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1.
Int J Legal Med ; 134(4): 1271-1274, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32458044

RESUMO

In the setting of the coronavirus disease 2019 (COVID-19) pandemic, only few data regarding lung pathology induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is available, especially without medical intervention interfering with the natural evolution of the disease. We present here the first case of forensic autopsy of a COVID-19 fatality occurring in a young woman, in the community. Diagnosis was made at necropsy and lung histology showed diffuse alveolar damage, edema, and interstitial pneumonia with a geographically heterogeneous pattern, mostly affecting the central part of the lungs. This death related to COVID-19 pathology highlights the heterogeneity and severity of central lung lesions after natural evolution of the disease.


Assuntos
Betacoronavirus , Infecções por Coronavirus/patologia , Pulmão/patologia , Pneumonia Viral/patologia , Adenoviridae/genética , Adenoviridae/isolamento & purificação , Adulto , Autopsia , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Bocavirus/genética , Bocavirus/isolamento & purificação , Proteína C-Reativa/análise , Coronavirus/genética , Coronavirus/isolamento & purificação , Feminino , Humanos , Influenzavirus A/genética , Influenzavirus A/isolamento & purificação , Influenzavirus B/genética , Influenzavirus B/isolamento & purificação , Macrófagos/patologia , Megacariócitos/patologia , Metapneumovirus/genética , Metapneumovirus/isolamento & purificação , Neutrófilos/patologia , Obesidade Mórbida , Pandemias , Pró-Calcitonina/sangue , Reação em Cadeia da Polimerase em Tempo Real , Vírus Sincicial Respiratório Humano/genética , Vírus Sincicial Respiratório Humano/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rhinovirus/genética , Rhinovirus/isolamento & purificação , Suíça , Linfócitos T/patologia
2.
Eur J Med Chem ; 186: 111861, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31734025

RESUMO

Respiratory syncytial virus (RSV) and influenza A virus (IAV) are two of the most common viruses that cause substantial morbidity and mortality in infants, young children, elderly persons, and immunocompromised individuals worldwide. Currently, there are no licensed vaccines or selective antiviral drugs against RSV infections and most IAV strains become resistant to clinical anti-influenza drug. Here, we described the discovery of a series of 2-((1H-indol-3-yl)thio)-N-phenyl-acetamide as novel and potent RSV and IAV dual inhibitors. Thirty-five derivatives were designed, prepared, and evaluated for their anti-RSV and anti-IAV activities. Among the tested compounds, 14'c, 14'e, 14'f, 14'h, and 14'i exhibited excellent activity against both RSV and IAV, which showed low micromolar to sub-micromolar EC50 values. Further, compounds 14'c and 14'e were identified as the most promising dual inhibitors with lesser cytotoxicity than the clinical drug, ribavirin. These findings may contribute to the development of a lead compound for the treatment of RSV and/or IAV infections.


Assuntos
Acetamidas/farmacologia , Antivirais/farmacologia , Desenho de Fármacos , Influenzavirus A/efeitos dos fármacos , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Acetamidas/síntese química , Acetamidas/química , Antivirais/síntese química , Antivirais/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
3.
Arch Virol ; 165(1): 201-206, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31745716

RESUMO

Neuraminidase (NA) thermostability of influenza A and B viruses isolated from birds, swine and humans was measured to evaluate its variability associated with host body temperature. The highest 50% inactivation temperature (IT50) was observed with H3N8 avian influenza virus (74 °C), and the lowest IT50 was observed with the seasonal human H3N2 virus (45.5 °C). The IT50 values of A(H1N1)pdm09 viruses 56.4-58.5 °C were statistically higher than that of the prepandemic strain A/Solomon Islands/03/06 (52.5 °C). An analysis of Ca2+ binding sites revealed the correspondence of amino acid changes to NA thermostability. This study demonstrates that changes in NA thermostability correspond to differences in host body temperature.


Assuntos
Influenzavirus A/enzimologia , Influenzavirus B/enzimologia , Neuraminidase/química , Animais , Aves/virologia , Temperatura Corporal , Estabilidade Enzimática , Humanos , Suínos , Termodinâmica , Proteínas Virais/química , Zoonoses/virologia
4.
BMC Infect Dis ; 19(1): 967, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718578

