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1.
Vet Q ; 40(1): 83-96, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32083983

RESUMO

Background: Bovine orthopneumovirus, formerly known as bovine respiratory syncytial virus (BRSV), is frequently associated with bovine respiratory disease (BRD).Aim: To perform the molecular characterization of the G and F proteins of Brazilian wild-type BRSV strains derived from bovine respiratory infections in both beef and dairy cattle.Materials and Methods: Ten BRSV strains derived from a dairy heifer rearing unit (n = 3) in 2011 and steers of three other feedlots (n = 7) in 2014 and 2015 were analyzed. For the BRSV G and F partial gene amplifications, RT-nested-PCR assays were performed with sequencing in both directions with forward and reverse primers used.Results: The G gene-based analysis revealed that two strains were highly similar to the BRSV sequences representative of subgroup III, including the Bayovac vaccine strain. However, the remaining seven Brazilian BRSV strains were diverse when compared with strains representative of the BRSV I to VIII subgroups. The central hydrophobic region of the Brazilian BRSV G gene showed the replacement of conserved cysteines and other residues of importance to antibody reactivity. The deduced F gene amino acid sequences from the Brazilian BRSV strains showed changes that were absent in the representative sequences of the known subgroups. Viral isolation on the nasopharyngeal swab suspensions failed to isolate BRSV.Conclusion: Results suggest that these strains represent a putative new subgroup of BRSV with mutations observed in the immunodominant region of the G protein. However, further studies on these Brazilian BRSV strains should be performed to establish their pathogenic potential.


Assuntos
Doenças dos Bovinos/virologia , Infecções por Vírus Respiratório Sincicial/veterinária , Vírus Sincicial Respiratório Bovino/classificação , Vírus Sincicial Respiratório Bovino/genética , Animais , Brasil , Bovinos , Feminino , Variação Genética , Masculino , Filogenia , Reação em Cadeia da Polimerase/veterinária , Infecções por Vírus Respiratório Sincicial/virologia , Análise de Sequência
2.
Medicine (Baltimore) ; 99(2): e18504, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914021

RESUMO

We aimed to evaluate the clinical significance of bacterial coexistence and the coinfection dynamics between bacteria and respiratory viruses among young children. We retrospectively analyzed clinical data from children aged < 5 years hospitalized with a community-acquired single respiratory viral infection of influenza, adenovirus, or RSV during 2 recent consecutive influenza seasons. Remnant respiratory specimens were used for bacterial PCR targeting Moraxella catarrhalis, Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus.A total of 102 children were included; median age was 0.8 years and 44.1% had underlying comorbidities. Overall, 6.8% (7/102) of cases were classified as severe diseases requiring intensive care unit admission and/or mechanical ventilation and ranged from 8.8% for a patient with RSV and 7.6% for those with adenovirus to 0% for those with influenza viruses. The overall viral-bacterial codetection rate was 59.8% (61/102); M catarrhalis was the most frequent (33.3%), followed by H influenzae (31.4%). Influenza cases showed higher bacterial codetection rates (80.0%; 8/10) compared with those with adenoviruses (69.2%; 9/13) and RSV (55.7%; 44/79). S pneumoniae and H influenzae codetections were associated with reduced severity (aOR, 0.24; 95% CI, 0.07-0.89), and reduced risk of wheezing (aOR, 0.36; 95% CI, 0.13-0.98), respectively.We observed the interactions between respiratory viruses and bacteria and the clinical significance of viral-bacterial coexistence in upper airway on disease severity. Future study will be necessary to elucidate the active interactions between different viruses and bacteria and give clues to risk stratified strategy in the management of respiratory infections among young children.


Assuntos
Adenoviridae/isolamento & purificação , Haemophilus influenzae/isolamento & purificação , Infecções Respiratórias/microbiologia , Infecções Respiratórias/virologia , Infecções por Adenoviridae/diagnóstico , Infecções por Adenoviridae/virologia , Bactérias/genética , Pré-Escolar , Coinfecção/microbiologia , Coinfecção/virologia , Infecções Comunitárias Adquiridas/diagnóstico , Infecções Comunitárias Adquiridas/microbiologia , Infecções Comunitárias Adquiridas/virologia , Feminino , Hospitalização , Humanos , Lactente , Recém-Nascido , Influenza Humana/diagnóstico , Influenza Humana/virologia , Masculino , Prevalência , Sons Respiratórios/diagnóstico , Sons Respiratórios/etiologia , Infecções por Vírus Respiratório Sincicial/diagnóstico , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/genética , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/epidemiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Staphylococcus aureus/isolamento & purificação , Streptococcus pneumoniae/isolamento & purificação , Vírus/genética
3.
PLoS Pathog ; 15(10): e1007984, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31622448

RESUMO

Human respiratory syncytial virus (RSV) is the most important cause of acute lower respiratory tract disease in infants worldwide. As a first line of defense against respiratory infections, innate immune responses, including the production of type I and III interferons (IFNs), play an important role. Upon infection with RSV, multiple pattern recognition receptors (PRRs) can recognize RSV-derived pathogen-associated molecular patterns (PAMPs) and mount innate immune responses. Retinoic-acid-inducible gene-I (RIG-I) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) have been identified as important innate receptors to mount type I IFNs during RSV infection. However, type I IFN levels remain surprisingly low during RSV infection despite strong viral replication. The poor induction of type I IFNs can be attributed to the cooperative activity of 2 unique, nonstructural (NS) proteins of RSV, i.e., NS1 and NS2. These viral proteins have been shown to suppress both the production and signaling of type I and III IFNs by counteracting a plethora of key host innate signaling proteins. Moreover, increasing numbers of IFN-stimulated genes (ISGs) are being identified as targets of the NS proteins in recent years, highlighting an underexplored protein family in the identification of NS target proteins. To understand the diverse effector functions of NS1 and NS2, Goswami and colleagues proposed the hypothesis of the NS degradasome (NSD) complex, a multiprotein complex made up of, at least, NS1 and NS2. