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1.
J Ethnopharmacol ; 270: 113788, 2021 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-33429033

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Siparuna species are used in Brazilian Folk Medicine for the treatment and prophylaxis of colds, fever, headache, gastrointestinal disorders and rheumatic pain. AIM OF THE STUDY: This study aimed to investigate a possible anti-influenza activity of 25 extracts from leaves of Amazonian S. cristata, S. decipiens, S. glycycarpa, S. reginae and S. sarmentosa based on their folk medicinal uses as well as to investigate their metabolic fingerprinting. The chemical composition of the active extracts was further dereplicated. MATERIAL AND METHODS: The chemical composition of the crude EtOH extracts from five Siparuna species were investigated by ESI (±) LC-QTOF-MS2. Organic extracts were obtained by liquid-liquid partition with solvents of increasing polarity, generating 25 extracts which were subjected to a quick DI-ESI (±) IT-MS fingerprint analysis. These extracts were tested against influenza virus replication and cellular toxicity using MDCK cells and influenza A/Michigan/45/2015 (H1N1)pdm09 virus. The compounds in the active BuOH extracts from S. glycycarpa and S. sarmentosa were annotated by ESI (±) LC-QTOF-MS2. RESULTS: Analysis of the EtOH extracts revealed the presence of alkaloids and flavonoids, in the positive and negative ionization modes. Out of the 25 organic extracts screened for their antiviral activity, the BuOH extracts from S. glycycarpa and S. sarmentosa were the most active, inhibiting 96.0 ± 1.3% and 89.5 ± 0.8% of influenza virus replication 24 h post-infection. These inhibitory effects were maintained until 72hpi. Alkaloids, O- and C-flavonoid glycosides, dihydrochalcones and a procyanidin dimer were annotated in these extracts. CONCLUSIONS: The inhibitory effect against influenza A(H1N1)pdm09 virus replication shown by Amazonian Siparuna species corroborates the use of these plants in Brazilian Folk Medicine, showing their potential as anti-influenza agents. These promising results stimulate the continuation of this study with the aim of isolating the compound(s) responsible for this bioactivity, thus contributing to a better knowledge of those species and to the research of natural products with potential anti-influenza activity.

2.
Artículo en Inglés | MEDLINE | ID: mdl-33321987

RESUMEN

SARS-CoV-2 is the causative agent of the current COVID-19 pandemic. Disease clinical manifestations range from asymptomatic to severe multiple organ damage. SARS-CoV-2 uses ACE2 as a cellular receptor, which is abundantly expressed in the small intestine, allowing viral replication in the gastrointestinal tract. Viral RNA has been detected in the stool of COVID-19 patients and viable viruses had been isolated in some of these samples. Thus, a putative role of SARS-CoV-2 fecal-oral transmission has been argued. SARS-CoV-2 is shed in human excreta and further disposed in the sewerage or in the environment, in poor basic sanitation settings. Wastewater-based epidemiology (WBE) is a valuable population level approach for monitoring viral pathogens and has been successfully used in different contexts. This review summarizes the current global experience on SARS-CoV-2 WBE in distinct continents and viral detection in polluted surface water. The advantages and concerns of this strategy for SARS-CoV-2 surveillance are discussed. Outcomes suggest that WBE is a valuable early warning alert and a helpful complementary surveillance tool to subside public health response, to tailor containment and mitigation measures and to determine target populations for testing. In poor sanitation settings, contaminated rivers could be alternatively used as a source for environmental surveillance.


Asunto(s)
/epidemiología , Pandemias , Monitoreo Epidemiológico Basado en Aguas Residuales , Humanos , Saneamiento , Aguas Residuales/virología
3.
Cephalalgia ; 40(13): 1452-1458, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33146040