RESUMO

BACKGROUND: Seasonal influenza causes a considerable burden to healthcare services every year. To better measure the impact of severe influenza cases in Romania, we analyzed active surveillance data collected during the 2017-2018 season from patients admitted for influenza-like illness (ILI) at a tertiary care hospital in Bucharest. METHODS: Patients admitted for acute ILI were included if they were resident in the Bucharest-Ilfov region, had been hospitalized for at least 24 h, and had onset of symptoms within 7 days before admission. Patient demographics, healthcare use, vaccination status, and outcome data were collected by questionnaire or by searching clinical records. Respiratory swabs were also obtained from each patient to confirm influenza A (A/H1 and A/H3 subtypes) or influenza B (Yamagata and Victoria lineages) infection by real-time reverse-transcription polymerase chain reaction assay. RESULTS: The study included 502 patients, many (45.2%) of whom were aged < 5 years. Overall, 108 patients (21.5%) had one or more comorbidities. Seventeen adults aged 18-64 years (3.4%) had been vaccinated against influenza. Patients were hospitalized for a median of 5 days and most (90.4%) were prescribed antiviral treatment. More than one-half of the patients (n = 259, 51.6%) were positive for influenza. Most influenza cases were caused by B viruses (172/259, 66.4%), which were mostly of the B/Yamagata lineage (85 of 94 characterized, 90.4%). Most of the subtyped A viruses were A/H1 (59/74, 79.7%). A/H1 viruses were frequently detected in influenza-positive admissions throughout the 2017-2018 season, whereas the predominant B/Yamagata viruses were detected around the middle of the season, with a peak in cases at week 7 of 2018. Eleven patients were admitted to an intensive care unit; of these, one patient with confirmed B/Yamagata infection died. CONCLUSIONS: These results show that seasonal influenza results in considerable hospitalization in Bucharest-Ilfov, Romania and suggest vaccine coverage should be extended, especially to the youngest age groups. The data from this study should help inform and optimize national influenza healthcare policies.


Assuntos
Hospitalização/estatística & dados numéricos , Influenza Humana/diagnóstico , Adolescente , Adulto , Idoso , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/diagnóstico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Vírus da Influenza B/genética , Vírus da Influenza B/isolamento & purificação , Vacinas contra Influenza/imunologia , Influenza Humana/complicações , Influenza Humana/epidemiologia , Influenzavirus A/genética , Influenzavirus A/isolamento & purificação , Masculino , Pessoa de Meia-Idade , Romênia/epidemiologia , Estações do Ano , Adulto Jovem
6.
Eur J Clin Microbiol Infect Dis ; 38(12): 2341-2348, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31463620

RESUMO

No studies evaluating the association between statins and outcomes of patients with seasonal influenza have been performed since the 2007-2008 and the 2009 pandemic H1N1 influenza seasons. All consecutive hospitalized patients between October 2017 and April 2018, diagnosed with laboratory-confirmed influenza A and B virus, were included. Patients were divided into two groups: statin and non-statin users. Outcomes were 30- and 90-day mortality, complications (pneumonia, myocarditis, encephalitis, intensive care unit (ICU) transfer, mechanical ventilation, vasopressor support), length of hospital stay, and readmission rates. A multivariate analysis was performed to adjust for mortality risk factors. To compare the groups, we matched patients to the nearest neighbor propensity score. Of the 526 patients ill with influenza A (201/526) and B (325/526), 36% (188/526) were statin users; 64% (338/526) were not. Statin users were older (78 vs.70; p = < 0.05) and suffered from more comorbidities (Charlson comorbidity scores of 6 vs.4; p < 0.005). The 30-day mortality rate among statin vs. non-statin users was 6% vs. 8% (p = 0.3). On multivariate analysis, statin use was not associated with mortality benefit (OR = 0.67 (0.29-1.36)). After propensity score matching, the results were unchanged (OR = 0.71 (0.29-1.71)). Statin users were diagnosed with less complicated diseases as they were less likely to receive vasopressor support, mechanical ventilation, and/or transfer to the ICU. Although statin users were significantly older and exhibited more comorbidities, 30-day mortality rates did not differ between statin users and non-users, which may signify a protective role of statins on seasonal influenza patients. Further studies performed during different influenza seasons and different subtypes are essential.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Influenza Humana/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Hospitalização , Hospitais Universitários , Humanos , Influenza Humana/diagnóstico , Influenza Humana/mortalidade , Influenza Humana/terapia , Influenzavirus A/isolamento & purificação , Influenzavirus B/isolamento & purificação , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pontuação de Propensão , Estudos Retrospectivos , Fatores de Risco , Centros de Atenção Terciária , Resultado do Tratamento
7.
Biosens Bioelectron ; 141: 111476, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31272058

