count of Baso with severe H1N1pdm09 disease, potentially identifying new therapeutic targets for patients with severe influenza.
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Estudio de Asociación del Genoma Completo , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana , Análisis de la Aleatorización Mendeliana , Humanos , Gripe Humana/virología , Gripe Humana/genética , Gripe Humana/epidemiología , Subtipo H1N1 del Virus de la Influenza A/genética , Japón/epidemiología , Predisposición Genética a la Enfermedad , Índice de Severidad de la Enfermedad , Polimorfismo de Nucleótido Simple , Aspartato Aminotransferasas/sangre , LDL-Colesterol/sangre , Asia Oriental/epidemiología , Pueblo Asiatico/genética , Pueblos del Este de AsiaRESUMEN
BACKGROUND: The clinical manifestations of COVID-19 range from asymptomatic, mild to moderate, severe, and critical disease. Host genetic variants were recognized to affect the disease severity. However, the genetic landscape differs among various populations. Therefore, we explored the variants associated with COVID-19 severity in the Guangdong population. METHODS: A total of 314 subjects were selected, of which the severe and critical COVID-19 patients were defined as "cases", and the mild and moderate patients were defined as "control". Twenty-two variants in interferon-related genes and FOXP4 were genotyped using the MassARRAY technology platform. RESULTS: IFN signaling gene MX1 rs17000900 CA + AA genotype was correlated with a reduced risk of severe COVID-19 in males (P = 0.001, OR = 0.050, 95%CI = 0.008-0.316). The AT haplotype comprised of MX1 rs17000900 and rs2071430 was more likely to protect against COVID-19 severity (P = 6.3E-03). FOXP4 rs1886814 CC genotype (P = 0.001, OR = 3.747, 95%CI = 1.746-8.043) and rs2894439 GA + AA genotype (P = 0.001, OR = 5.703, 95% CI = 2.045-15.903) were correlated with increased risk of severe COVID-19. Haplotype CA comprised of rs1886814 and rs2894439 was found to be correlated with adverse outcomes (P = 7.0E-04). FOXP4 rs1886814 CC (P = 0.0004) and rs2894439 GA + AA carriers had higher neutralizing antibody titers (P = 0.0018). The CA + AA genotype of MX1 rs17000900 tended to be correlated with lower neutralizing antibody titers than CC genotype (P = 0.0663), but the difference was not statistically significant. CONCLUSION: Our study found a possible association between MX1 and FOXP4 polymorphisms and the severity of COVID-19. Distinguishing high-risk patients who develop severe COVID-19 will provide clues for early intervention and individual treatment strategies.
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COVID-19 , Factores de Transcripción Forkhead , Polimorfismo de Nucleótido Simple , Humanos , Masculino , Anticuerpos Neutralizantes , COVID-19/genética , COVID-19/metabolismo , Factores de Transcripción Forkhead/genética , Genotipo , Haplotipos , Interferones/metabolismo , Proteínas de Resistencia a Mixovirus/metabolismoRESUMEN
OBJECTIVES: The aim of this study was to evaluate the individual and combined effects of maternal smoking during pregnancy (MSDP) and personal smoking on mortality and life expectancy. STUDY DESIGN: A prospective cohort study based on the UK Biobank, with a median follow-up of 12.47 years. METHODS: This study employed multivariate Cox regression to determine the relative risks of mortality from all causes and specific diseases according to maternal and/or personal smoking status and pack-years of smoking (0, 1-20, 21-30, >30). Additionally, this study estimated the additive interaction between the two exposures. Life table analyses were performed using the estimated age-specific mortality rates to forecast life expectancy. RESULTS: Results indicated that MSDP elevated the risk of all-cause mortality (HR = 1.12, 95% CI: 1.09-1.15) and mortality due to neoplasms (HR = 1.10, 95% CI: 1.06-1.12), circulatory (HR = 1.13, 95% CI: 1.06-1.19), respiratory (HR = 1.27, 95% CI: 1.16-1.40) and digestive system diseases (HR = 1.22, 95% CI: 1.08-1.38). Notably, both multiplicative and additive interactions were observed between maternal and personal smoking, with Relative Excess Risk due to Interaction (RERI) values for mortality from all causes, neoplasms, circulatory, and respiratory diseases being 0.21, 0.22, 0.16, and 0.76, respectively. This study also found a trend towards shorter gained life expectancy when maternal smoking and increasing pack-years of personal smoking were combined. CONCLUSIONS: In this cohort study of UK Biobank, MSDP was associated with an increased risk of all-cause mortality and reduced life expectancy, suggesting that quitting smoking during pregnancy might have health and longevity benefits for both generations.