RESUMEN

BACKGROUND: Headache is a frequent complaint in COVID-19 patients. However, no detailed information on headache characteristics is provided in these reports. Our objective is to describe the characteristics of headache and the cerebrospinal fluid (CSF) profile in COVID-19 patients, highlighting the cases of isolated intracranial hypertension. METHODS: In this cross-sectional study, we selected COVID-19 patients who underwent lumbar puncture due to neurological complaints from April to May 2020. We reviewed clinical, imaging, and laboratory data of patients with refractory headache in the absence of other encephalitic or meningitic features. CSF opening pressures higher than 250 mmH2O were considered elevated, and from 200 to 250 mmH2O equivocal. RESULTS: Fifty-six COVID-19 patients underwent lumbar puncture for different neurological conditions. A new, persistent headache that prompted a CSF analysis was diagnosed in 13 (23.2%). The pain was throbbing, holocranial or bilateral in the majority of patients. All patients had normal CSF analysis and RT-qPCR for SARS-CoV-2 was negative in all samples. Opening pressure >200 mmH2O was present in 11 patients and, in six of these, > 250 mmH2O. 6/13 patients had complete improvement of the pain, five had partial improvement, and two were left with a daily persistent headache. CONCLUSIONS: In a significant proportion of COVID-19 patients, headache was associated to intracranial hypertension in the absence of meningitic or encephalitic features. Coagulopathy associated with COVID-19 could be an explanation, but further studies including post-mortem analysis of areas of production and CSF absorption (choroid plexuses and arachnoid granulations) are necessary to clarify this issue.


Asunto(s)
Infecciones por Coronavirus/complicaciones , Hipertensión Intracraneal/virología , Neumonía Viral/complicaciones , Adulto , Anciano , Betacoronavirus , Presión del Líquido Cefalorraquídeo , Infecciones por Coronavirus/líquido cefalorraquídeo , Estudios Transversales , Femenino , Cefalea/líquido cefalorraquídeo , Cefalea/etiología , Humanos , Hipertensión Intracraneal/líquido cefalorraquídeo , Hipertensión Intracraneal/epidemiología , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/líquido cefalorraquídeo , Estudios Retrospectivos , Punción Espinal
4.
Int. J. Environ. Res. Public Health ; 17(24): 1-19, Nov. 10, 2020. ilus., tab
Artículo en Inglés | Coleciona SUS, CONASS, SES-RS | ID: biblio-1140629

RESUMEN

SARS-COV-2 is the causative agent of the current COVID-19 pandemic. Disease clinical manifestations range from asymptomatic to severe multiple organ damage. SARS-CoV-2 uses ACE2 as a cellular receptor, which is abundantly expressed in the small intestine, allowing viral replication in the gastrointestinal tract. Viral RNA has been detected in the stool of COVID-19 patients and viable viruses had been isolated in some of these samples. Thus, a putative role of SARS-CoV-2 fecal-oral transmission has been argued. SARS-CoV-2 is shed in human excreta and further disposed in the sewerage or in the environment, in poor basic sanitation settings. Wastewater-based epidemiology (WBE) is a valuable population level approach for monitoring viral pathogens and has been successfully used in di_erent contexts. This review summarizes the current global experience on SARS-CoV-2 WBE in distinct continents and viral detection in polluted surface water. The advantages and concerns of this strategy for SARS-CoV-2 surveillance are discussed. Outcomes suggest that WBE is a valuable early warning alert and a helpful complementary surveillance tool to subside public health response, to tailor containment and mitigation measures and to determine target populations for testing. In poor sanitation settings, contaminated rivers could be alternatively used as a source for environmental surveillance.


Asunto(s)
Humanos , Monitoreo del Ambiente/métodos , Infecciones por Coronavirus/epidemiología , Enfermedades Transmitidas por el Agua/epidemiología , Monitoreo Epidemiológico Basado en Aguas Residuales , Aguas Superficiales , Brotes de Enfermedades , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/transmisión , Aguas Residuales/análisis , Aguas Residuales/virología , Betacoronavirus/patogenicidad , Enfermedades Gastrointestinales/virología
5.
Artículo en Inglés | MEDLINE | ID: mdl-32754450