RESUMO

The ability of influenza viruses to rapidly evolve has caused significant challenges in viral surveillance, diagnosis, and therapeutic development. Molecular sequencing methods, though powerful tools for monitoring influenza evolution at the genetic level, are not able to fully characterize the antigenic properties of influenza viruses. Understanding influenza virus antigenicity is critical to vaccine development and disease prevention. Traditional immunoassays which have been widely used for evaluating influenza antigenicity have limited throughput. To alleviate these problems, new bioanalytical tools to investigate influenza antigenicity by measuring antibody-antigen binding are an active area of research. Herein, we review immunosensor technologies from the aspects of various sensing principles, while highlighting recent developments in multiplex, label-free detection strategies. Highlighted technologies include electrochemical immunosensors relying on impedimetric detection; these demonstrate simple design and cost effectiveness for mass production. Antibody arrays implemented on an optical interferometric sensor system allow systematic characterization of influenza antigenicity. Quartz microbalance immunosensors are highly sensitive but have yet to be explored for multiplex sensing. Immunosensors made on lateral flow strips have shown promise in rapid diagnosis of influenza subtypes. We anticipate that these and other technologies discussed in the review will facilitate advances in the study of influenza, and other viral pathogens.


Assuntos
Técnicas Biossensoriais/métodos , Influenza Humana/diagnóstico , Orthomyxoviridae/isolamento & purificação , Animais , Antígenos Virais/análise , Antígenos Virais/imunologia , Técnicas Biossensoriais/instrumentação , Desenho de Equipamento , Humanos , Imunoensaio/instrumentação , Imunoensaio/métodos , Influenza Humana/imunologia , Influenza Humana/virologia , Influenzavirus A/imunologia , Influenzavirus A/isolamento & purificação , Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/diagnóstico , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia
8.
PLoS One ; 14(7): e0220401, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31356626

RESUMO

The 2017-2018 influenza epidemic season in Russia was characterized by a relatively low morbidity and mortality. We evaluated herd immunity prior to the 2017-2018 influenza season in hemagglutination inhibition assay, and performed characterization of influenza viruses isolated from severe or fatal influenza cases and from influenza cases in people vaccinated in the fall of 2017. During the 2017-2018 epidemic season, 87 influenza A and B viruses were isolated and viruses of the 75 influenza cases, including selected viral isolates and viruses analyzed directly from the original clinical material, were genetically characterized. The analyzed A(H1N1)pdm09 viruses belonged to clade 6B.1, B/Yamagata-like viruses belonged to clade 3, and B/Victoria-like viruses belonged to clade 1A and they were antigenically similar to the corresponding vaccine strains. A(H3N2) viruses belonged to clade 3C.2a and were difficult to characterize antigenically and the analysis indicated antigenic differences from the corresponding egg-grown vaccine strain. The next generation sequencing revealed the presence of D222/G/N polymorphism in the hemagglutinin gene in 32% of the analyzed A(H1N1)pdm09 lethal cases. This study demonstrated the importance of monitoring D222G/N polymorphism, including detection of minor viral variants with the mutations, in the hemagglutinin gene of A(H1N1)pdm09 for epidemiological surveillance. One strain of influenza virus A(H1N1)pdm09 was resistant to oseltamivir and had the H275Y amino acid substitution in the NA protein. All other isolates were susceptible to NA inhibitors. Prior to the 2017-2018 epidemic season, 67.4 million people were vaccinated, which accounted for 46.6% of the country's population. Just before the epidemic season 33-47% and 24-30% of blood sera samples collected within the territory of Russia showed the presence of protective antibody titers against vaccine strains of influenza A and influenza B/Victoria-like, respectively. Mass vaccination of the population had evidently reduced the severity of the flu epidemic during the 2017-2018 influenza epidemic season in Russia.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza B/classificação , Influenza Humana/epidemiologia , Influenzavirus A/classificação , Adolescente , Adulto , Criança , Pré-Escolar , Farmacorresistência Viral , Epidemias , Monitoramento Epidemiológico , Feminino , Testes de Inibição da Hemaglutinação , Humanos , Lactente , Recém-Nascido , Vírus da Influenza B/genética , Vírus da Influenza B/imunologia , Influenza Humana/virologia , Influenzavirus A/genética , Influenzavirus A/imunologia , Masculino , Pessoa de Meia-Idade , Filogenia , Polimorfismo Genético , RNA Viral/genética , Federação Russa/epidemiologia , Adulto Jovem
9.
Infect Genet Evol ; 74: 103918, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31200112

RESUMO

The H6N1 subtype avian influenza virus (AIV) is a zoonotic infectious disease pathogen, which poses a threat to human health. In order to study the possible substitution of H6N1 AIV for mammals, an avian-origin H6N1 virus was successively passaged in mice. The results showed that PB2 (L193H and E627K), PA (S709F) and HA (V127I) proteins had multiple amino acid substitutions. The virulence of the mouse-adapted virus was stronger than that of the wild virus, and it was highly pathogenic to mice. Therefore, continued surveillance of these substitutions in poultry H6N1 viruses is required.