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Esperanza de Vida , Neoplasias , Femenino , Embarazo , Humanos , Causas de Muerte , Estudios de Cohortes , Estudios Prospectivos , Fumar/efectos adversos , Factores de RiesgoRESUMEN
The continuous evolution of avian influenza viruses (AIVs) of subtype H3 in China and the emergence of human infection with AIV subtype H3N8 highlight their threat to public health. Through surveillance in poultry-associated environments during 2009-2022, we isolated and sequenced 188 H3 AIVs across China. Performing large-scale sequence analysis with publicly available data, we identified 4 sublineages of H3 AIVs established in domestic ducks in China via multiple introductions from wild birds from Eurasia. Using full-genome analysis, we identified 126 distinct genotypes, of which the H3N2 G23 genotype predominated recently. H3N8 G25 viruses, which spilled over from birds to humans, might have been generated by reassortment between H3N2 G23, wild bird H3N8, and poultry H9N2 before February 2021. Mammal-adapted and drug-resistance substitutions occasionally occurred in H3 AIVs. Ongoing surveillance for H3 AIVs and risk assessment are imperative for potential pandemic preparedness.
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Subtipo H3N8 del Virus de la Influenza A , Subtipo H9N2 del Virus de la Influenza A , Gripe Aviar , Humanos , Animales , Subtipo H3N8 del Virus de la Influenza A/genética , Subtipo H3N2 del Virus de la Influenza A/genética , Subtipo H9N2 del Virus de la Influenza A/genética , Genoma Viral , Filogenia , Aves , Aves de Corral , China/epidemiología , MamíferosRESUMEN
The 2019 novel coronavirus (SARS-CoV-2) has spread rapidly worldwide and was declared a pandemic by the WHO in March 2020. The evolution of SARS-CoV-2, either in its natural reservoir or in the human population, is still unclear, but this knowledge is essential for effective prevention and control. We propose a new framework to systematically identify recombination events, excluding those due to noise and convergent evolution. We found that several recombination events occurred for SARS-CoV-2 before its transfer to humans, including a more recent recombination event in the receptor-binding domain. We also constructed a probabilistic mutation network to explore the diversity and evolution of SARS-CoV-2 after human infection. Clustering results show that the novel coronavirus has diverged into several clusters that cocirculate over time in various regions and that several mutations across the genome are fixed during transmission throughout the human population, including D614G in the S gene and two accompanied mutations in ORF1ab. Together, these findings suggest that SARS-CoV-2 experienced a complicated evolution process in the natural environment and point to its continuous adaptation to humans. The new framework proposed in this study can help our understanding of and response to other emerging pathogens.
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Evolución Molecular , Recombinación Genética , SARS-CoV-2/genética , COVID-19/virología , Humanos , Filogenia , Reproducibilidad de los ResultadosRESUMEN
Avian influenza A viruses (IAVs) that cross the species barrier to infect humans have the potential to initiate a new pandemic. However, the host factors influencing avian IAV infection remain poorly understood. To address this knowledge gap, we conducted a two-sample Mendelian randomization (MR) analysis by integrating our in-house genome-wide association study (GWAS) of avian IAV H7N9 susceptibility (with 217 cases and 116 controls) with the largest GWAS of serum IgA levels to date (sample size 41 263). Using the inverse-variance weighted (IVW) method, we discovered that genetically decreased serum IgA levels were associated with an increased risk of H7N9 infection (ß = -2.528, 95% confidence interval [CI]: -4.572 to -0.484; p = 0.015). Consistent results were obtained from three other MR methods, including robust IVW estimation (ß = -2.506, 95% CI: -4.109 to -0.902; p = 0.002), generalized summary-data-based MR (GSMR) (ß = -2.238, 95% CI: -4.106 to -0.602; p = 0.019), and MR-pleiotropy residual sum and outlier (MR-PRESSO) (ß = -2.528, 95% CI: -4.396 to -0.892; p = 0.026). In conclusion, our analysis provided compelling evidence support a causal relationship between genetically predicted serum IgA levels and avian IAV H7N9 susceptibility.