RESUMEN

Influenza is a major public health problem that causes acute respiratory infection in humans. Identification of host factors influencing in disease outcome is critical for recognition of individuals with increased risk. Investigations on the role of rs34481144A and rs12252C IFITM3 polymorphisms in influenza A(H1N1)pdm09 severity is not yet conclusively determined. This study aimed to evaluate such polymorphisms frequencies and IFITM3 levels in an infected Brazilian cohort of 314 influenza A(H1N1)pdm09 cases and its putative association with clinical, epidemiological and virological data. Individuals were clinically classified into mild, severe and fatal cases. IFITM3 polymorphisms were detected by specific Taqman probes in real time PCR reactions. IFITM3 levels were determined by quantitative real time PCR. Thus, the different clinical groups presented similar distribution of rs34481144 and rs12252 genotypes and allelic frequencies. There was no significant association between the polymorphisms with severity of disease by using distinct genetic models. Additionally, geographic distribution of mutants showed that rs34481144A allele was more predominant in Brazilian Southern region. In contrast, rs12252C allele presented similar frequencies in all regions. Individuals with the distinct rs34481144 and rs12252 genotypes showed similar levels of IFITM3 and viral load in their respiratory specimens. Furthermore, IFITM3 levels were comparable in the distinct clinical groups and were not correlated with influenza viral load in analyzed samples. Thereby, rs34481144A and rs12252C polymorphisms were not associated with severity or mortality of influenza A(H1N1)pdm09 infection nor with IFITM3 transcript levels and influenza viral load in upper respiratory tract samples in a Brazilian cohort.

6.
Antimicrob Agents Chemother ; 64(10)2020 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-32759267

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of clinically approved drugs to be repurposed to combat 2019 CoV disease (COVID-19) would allow the rapid implementation of potentially life-saving procedures. The major protease (Mpro) of SARS-CoV-2 is considered a promising target, based on previous results from related CoVs with lopinavir (LPV), an HIV protease inhibitor. However, limited evidence exists for other clinically approved antiretroviral protease inhibitors. Extensive use of atazanavir (ATV) as antiretroviral and previous evidence suggesting its bioavailability within the respiratory tract prompted us to study this molecule against SARS-CoV-2. Our results show that ATV docks in the active site of SARS-CoV-2 Mpro with greater strength than LPV, blocking Mpro activity. We confirmed that ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells and a human pulmonary epithelial cell line. ATV/RTV also impaired virus-induced enhancement of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.


Asunto(s)
Antivirales/farmacología , Sulfato de Atazanavir/farmacología , Betacoronavirus/efectos de los fármacos , Citocinas/metabolismo , Ritonavir/farmacología , Animales , Sulfato de Atazanavir/química , Betacoronavirus/patogenicidad , Betacoronavirus/fisiología , Muerte Celular/efectos de los fármacos , Chlorocebus aethiops , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/patología , Cisteína Endopeptidasas/química , Cisteína Endopeptidasas/metabolismo , Quimioterapia Combinada , Humanos , Inflamación/metabolismo , Inflamación/virología , Lopinavir/farmacología , Simulación del Acoplamiento Molecular , Monocitos/virología , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/metabolismo , Neumonía Viral/patología , Inhibidores de Proteasas/farmacología , Células Vero , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacos
9.
PLoS One ; 14(7): e0218925, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31283762

RESUMEN

Analyses of the 2009 H1N1 influenza pandemic and post-pandemic years showed high attack rates and severity among indigenous populations. This study presents the characteristics of the first documented influenza outbreak in indigenous peoples in Brazil, that occurred from 30th March to 14th April 2016 in a Guarani village in Southeast Region. Acute respiratory infections were prospectively investigated. The majority of the 73 cases were influenza-like illness (ILI) (63.0%) or severe acute respiratory infection (SARI) (20.5%). The ILI+SARI attack rate (35.9%) decreased with increasing age. There was a high influenza vaccination rate (86.3%), but no statistically significant difference in vaccination rates between severe and non-severe cases was seen (p = 0.334). Molecular analyses of 19.2% of the cases showed 100% positivity for influenza A(H1N1)pdm09 and/or hRSV. Influenza A(H1N1)pdm09 was included in the 6B.1 genetic group, a distinct cluster with 13 amino acid substitutions of A/California/07/2009-like. The hRSV were clustered in the BA-like genetic group. The early arrival of the influenza season overlapping usual hRSV season, the circulation of a drifted influenza virus not covered by vaccine and the high prevalence of risk factors for infection and severity in the village jointly can explain the high attack rate of ARI, even with a high rate of influenza vaccination. The results reinforce the importance of surveillance of respiratory viruses, timely vaccination and controlling risk factors for infection and severity of in the indigenous populations in order to preventing disease and related deaths, particularly in children.