Assuntos
Substituição de Aminoácidos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Influenza Humana/virologia , Influenzavirus A/patogenicidade , RNA Replicase/genética , Proteínas Virais/genética , Células A549 , Animais , Aves , Modelos Animais de Doenças , Cães , Evolução Molecular , Humanos , Influenza Aviária/virologia , Influenzavirus A/genética , Células Madin Darby de Rim Canino , Camundongos , Fatores de Virulência/genética
10.
Eur J Med Chem ; 178: 64-80, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176096

RESUMO

Encouraged by our earlier discovery of neuraminidase inhibitors targeting 150-cavity or 430-cavity, herein, to yield more potent inhibitors, we designed, synthesized, and biologically evaluated a series of novel oseltamivir derivatives via modification of C-1 and C5-NH2 of oseltamivir by exploiting 150-cavity and/or 430-cavity. Among the synthesized compounds, compound 15e, the most potent N1-selective inhibitor targeting 150-cavity, showed 1.5 and 1.8 times greater activity than oseltamivir carboxylate (OSC) against N1 (H5N1) and N1 (H5N1-H274Y). In cellular assays, 15e also exhibited greater potency than OSC against H5N1 with EC50 of 0.66 µM. In addition, 15e demonstrated low cytotoxicity in vitro and low acute toxicity in mice. Molecular docking studies provided insights into the high potency of 15e against N1 and N1-H274Y mutant NA. Overall, we envisioned that the significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors may lead to further investigation of more potent anti-influenza agents.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Neuraminidase/antagonistas & inibidores , Oseltamivir/análogos & derivados , Oseltamivir/farmacologia , Proteínas Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/química , Antivirais/toxicidade , Domínio Catalítico , Linhagem Celular , Galinhas , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/toxicidade , Feminino , Influenzavirus A/enzimologia , Influenzavirus B/enzimologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Neuraminidase/química , Oseltamivir/síntese química , Oseltamivir/toxicidade , Proteínas Virais/química
12.
Artigo em Inglês | MEDLINE | ID: mdl-30929566

RESUMO

Dengue (DENV) viral infection is a global public health problem that infrequently develops life threatening diseases such as dengue hemorrhagic fever (DFS) and dengue shock syndrome (DSS). Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic human corona virus with 38% fatality rate of infected patients. A series of 4-arylhydrazono-5-trifluoromethyl-pyrazolones, their ribofuranosyl, and 5'-deoxyribofuranosyl nucleosides were synthesized, geometry optimized using Density functional theory (DFT), and evaluated for their antiviral activity. 2-Nitrophenylhydrazonopyra-zolone derivative 5 showed significant activity against MERS-CoV (EC50 = 4.6 µM). The nucleoside analog 8 showed moderate activity against DENV-2 (EC50 = 10 µM), while the activity was abolished with the corresponding 5'-deoxyribonucleoside analogs. The identified hits in this study set this category of compounds for further future optimizations.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Pirazolonas/química , Vírus da Dengue/efeitos dos fármacos , Desenho de Fármacos , Hepacivirus/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Influenzavirus A/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Estrutura Molecular , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
13.
J Med Chem ; 61(19): 8734-8745, 2018 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-30192544

RESUMO

Class I enveloped viruses share similarities in their apparent use of a hexameric coiled-coil assembly to drive the merging of virus and host cell membranes. Inhibition of coiled coil-mediated interactions using bioactive peptides that replicate an α-helical chain from the viral fusion machinery has significant antiviral potential. Here, we present the construction of a series of lipopeptides composed of a de novo heptad repeat sequence-based α-helical peptide plus a hydrocarbon tail. Promisingly, the constructs adopted stable α-helical conformations and exhibited relatively broad-spectrum antiviral activities against Middle East respiratory syndrome coronavirus (MERS-CoV) and influenza A viruses (IAVs). Together, these findings reveal a new strategy for relatively broad-spectrum antiviral drug discovery by relying on the tunability of the α-helical coiled-coil domains present in all class I fusion proteins and the amphiphilic nature of the individual helices from this multihelix motif.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Descoberta de Drogas , Influenza Humana/tratamento farmacológico , Lipopeptídeos/farmacologia , Proteínas Virais de Fusão/antagonistas & inibidores , Sequência de Aminoácidos , Antivirais/química , Infecções por Coronavirus/virologia , Células HEK293 , Humanos , Influenza Humana/virologia , Influenzavirus A/efeitos dos fármacos , Lipopeptídeos/química , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Conformação Proteica em alfa-Hélice , Internalização do Vírus
14.
Emerg Infect Dis ; 24(10): 1825-1834, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30226188