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Subtipo H7N9 del Virus de la Influenza A , Animales , Humanos , Subtipo H7N9 del Virus de la Influenza A/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Bases de Datos Factuales , Inmunoglobulina ARESUMEN
Currently, the clinical factors affecting immune responses to influenza vaccines have not been systematically explored. The mechanism of low responsiveness to influenza vaccination (LRIV) is complicated and not thoroughly elucidated. Thus, we integrate our in-house genome-wide association studies (GWAS) analysis result of LRIV (N = 111, Ncase [Low Responders] = 34, Ncontrol [Responders] = 77) with the GWAS summary of 10 blood-based biomarkers (sample size ranging from 62 076-108 794) deposited in BioBank Japan (BBJ) to comprehensively explore the shared genetics between LRIV and blood-based biomarkers to investigate the causal relationships between blood-based biomarkers and LRIV by Mendelian randomization (MR). The applications of four MR approaches (inverse-variance-weighted [IVW], weighted median, weighted mode, and generalized summary-data-based MR [GSMR]) suggested that the genetically instrumented LRIV was associated with decreased eosinophil count (ß = -5.517 to -4.422, p = 0.004-0.039). Finally, we conclude that the low level of eosinophil count is a suggestive risk factor for LRIV.
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Estudio de Asociación del Genoma Completo , Gripe Humana , Humanos , Análisis de la Aleatorización Mendeliana , Eosinófilos , Gripe Humana/prevención & control , Biomarcadores , Polimorfismo de Nucleótido SimpleRESUMEN
Whether the immune imprinting caused by severe acute respiratory syndrome coronavirus (SARS-CoV) affects the efficiency of SARS-CoV-2 vaccination has attracted global concern. Little is known about the dynamic changes of antibody response in SARS convalescents inoculated with three doses of inactivated SARS-CoV-2 vaccine although lack of cross-neutralizing antibody response to SARS-CoV-2 in SARS survivors has been reported. We longitudinally examined the neutralizing antibodies (nAbs) against SARS-CoV and SARS-CoV-2 as well as spikes binding IgA, IgG, IgM, IgG1, and IgG3 antibodies in 9 SARS-recovered donors and 21 SARS-naïve donors. Stably higher nAbs and spike antigens-specific IgA, IgG antibodies against SARS-CoV-2 were observed in SARS-recovered donors compared with SARS-naïve donors during the period with two doses of BBIBP-CorV vaccination. However, the third-dose BBIBP-CorV stimulated a sharply and shortly higher increase of nAbs in SARS-naïve donors than in SARS-recovered donors. It is worth noting that, regardless of prior SARS infection, the Omicron subvariants were found to subvert immune responses. Moreover, certain subvariants such as BA.2, BA.2.75, or BA.5 exhibited a high degree of immune evasion in SARS survivors. Interestingly, BBIBP-CorV recalled higher nAbs against SARS-CoV compared with SARS-CoV-2 in SARS-recovered donors. In SARS survivors, a single dose of inactivated SARS-CoV-2 vaccine provoked immune imprinting for the SARS antigen, providing protection against wild-type SARS-CoV-2, and the earlier variants of concern (VOCs) including Alpha, Beta, Gamma, and Delta but not against Omicron subvariants. As such, it is important to evaluate the type and dosage of SARS-CoV-2 vaccine for SARS survivors.