Asunto(s)
Vacunas contra la Influenza/uso terapéutico , Gripe Humana/epidemiología , Trastornos Respiratorios/epidemiología , Infecciones del Sistema Respiratorio/epidemiología , Adolescente , Brasil/epidemiología , Niño , Preescolar , Brotes de Enfermedades , Femenino , Humanos , Lactante , Subtipo H1N1 del Virus de la Influenza A/patogenicidad , Gripe Humana/prevención & control , Gripe Humana/virología , Masculino , Trastornos Respiratorios/prevención & control , Trastornos Respiratorios/virología , Infecciones del Sistema Respiratorio/prevención & control , Infecciones del Sistema Respiratorio/virología , Estaciones del Año , Vacunación
10.
J Exp Med ; 216(9): 2057-2070, 2019 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-31270247

RESUMEN

Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease. Severe illness by MMR vaccines can be caused by inborn errors of type I and/or III interferon (IFN) immunity (mutations in IFNAR2, STAT1, or STAT2). Adverse reactions to the YF vaccine have remained unexplained. We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients' fibroblast phenotypes are rescued with WT IFNAR1 Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals.


Asunto(s)
Patrón de Herencia/genética , Vacuna Antisarampión/efectos adversos , Receptor de Interferón alfa y beta/deficiencia , Vacuna contra la Fiebre Amarilla/efectos adversos , Adolescente , Alelos , Niño , Femenino , Humanos , Inmunidad , Lactante , Interferón Tipo I/metabolismo , Masculino , Vacuna Antisarampión/inmunología , Proteínas Mutantes/metabolismo , Mutación/genética , Linaje , Receptor de Interferón alfa y beta/genética , Transducción de Señal , Vacuna contra la Fiebre Amarilla/inmunología
11.
BMC Infect Dis ; 19(1): 415, 2019 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-31088481

RESUMEN

BACKGROUND: The Global Influenza Hospital Surveillance Network is an international platform whose primary objective is to study severe cases of influenza requiring hospitalization. METHODS: During the 2015-2016 influenza season, 11 sites in the Global Influenza Hospital Surveillance Network in nine countries (Russian Federation, Czech Republic, Turkey, France, China, Spain, Mexico, India, and Brazil) participated in a prospective, active-surveillance, hospital-based epidemiological study. Influenza infection was confirmed by reverse transcription-polymerase chain reaction. Influenza vaccine effectiveness (IVE) against laboratory-confirmed influenza was estimated using a test-negative approach. RESULTS: 9882 patients with laboratory results were included of which 2415 (24.4%) were positive for influenza, including 1415 (14.3%) for A(H1N1)pdm09, 235 (2.4%) for A(H3N2), 180 (1.8%) for A not subtyped, 45 (0.5%) for B/Yamagata-lineage, 532 (5.4%) for B/Victoria-lineage, and 33 (0.3%) for B not subtyped. Of included admissions, 39% were < 5 years of age and 67% had no underlying conditions. The odds of being admitted with influenza were higher among pregnant than non-pregnant women (odds ratio, 2.82 [95% confidence interval (CI), 1.90 to 4.19]). Adjusted IVE against influenza-related hospitalization was 16.3% (95% CI, 0.4 to 29.7). Among patients targeted for influenza vaccination, adjusted IVE against hospital admission with influenza was 16.2% (95% CI, - 3.6 to 32.2) overall, 23.0% (95% CI, - 3.3 to 42.6) against A(H1N1)pdm09, and - 25.6% (95% CI, - 86.3 to 15.4) against B/Victoria lineage. CONCLUSIONS: The 2015-2016 influenza season was dominated by A(H1N1)pdm09 and B/Victoria-lineage. Hospitalization with influenza often occurred in healthy and young individuals, and pregnant women were at increased risk of influenza-related hospitalization. Influenza vaccines provided low to moderate protection against hospitalization with influenza and no protection against the predominant circulating B lineage, highlighting the need for more effective and broader influenza vaccines.


Asunto(s)
Vacunas contra la Influenza/inmunología , Gripe Humana/diagnóstico , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Subtipo H3N2 del Virus de la Influenza A/aislamiento & purificación , Gripe Humana/epidemiología , Gripe Humana/prevención & control , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Embarazo , Estudios Prospectivos , Estaciones del Año , Resultado del Tratamiento , Adulto Joven
12.
Infect Genet Evol ; 67: 55-59, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30389547