RESUMO

The World Health Organization selects influenza vaccine compositions biannually to cater to peaks in temperate regions. In tropical and subtropical regions, where influenza seasonality varies and epidemics can occur year-round, the choice of vaccine remains uncertain. Our 17-year molecular epidemiologic survey showed that most influenza A(H3N2) (9/11) and B (6/7) vaccine strains had circulated in East Asia >1 year before inclusion into vaccines. Northern Hemisphere vaccine strains and circulating strains in East Asia were closely matched in 7 (20.6%) of 34 seasons for H3N2 and 5 (14.7%) of 34 seasons for B. Southern Hemisphere vaccines also had a low probability of matching (H3N2, 14.7%; B, 11.1%). Strain drift among seasons was common (H3N2, 41.2%; B, 35.3%), and biannual vaccination strategy (Northern Hemisphere vaccines in November followed by Southern Hemisphere vaccines in May) did not improve matching. East Asia is an important contributor to influenza surveillance but often has mismatch between vaccine and contemporarily circulating strains.


Assuntos
Variação Genética , Vacinas contra Influenza/genética , Influenza Humana/epidemiologia , Influenza Humana/virologia , Influenzavirus A/genética , Influenzavirus B/genética , Estações do Ano , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , História do Século XX , História do Século XXI , Hong Kong/epidemiologia , Humanos , Vacinas contra Influenza/imunologia , Influenza Humana/história , Influenza Humana/prevenção & controle , Influenzavirus A/classificação , Influenzavirus A/imunologia , Influenzavirus B/classificação , Influenzavirus B/imunologia , Epidemiologia Molecular , Filogenia , RNA Viral , Estudos Retrospectivos
15.
Rev. esp. geriatr. gerontol. (Ed. impr.) ; 53(supl.2): 185-202, sept. 2018. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-178172

RESUMO

La gripe es un importante problema de salud pública, particularmente en las personas susceptibles de presentar complicaciones asociadas, personas mayores, niños menores de 2 años, enfermos crónicos, inmunocomprometidos y embarazadas. Pero, además, la gripe tiene un gran impacto sanitario con un aumento de la demanda asistencial y un espectacular aumento de las visitas ambulatorias, sobrecargando los servicios de urgencias y hospitalarios. Durante los brotes epidémicos, las tasas de hospitalización de las personas mayores de 65 años son máximas y la mortalidad notificada por gripe en la temporada 2017/2018 ha sido de 960 defunciones. La vacunación antigripal estacional es el método con una mayor relación coste-efectividad de prevención primaria de la gripe, reduciendo las enfermedades respiratorias relacionadas, el número de visitas a las consultas médicas, el número de hospitalizaciones y muertes en personas de alto riesgo y el absentismo laboral en adultos. En los últimos años la gripe B ha recibido escasa atención en la literatura científica y, sin embargo, en períodos interepidémicos, la gripe B puede ser una de las principales causas de epidemias de gripe estacional, causando una considerable morbimortalidad y un aumento de costes. La vacuna tetravalente, a diferencia de la trivalente, obtiene una protección inmunológica frente al segundo linaje de la gripe B y, de acuerdo con una revisión crítica de la literatura científica, proporciona una protección más amplia sin afectar a la inmunogenicidad de las otras 3 cepas vacunales comunes a las vacunas trivalente y tetravalente. La vacuna tetravalente es coste-efectiva al disminuir el número de casos de gripe y siempre es una intervención rentable, con un importante ahorro de coste para el sistema de salud y para la sociedad, disminuyendo las tasas de hospitalización y de mortalidad asociadas a las complicaciones de la gripe