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COVID-19 , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , Humanos , Vacunas contra la COVID-19 , Formación de Anticuerpos , COVID-19/prevención & control , SARS-CoV-2 , Anticuerpos Neutralizantes , Inmunoglobulina G , Inmunoglobulina A , Anticuerpos AntiviralesRESUMEN
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is ongoing and multiple studies have elucidated its pathogenesis, however, the related- microbiome imbalance caused by SARS-CoV-2 is still not clear. In this study, we have comprehensively compared the microbiome composition and associated function alterations in the oropharyngeal swabs of healthy controls and coronavirus disease 2019 (COVID-19) patients with moderate or severe symptoms by metatranscriptomic sequencing. We did observe a reduced microbiome alpha-diversity but significant enrichment of opportunistic microorganisms in patients with COVID-19 compared with healthy controls, and the microbial homeostasis was rebuilt following the recovery of COVID-19 patients. Correspondingly, less functional genes in multiple biological processes and weakened metabolic pathways such as carbohydrate metabolism, energy metabolism were also observed in COVID-19 patients. We only found higher relative abundance of limited genera such as Lachnoanaerobaculum between severe patients and moderate patients while no worthy-noting microbiome diversity and function alteration were observed. Finally, we noticed that the co-occurrence of antibiotic resistance and virulence was closely related to the microbiome alteration caused by SRAS-CoV-2. Overall, our findings demonstrate that microbial dysbiosis may enhance the pathogenesis of SARS-CoV-2 and the antibiotics treatment should be critically considered.
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COVID-19 , Microbiota , Humanos , SARS-CoV-2 , Disbiosis , Farmacorresistencia MicrobianaRESUMEN
Influenza H7N9 virus causes human infections with about 40% case fatality rate. The severe cases usually present with pneumonia; however, some present with central nervous system complications. Pneumonia syndrome is attributed to the cytokine storm after infection with H7N9, but the pathogenic mechanism of central nervous system complications has not been clarified. This study used immortalized human brain microvascular endothelial cells hCMEC/D3 to simulate the blood-brain barrier. It demonstrated that H7N9 virus could infect brain microvascular endothelial cells and compromise the blood-brain barrier integrity and permeability by down-regulating the expression of cell junction-related proteins, including claudin-5, occludin, and vascular endothelial (VE)-cadherin. These results suggested that H7N9 could infect the blood-brain barrier in vitro and affect its functions, which could be a potential mechanism for the pathogenesis of H7N9 viral encephalopathy.
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Subtipo H7N9 del Virus de la Influenza A , Gripe Humana , Neumonía , Humanos , Células Endoteliales/metabolismo , EncéfaloRESUMEN
This study aims to screen and identify specific cluster miRNAs of H7N9 virus-infected N2a cells and explore the possible pathogenesis of these miRNAs. The N2a cells are infected with H7N9 and H1N1 influenza viruses, and the cells are collected at 12, 24 and 48 h to extract total RNA. To sequence miRNAs and identify different virus-specific miRNAs, high-throughput sequencing technology is used. Fifteen H7N9 virus-specific cluster miRNAs are screened, and eight of them are included in the miRBase database. These cluster-specific miRNAs regulate many signaling pathways, such as the PI3K-Akt signaling pathway, the RAS signaling pathway, the cAMP signaling pathway, actin cytoskeleton regulation and cancer-related genes. The study provides a scientific basis for the pathogenesis of H7N9 avian influenza, which is regulated by miRNAs.