RESUMEN

BACKGROUND: Influenza is an acute and highly contagious viral respiratory infection that causes significant morbidity and mortality. The identification of host genetic factors associated with susceptibility and severity of influenza virus infection is of paramount importance. Previous studies evaluating the potential involvement of the CCR5Δ32 polymorphism (rs333), a 32 base pair deletion in CC motif chemokine receptor 5 (CCR5) gene, in severity and mortality of influenza A(H1N1)pdm09 infected individuals have been reported, but their results are quite conflicting. OBJECTIVES: The aim of this study was the evaluation of the CCR5Δ32 frequency in individuals with mild, severe and fatal influenza A(H1N1)pdm09 infection and its putative association with clinical and epidemiologic data. PATIENTS/METHODS: A total of 432 individuals were included in this study and classified according to their clinical status, into the following groups: influenza like illness (ILI) (n = 153); severe acute respiratory infection (SARI) (n = 173) and fatal (n = 106) cases. The samples were collected in the post pandemic period, from 2012 to 2018. Individuals were further stratified according to their clinical and epidemiological data. The CCR5Δ32 variant was genotyped by PCR amplification and a subset of samples was further submitted to Sanger sequencing. RESULTS: The different clinical groups (ILI, SARI and fatal) presented similar distribution of wt/wt and wt/Δ32 genotypes and CCR5Δ32 allele frequencies. Genotype Δ32/Δ32 was not detected in our study. Additionally, no association between wt/wt and wt/Δ32 genotypes and dyspnea, a clinical factor for influenza complications was found. Similarly, no significant differences in the distribution of wt/wt and wt/Δ32 genotypes and CCR5Δ32 variant allele frequencies were observed in samples from the different Brazilian geographical regions. CONCLUSIONS: The CCR5Δ32 variant does not influence the susceptibility to influenza A(H1N1)pdm09 severe disease or mortality in individuals from Brazil.


Asunto(s)
Predisposición Genética a la Enfermedad , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana/epidemiología , Gripe Humana/genética , Polimorfismo Genético , Receptores CCR5/genética , Eliminación de Secuencia , Adulto , Alelos , Brasil/epidemiología , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Gripe Humana/mortalidad , Gripe Humana/virología , Masculino , Persona de Mediana Edad , Mortalidad , Vigilancia en Salud Pública , Índice de Severidad de la Enfermedad
13.
J Gen Virol ; 99(12): 1608-1613, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30394870

RESUMEN

Influenza A and B virions are packaged with their polymerases to catalyse RNA-dependent RNA polymerase activity. Since there is no evidence to rule in or out the permissiveness of influenza virions to triphosphate ribonucleotides, we functionally evaluated this. We found the means to stimulate influenza A and B RNA polymerase activity inside the virion, called natural endogenous RNA polymerase (NERP) activity. Stimulation of NERP activity increased up to 3 log10 viral RNA content, allowing the detection of influenza virus in otherwise undetectable clinical samples. NERP activation also improved our capacity to sequence misidentified regions of the influenza genome from clinical samples. By treating the samples with the ribavirin triphosphate we inhibited NERP activity, which confirms our hypothesis and highlights that this assay could be used to screen antiviral drugs. Altogether, our data show that NERP activity could be explored to increase molecular diagnostic sensitivity and/or to develop antiviral screening assays.


Asunto(s)
ARN Polimerasas Dirigidas por ADN/análisis , Virus de la Influenza A/enzimología , Virus de la Influenza B/enzimología , Virión/enzimología , Antivirales/metabolismo , Inhibidores Enzimáticos/metabolismo , ARN Viral/biosíntesis , Ribavirina/metabolismo , Ribonucleótidos/metabolismo , Ensamble de Virus
14.
Front Immunol ; 9: 975, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29867955