Influenza is a significant health problem, particularly in those persons susceptible to having associated complications, older people, children less than 2 years, patients with chronic diseases, immunocompromised patients, and pregnant women. But influenza also has a large impact on the health system, with an increase in the healthcare demand and a spectacular increase in outpatient visits, overloading the emergency and hospital services. During epidemic outbreaks, the hospital admission rates of people over 65 years are at a maximum, and the mortality notified for the 2017/2018 influenza season was 960 deaths. The seasonal anti-influenza vaccine is the method with a better cost-effective ratio of primary prevention of influenza, reducing associated respiratory diseases, the number of hospital admissions, and deaths in high risk individuals, as well as work absenteeism in adults. In the last few years, influenza B has received little attention in the scientific literature, although in the periods between epidemics influenza B can be one of the main causes of seasonal epidemics, causing considerable morbidity and mortality and an increase in costs. The quadrivalent vaccine has a second-line immunological protection against influenza B, and according to a critical review of the scientific literature, it provides wider protection without affecting immunogenicity of the other three vaccine strains common to the trivalent and tetravalent vaccine. The quadrivalent vaccine is cost-effective in reducing the number of influenza cases, and is always a worthwhile intervention, with a significant cost saving for the health system and for society, by reducing the hospital admission rates and mortality associated with the complications of influenza


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Vacinas contra Influenza/análise , Influenza Humana/prevenção & controle , Imunogenicidade da Vacina , Influenza Humana/epidemiologia , Análise Custo-Benefício , Imunossenescência/imunologia , Envelhecimento/imunologia , Efeitos Psicossociais da Doença , Espanha/epidemiologia , Vírus da Influenza A/patogenicidade , Influenzavirus A/patogenicidade , Vírus da Influenza B/patogenicidade , Influenzavirus B/patogenicidade , Vacinas Anti-Haemophilus/análise , Vigilância de Produtos Comercializados/tendências
16.
Viral Immunol ; 31(6): 457-469, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29870311

RESUMO

Influenza virus infections can be complicated by bacterial superinfections, which are medically relevant because of a complex interaction between the host, the virus, and the bacteria. Studies to date have implicated several influenza virus genes, varied host immune responses, and bacterial virulence factors, however, the host-pathogen interactions that predict survival versus lethal outcomes remain undefined. Previous work by our group showed that certain influenza viruses could yield a survival phenotype (A/swine/Texas/4199-2/98-H3N2, TX98), whereas others were associated with a lethal phenotype (A/Puerto Rico/8/34-H1N1, PR8). Based on this observation, we developed the hypothesis that individual influenza virus genes could contribute to a superinfection, and that the host response after influenza virus infection could influence superinfection severity. The present study analyzes individual influenza virus gene contributions to superinfection severity using reassortant viruses created using TX98 and PR8 viral genes. Host and pathogen interactions, relevant to survival and lethal phenotypes, were studied with a focus on pathogen clearance, host cellular infiltrates, and cytokine levels after infection. Specifically, we found that the hemagglutinin gene expressed by an influenza virus can contribute to the severity of a secondary bacterial infection, likely through modulation of host proinflammatory responses. Altogether, these results advance our understanding of molecular mechanisms underlying influenza virus-bacteria superinfections and identify viral and corresponding host factors that may contribute to morbidity and mortality.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Influenza Humana/imunologia , Influenzavirus A/imunologia , Vírus Reordenados/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus pyogenes/imunologia , Superinfecção/imunologia , Animais , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Influenza Humana/diagnóstico , Influenza Humana/mortalidade , Influenza Humana/virologia , Influenzavirus A/metabolismo , Camundongos Endogâmicos BALB C , Vírus Reordenados/metabolismo , Índice de Gravidade de Doença , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/mortalidade , Superinfecção/microbiologia , Superinfecção/mortalidade , Fatores de Virulência/imunologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-29765910

RESUMO

Interferon (IFN)-sensitive and replication-incompetent influenza viruses are likely to be the alternatives to inactivated and attenuated virus vaccines. Some IFN-sensitive influenza vaccine candidates with modified non-structural protein 1 (NS1) are highly attenuated in IFN-competent hosts but induce robust antiviral immune responses. However, little research has been done on the manufacturability of these IFN-sensitive vaccine viruses. Here, RIG-I-knockout 293T cells were used to package the IFN-sensitive influenza A/WSN/33 (H1N1) virus expressing the mutant NS1 R38A/K41A. We found that the packaging efficiency of the NS1 R38A/K41A virus in RIG-I-knockout 293T cells was much higher than that in 293T cells. Moreover, the NS1 R38A/K41A virus almost lost its IFN antagonist activity and could no longer replicate in A549, MDCK, and Vero cells after 3-6 passages. This indicated that the replication of NS1 R38A/K41A virus is limited in conventional cells. Therefore, we further established a stable Vero cell line expressing the wild-type (WT) NS1 of the WSN virus, based on the Tet-On 3G system. The NS1 R38A/K41A virus was able to steadily propagate in this IFN-deficient cell line for at least 20 passages. In a mouse model, the NS1 R38A/K41A virus showed more than a 4-log reduction in lung virus titers compared to the WT virus at 3 and 5 days post infection. Furthermore, we observed that the NS1 R38A/K41A virus triggered high-level of IFN-α/ß production in lung tissues and was eliminated from the host in a relatively short period of time. Additionally, this virus induced high-titer neutralizing antibodies against the WT WSN, A/Puerto Rico/8/1934 (PR8), or A/California/04/2009 (CA04) viruses and provided 100% protection against the WT WSN virus. Thus, we found that the replication of the NS1 R38A/K41A virus was limited in IFN-competent cells and mice. We also presented a promising IFN-deficient system, involving a RIG-I-knockout 293T cell line to package the IFN-sensitive vaccine virus and a stable Vero cell line expressing NS1 to propagate the IFN-sensitive vaccine virus. The IFN-deficient system is applicable for the manufacture of IFN-sensitive vaccine virus.