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Subtipo H1N1 del Virus de la Influenza A , Subtipo H7N9 del Virus de la Influenza A , Gripe Aviar , Gripe Humana , MicroARNs , Animales , Humanos , Subtipo H7N9 del Virus de la Influenza A/genética , MicroARNs/genética , Subtipo H1N1 del Virus de la Influenza A/genética , Fosfatidilinositol 3-Quinasas , Gripe Humana/genéticaRESUMEN
BACKGROUND: The influenza viruses pose a threat to human health and medical services, and vaccination is an important way to prevent infection. However, the effectiveness of influenza vaccines is affected by various aspects. This study aimed to explore factors related to the immune response to influenza vaccines. METHODS: The study was conducted from September 2019 to September 2021, and a total of 593 volunteers were recruited from the Center for Disease Control and Prevention in 3 provinces in China. The hemagglutination inhibition assay was used to measure antibody levels. The Chi-square test, multivariable logistic regression analysis, and sum-rank test were used to analyze the factors associated with influenza vaccine immune response. RESULTS: The Chi-square test showed that seroconversion rates and response rate were associated with age group, vaccination history, chronic conditions, the frequency of colds, and region (P < 0.05). The multivariable logistic regression analysis showed that age was an important factor that affected participants' seroconversion rates for A/H1N1, A/H3N2, B/Victoria, and response status (18-64 vs. ≤5: OR = 2.77, P < 0.001; ≥65 vs. ≤5: OR = 0.38, P = 0.01; 18-64 vs. ≤5: OR = 2.64, P = 0.03). Vaccination history was also an affecting factor for A/H1N1, B/Victoria, and response status (yes vs. no: OR = 0.4 / 0.44 / 0.25, P < 0.001). The frequency of colds and chronic conditions were also affecting factors for participants' seroconversion rates and response levels to different degrees. The sum-rank test showed that the fold changes for A/H1N1, B/Victoria, and B/Yamagata were associated with age group and vaccination history (P < 0.01). The fold changes for A/H3N2 were associated with the frequency of colds (P < 0.05), and those for B/Victoria were associated with gender and chronic conditions (P < 0.05). CONCLUSIONS: Vaccination history, age, health condition, and frequency of colds were important factors affecting the seroconversion rate of the influenza vaccine in human. There is a need for developing optimized vaccination strategies for vulnerable groups to improve the efficacy of influenza vaccines in human.
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Resfriado Común , Subtipo H1N1 del Virus de la Influenza A , Vacunas contra la Influenza , Gripe Humana , Humanos , Gripe Humana/prevención & control , Virus de la Influenza B , Subtipo H3N2 del Virus de la Influenza A , Vacunas de Productos Inactivados , Anticuerpos Antivirales , Pruebas de Inhibición de Hemaglutinación , Inmunogenicidad VacunalRESUMEN
The recent rise in the frequency of influenza A(H5N6) infections in China has raised serious concerns about whether the risk for human infection has increased. We surveyed epidemiologic, clinical, and genetic data of human infections with A(H5N6) viruses. Severe disease occurred in 93.8% of cases, and the fatality rate was 55.4%. Median patient age was 51 years. Most H5N6 hemagglutinin (HA) genes in human isolates in 2021 originated from subclade 2.3.4.4b; we estimated the time to most recent common ancestor as June 16, 2020. A total of 13 genotypes with HA genes from multiple subclades in clade 2.3.4.4 were identified in human isolates. Of note, 4 new genotypes detected in 2021 were the major causes of increased H5N6 virus infections. Mammalian-adapted mutations were found in HA and internal genes. Although we found no evidence of human-to-human transmission, continuous evolution of H5N6 viruses may increase the risk for human infections.
Asunto(s)
Virus de la Influenza A , Gripe Aviar , Gripe Humana , Animales , China/epidemiología , Humanos , Mamíferos , Persona de Mediana Edad , Filogenia , Virus Reordenados/genéticaRESUMEN
New antiviral influenza treatments can effectively alleviate illness while reducing viral shedding. However, how such effects can translate into lower population infections of seasonal influenza in China remains unknown. To shed light on the public health impacts of novel antiviral agents for influenza, we constructed a dynamic transmission model to simulate the seasonal influenza epidemics in China. Two antivirus treatments, baloxavir and oseltamivir, were evaluated by estimating their impacts on the incidences of influenza infection in a single flu season. In the base-case analysis of a 10% antiviral treatment uptake rate, 2760 and 3420 per 10 000 persons contracted influenza under the treatment of baloxavir and oseltamivir, respectively. These incidence rates amounted to an 18.90% relative risk reduction (RRR) of infection associated with baloxavir in relation to oseltamivir. The corresponding RRR was 82.16% when the antiviral treatment uptake rate was increased to 35%. In addition, the peak of the prevalence of infected individuals per 10 000 persons under the baloxavir treatment was 177 (range: 93-274) fewer than that of oseltamivir. Our analyses suggest that the baloxavir treatment strategy reduces the incidence of influenza in China compared with oseltamivir in the setting of a seasonal flu epidemic. Also, increasing the uptake rate of antiviral treatment can potentially prevent millions of infections during a single flu season.