RESUMEN

Influenza A virus (IAV) infection causes severe pulmonary disease characterized by intense leukocyte infiltration. Phosphoinositide-3 kinases (PI3Ks) are central signaling enzymes, involved in cell growth, survival, and migration. Class IB PI3K or phosphatidyl inositol 3 kinase-gamma (PI3Kγ), mainly expressed by leukocytes, is involved in cell migration during inflammation. Here, we investigated the contribution of PI3Kγ for the inflammatory and antiviral responses to IAV. PI3Kγ knockout (KO) mice were highly susceptible to lethality following infection with influenza A/WSN/33 H1N1. In the early time points of infection, infiltration of neutrophils was higher than WT mice whereas type-I and type-III IFN expression and p38 activation were reduced in PI3Kγ KO mice resulting in higher viral loads when compared with WT mice. Blockade of p38 in WT macrophages infected with IAV reduced levels of interferon-stimulated gene 15 protein to those induced in PI3Kγ KO macrophages, suggesting that p38 is downstream of antiviral responses mediated by PI3Kγ. PI3Kγ KO-derived fibroblasts or macrophages showed reduced type-I IFN transcription and altered pro-inflammatory cytokines suggesting a cell autonomous imbalance between inflammatory and antiviral responses. Seven days after IAV infection, there were reduced infiltration of natural killer cells and CD8+ T lymphocytes, increased concentration of inflammatory cytokines in bronchoalveolar fluid, reduced numbers of resolving macrophages, and IL-10 levels in PI3Kγ KO. This imbalanced environment in PI3Kγ KO-infected mice culminated in enhanced lung neutrophil infiltration, reactive oxygen species release, and lung damage that together with the increased viral loads, contributed to higher mortality in PI3Kγ KO mice compared with WT mice. In humans, we tested the genetic association of disease severity in influenza A/H1N1pdm09-infected patients with three potentially functional PIK3CG single-nucleotide polymorphisms (SNPs), rs1129293, rs17847825, and rs2230460. We observed that SNPs rs17847825 and rs2230460 (A and T alleles, respectively) were significantly associated with protection from severe disease using the recessive model in patients infected with influenza A(H1N1)pdm09. Altogether, our results suggest that PI3Kγ is crucial in balancing antiviral and inflammatory responses to IAV infection.


Asunto(s)
Fosfatidilinositol 3-Quinasa Clase Ib/genética , Inflamación , Gripe Humana/inmunología , Infecciones por Orthomyxoviridae/inmunología , Adolescente , Adulto , Animales , Antivirales , Linfocitos T CD8-positivos/inmunología , Fosfatidilinositol 3-Quinasa Clase Ib/inmunología , Citocinas/inmunología , Modelos Animales de Enfermedad , Femenino , Estudios de Asociación Genética , Humanos , Subtipo H1N1 del Virus de la Influenza A , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Infiltración Neutrófila , Polimorfismo de Nucleótido Simple , Adulto Joven
15.
Antiviral Res ; 154: 35-43, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29601892

RESUMEN

Neuraminidase inhibitors (NAIs) are the main class of antivirals currently used for the treatment of influenza infections. As influenza viruses are constantly evolving, drug-resistance can emerge resulting in reduced effectiveness of treatment. This study evaluated the presence of molecular markers associated with NAI susceptibility in 724 influenza A(H1N1)pdm09 positive samples from Brazilian surveillance system from the 2014-2016 seasons, including 76 isolates tested for oseltamivir (OST) susceptibility and 23 isolates also tested for zanamivir, peramivir and laninamivir susceptibility. We identified the H275Y (n = 3) and I223K (n = 1) NA substitutions, associated with reduced inhibition (RI) by the NAIs. Noteworthy, no epidemiological links were identified among the patients infected with the mutant viruses. Phylogenetic analysis from NA and hemagglutinin genes showed that mutant viruses were not clustered. All mutant virus strains carried the permissive substitutions V241I and N369K, in addition to the N386K, which has been shown to destabilize the NA structure. Functional NA analysis of one virus containing the H275Y mutation confirmed its highly RI profile to OST and peramivir and demonstrated that it had decreased viral replication and NA thermostability compared to the wild type virus. The remaining tested isolates presented normal inhibition profile to the NAIs tested. In conclusion, the overall frequency of influenza A(H1N1)pdm09 viruses bearing mutations associated with NAI RI was 0.6%, similar to what has been observed in recent global studies.


Asunto(s)
Antivirales/farmacología , Farmacorresistencia Viral/genética , Inhibidores Enzimáticos/farmacología , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H1N1 del Virus de la Influenza A/genética , Neuraminidasa/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Monitoreo Epidemiológico , Femenino , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Humanos , Lactante , Recién Nacido , Gripe Humana/tratamiento farmacológico , Gripe Humana/epidemiología , Masculino , Persona de Mediana Edad , Mutación , Neuraminidasa/genética , Replicación Viral/efectos de los fármacos , Adulto Joven
16.
BMJ Open ; 8(2): e017603, 2018 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-29449287