Assuntos
Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/virologia , Influenzavirus A/imunologia , Interferons/imunologia , Proteínas não Estruturais Virais/imunologia , Células A549 , Animais , Chlorocebus aethiops , Cães , Feminino , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vacinas contra Influenza/genética , Influenzavirus A/genética , Interferons/antagonistas & inibidores , Interferons/genética , Pulmão/imunologia , Pulmão/virologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Células Vero , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
18.
J Control Release ; 282: 120-130, 2018 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-29673645

RESUMO

Influenza vaccines that can be administered intranasally or by other needle-free delivery routes have potential advantages over injected formulations in terms of patient compliance, cost, and ease of global distribution. Supramolecular peptide nanofibers have been investigated previously as platforms for vaccines and immunotherapies and have been shown to raise immune responses in the absence of exogenous adjuvants and without measurable inflammation. However, at present it has not been tested whether the immunogenicity of these materials extends to the intranasal route. Here we investigated the extent to which self-assembled peptide nanofibers bearing an influenza peptide epitope elicit antigen-specific CD8+ T cell responses when delivered intranasally, and we compared these responses with those elicited by subcutaneous immunization. Peptides containing an epitope from influenza acid polymerase (PA) and the Q11 self-assembly domain formed nanofibers that were avidly taken up by dendritic cells in lung-draining mediastinal lymph nodes after intranasal immunization. Intranasally delivered nanofibers generated greater antigen-specific CD8+ T cell responses in the lung-draining lymph nodes than subcutaneous immunizations while retaining the non-inflammatory character of the materials observed in other delivery sites. The CD8+ T cells elicited systemically were functional as assessed by their ability to produce IFN-γ ex vivo, lyse epitope-pulsed target cells in vivo, and diminish viral loads in infected mice. Compared to subcutaneously delivered nanofibers, intranasally delivered peptide nanofibers significantly increased the number of persisting antigen-specific tissue resident memory CD8+ T cells in the lung, allowing for a more rapid response to infection at 6 weeks post-vaccination. These results indicate that intranasally delivered self-assembled peptide nanofibers are immunogenic when delivering CD8+ epitopes without adjuvant or CD4+ epitopes, are non-inflammatory, and promote more lung-resident memory CD8+ T cells compared to subcutaneous immunization.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vacinas contra Influenza/administração & dosagem , Influenzavirus A/imunologia , Nanofibras/administração & dosagem , Infecções por Orthomyxoviridae/prevenção & controle , Peptídeos/administração & dosagem , Administração Intranasal , Animais , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/uso terapêutico , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/uso terapêutico , Camundongos Endogâmicos C57BL , Nanofibras/uso terapêutico , Nanofibras/ultraestrutura , Infecções por Orthomyxoviridae/imunologia , Peptídeos/imunologia , Peptídeos/uso terapêutico
19.
Nutrients ; 10(4)2018 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-29587438

RESUMO

Influenza virus infection is a major global public health problem, and the efficacy of influenza vaccination is not satisfactory. Vitamin D is involved in many immune-mediated inflammatory processes. The impact of vitamin D levels on the immunogenic response to influenza vaccination is not clear. We performed a comprehensive literature search and systematic review of studies that investigated vitamin D and influenza vaccination. Data pertaining to study population, vaccine components, vitamin D levels, and immunogenic response were analyzed. Nine studies, with a combined study population of 2367 patients, were included in the systematic review. Four studies were included in the meta-analysis to investigate the influence of vitamin D deficiency (VDD) on the seroprotection (SP) rates and seroconversion (SC) rates following influenza vaccination. We found no significant association between vitamin D level and the immunogenic response to influenza vaccination. However, strain-specific differences may exist. We observed lower SP rates of influenza A virus subtype H3N2 (A/H3N2) and B strain in VDD patients than patients with normal vitamin D levels (A/H3N2: 71.8% vs. 80.1%, odds ratio (OR): 0.63, 95% confidence interval (CI): 0.43-0.91, p = 0.01; B strain: 69.6% vs. 76.4%, OR: 0.68, 95% CI: 0.5-0.93, p = 0.01). However, the SP rates of A/H1N1 and SC rates of all three strains were not significantly different in VDD and control groups. In conclusion, no association was observed between VDD and immunogenic response to influenza vaccination.