RESUMEN

BACKGROUND: Influenza-like illness occurs annually worldwide, with peak timing and severity varying seasonally, resulting in significant annual mortality. OBJECTIVES: There were three objectives: (1) to describe the epidemiological and clinical features of hospitalised patients with severe acute respiratory infection caused by influenza and other respiratory viruses (ORVs); (2) to report the influenza seasonality in the region and (3) to correlate findings of influenza circulation and immunisation time in Brazil. PATIENTS/METHODS: This study took place in three Brazilian hospitals located in cities with different climatic conditions (Curitiba (south), Rio de Janeiro (south-east) and Fortaleza (north-east)). Patients presenting with an acute process with indication for admission consisting of a predefined set of conditions potentially associated with recent influenza infection were enrolled. RESULTS: We screened 1666 patients, with 595 meeting the inclusion criteria. Influenza viruses and ORVs were detected in 6.5% and 59% of patients, respectively. Influenza-positive cases fell into the severe spectrum as compared with those with ORVs (30% vs 11%), but without any difference in mortality rates. Epidemiological results revealed variations in the peak time of influenza infections between north-east (Fortaleza) and south (Curitiba) Brazil, basically following the rain period of each region. In north-east Brazil, viral circulation was prevalent in the first 4 months of the year, indicating that the vaccination campaign occurred in a postseasonal period, possibly explaining the low effectiveness. CONCLUSIONS: The active-surveillance model is a valuable tool for investigating respiratory virus impact on hospitalised patients, with influenza-infection monitoring enabling implementation of adequate preventive measures.


Asunto(s)
Clima , Hospitalización , Hospitales , Vacunas contra la Influenza , Gripe Humana/epidemiología , Estaciones del Año , Vacunación , Adolescente , Adulto , Anciano , Brasil/epidemiología , Niño , Preescolar , Ciudades , Femenino , Humanos , Programas de Inmunización , Lactante , Gripe Humana/prevención & control , Gripe Humana/virología , Masculino , Persona de Mediana Edad , Vigilancia de la Población/métodos , Prevalencia , Infecciones del Sistema Respiratorio , Adulto Joven
17.
Antiviral Res ; 146: 12-20, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28802866

RESUMEN

Four World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance, Epidemiology and Control of Influenza (WHO CCs) assessed antiviral susceptibility of 14,330 influenza A and B viruses collected by WHO-recognized National Influenza Centres (NICs) between May 2015 and May 2016. Neuraminidase (NA) inhibition assay was used to determine 50% inhibitory concentration (IC50) data for NA inhibitors (NAIs) oseltamivir, zanamivir, peramivir and laninamivir. Furthermore, NA sequences from 13,484 influenza viruses were retrieved from public sequence databases and screened for amino acid substitutions (AAS) associated with reduced inhibition (RI) or highly reduced inhibition (HRI) by NAIs. Of the viruses tested by WHO CCs 93% were from three WHO regions: Western Pacific, the Americas and Europe. Approximately 0.8% (n = 113) exhibited either RI or HRI by at least one of four NAIs. As in previous seasons, the most common NA AAS was H275Y in A(H1N1)pdm09 viruses, which confers HRI by oseltamivir and peramivir. Two A(H1N1)pdm09 viruses carried a rare NA AAS, S247R, shown in this study to confer RI/HRI by the four NAIs. The overall frequency of A(H1N1)pdm09 viruses containing NA AAS associated with RI/HRI was approximately 1.8% (125/6915), which is slightly higher than in the previous 2014-15 season (0.5%). Three B/Victoria-lineage viruses contained a new AAS, NA H134N, which conferred HRI by zanamivir and laninamivir, and borderline HRI by peramivir. A single B/Victoria-lineage virus harboured NA G104E, which was associated with HRI by all four NAIs. The overall frequency of RI/HRI phenotype among type B viruses was approximately 0.6% (43/7677), which is lower than that in the previous season. Overall, the vast majority (>99%) of the viruses tested by WHO CCs were susceptible to all four NAIs, showing normal inhibition (NI). Hence, NAIs remain the recommended antivirals for treatment of influenza virus infections. Nevertheless, our data indicate that it is prudent to continue drug susceptibility monitoring using both NAI assay and sequence analysis.


Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza B/efectos de los fármacos , Neuraminidasa/antagonistas & inhibidores , Ácidos Carbocíclicos , Sustitución de Aminoácidos , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Ciclopentanos/farmacología , Farmacorresistencia Viral/genética , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/uso terapéutico , Monitoreo Epidemiológico , Salud Global , Guanidinas/farmacología , Humanos , Subtipo H1N1 del Virus de la Influenza A/enzimología , Subtipo H1N1 del Virus de la Influenza A/genética , Virus de la Influenza B/enzimología , Virus de la Influenza B/genética , Gripe Humana/tratamiento farmacológico , Gripe Humana/virología , Concentración 50 Inhibidora , Pruebas de Sensibilidad Microbiana , Oseltamivir/farmacología , Piranos , Estaciones del Año , Ácidos Siálicos , Organización Mundial de la Salud , Zanamivir/análogos & derivados
18.
Braz. j. infect. dis ; 21(1): 102-106, Jan.-Feb. 2017. graf
Artículo en Inglés | LILACS | ID: biblio-1039181

RESUMEN

Abstract This study was conducted to provide information on the genetic diversity of human parvovirus B19 (B19V) circulating in the municipality of Niterói, Rio de Janeiro, Southeast Brazil during 1996-2006, a period with two distinct outbreaks of B19V infection: 1999-2000 and 2004-2005. A total of 27 sera from patients with erythema infectiosum and five sera from HIV-infected patients that tested positive for B19V DNA during the study period were analyzed. To genotype B19V strains, a semi-nested PCR for partial amplification of the capsid gene was performed and sequence analysis revealed that 31 sequences belonged to subgenotype 1a (G1a) of the main genotype 1 and one sequence was characterized as subgenotype 3b (G3b). The phylogenetic tree supported the division of the G1a into two well-defined clades with 1.3% of divergence. The low diversity of the G1a strains may be explained by the fact that all patients had acute B19V infection and 30/32 sera were collected during two distinct outbreaks. The G3b strain was from an HIV-infected patient who seroconverted to anti-B19 IgG antibodies in September/2005. This is the first report of G3b in the state of Rio de Janeiro.


Asunto(s)
Humanos , Masculino , Femenino , Niño , Adolescente , Adulto , Persona de Mediana Edad , Adulto Joven , Brotes de Enfermedades , Parvovirus B19 Humano/genética , Eritema Infeccioso/epidemiología , Eritema Infeccioso/virología , Filogenia , Brasil/epidemiología , Reacción en Cadena de la Polimerasa , Eritema Infeccioso/genética , Análisis de Secuencia de ADN , Genotipo
19.
Front Immunol ; 8: 1799, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29326698

RESUMEN

Rationale: Influenza A infections are a leading cause of morbidity and mortality worldwide especially when associated with secondary pneumococcal infections. Inflammation is important to control pathogen proliferation but may also cause tissue injury and death. CXCR1/2 are chemokine receptors relevant for the recruitment of neutrophils. We investigated the role of CXCR1/2 during influenza, pneumococcal, and post-influenza pneumococcal infections. Methods: Mice were infected with influenza A virus (IAV) or Streptococcus pneumoniae and then treated daily with the CXCR1/2 antagonist DF2162. To study secondary pneumococcal infection, mice were infected with a sublethal inoculum of IAV then infected with S. pneumoniae 14 days later. DF2162 was given in a therapeutic schedule from days 3 to 6 after influenza infection. Lethality, weight loss, inflammation, virus/bacteria counts, and lung injury were assessed. Results: CXCL1 and CXCL2 were produced at high levels during IAV infection. DF2162 treatment decreased morbidity and this was associated with decreased infiltration of neutrophils in the lungs and reduced pulmonary damage and viral titers. During S. pneumoniae infection, DF2162 treatment decreased neutrophil recruitment, pulmonary damage, and lethality rates, without affecting bacteria burden. Therapeutic treatment with DF2162 during sublethal IAV infection reduced the morbidity associated with virus infection and also decreased the magnitude of inflammation, lung damage, and number of bacteria in the blood of mice subsequently infected with S. pneumoniae. Conclusion: Modulation of the inflammatory response by blocking CXCR1/2 improves disease outcome during respiratory influenza and pneumococcal infections, without compromising the ability of the murine host to deal with infection. Altogether, inhibition of CXCR1/2 may be a valid therapeutic strategy for treating lung infections caused by these pathogens, especially controlling secondary bacterial infection after influenza.

20.
Emerg Infect Dis ; 23(1): 152-154, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27983507
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