Assuntos
Imunogenicidade da Vacina , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Influenzavirus A/imunologia , Influenzavirus B/imunologia , Vacinação , Deficiência de Vitamina D/imunologia , Adulto , Idoso , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Feminino , Humanos , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/imunologia , Influenza Humana/diagnóstico , Influenza Humana/imunologia , Influenza Humana/virologia , Influenzavirus A/patogenicidade , Influenzavirus B/patogenicidade , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Resultado do Tratamento , Vacinação/efeitos adversos , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/diagnóstico
20.
Stem Cell Res Ther ; 9(1): 17, 2018 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-29378639

RESUMO

BACKGROUND: Mesenchymal stem (stromal) cells (MSCs) mediate their immunoregulatory and tissue repair functions by secreting paracrine factors, including extracellular vesicles (EVs). In several animal models of human diseases, MSC-EVs mimic the beneficial effects of MSCs. Influenza viruses cause annual outbreaks of acute respiratory illness resulting in significant mortality and morbidity. Influenza viruses constantly evolve, thus generating drug-resistant strains and rendering current vaccines less effective against the newly generated strains. Therefore, new therapies that can control virus replication and the inflammatory response of the host are needed. The objective of this study was to examine if MSC-EV treatment can attenuate influenza virus-induced acute lung injury in a preclinical model. METHODS: We isolated EVs from swine bone marrow-derived MSCs. Morphology of MSC-EVs was determined by electron microscopy and expression of mesenchymal markers was examined by flow cytometry. Next, we examined the anti-influenza activity of MSC-EVs in vitro in lung epithelial cells and anti-viral and immunomodulatory properties in vivo in a pig model of influenza virus. RESULTS: MSC-EVs were isolated from MSC-conditioned medium by ultracentrifugation. MSC-EVs were round-shaped and, similarly to MSCs, expressed mesenchymal markers and lacked the expression of swine leukocyte antigens I and II. Incubation of PKH-26-labeled EVs with lung epithelial cells revealed that MSC-EVs incorporated into the epithelial cells. Next, we examined the anti-influenza and anti-inflammatory properties of MSC-EVs. MSC-EVs inhibited the hemagglutination activity of avian, swine, and human influenza viruses at concentrations of 1.25-5 µg/ml. MSC-EVs inhibited influenza virus replication and virus-induced apoptosis in lung epithelial cells. The anti-influenza activity of MSC-EVs was due to transfer of RNAs from EVs to epithelial cells since pre-incubation of MSC-EVs with RNase enzyme abrogated the anti-influenza activity of MSC-EVs. In a pig model of influenza virus, intratracheal administration of MSC-EVs 12 h after influenza virus infection significantly reduced virus shedding in the nasal swabs, influenza virus replication in the lungs, and virus-induced production of proinflammatory cytokines in the lungs of influenza-infected pigs. The histopathological findings revealed that MSC-EVs alleviated influenza virus-induced lung lesions in pigs. CONCLUSIONS: Our data demonstrated in a relevant preclinical large animal model of influenza virus that MSC-EVs possessed anti-influenza and anti-inflammatory properties and that EVs may be used as cell-free therapy for influenza in humans.


Assuntos
Lesão Pulmonar Aguda/terapia , Vesículas Extracelulares/transplante , Células-Tronco Mesenquimais/metabolismo , Infecções por Orthomyxoviridae/patologia , Mucosa Respiratória/patologia , Lesão Pulmonar Aguda/virologia , Animais , Anti-Inflamatórios/metabolismo , Apoptose , Terapia Baseada em Transplante de Células e Tecidos/métodos , Citocinas/metabolismo , Modelos Animais de Doenças , Células Epiteliais/virologia , Influenzavirus A/metabolismo , Infecções por Orthomyxoviridae/virologia , RNA Viral/genética , Mucosa Respiratória/citologia , Mucosa Respiratória/virologia , Suínos , Replicação Viral
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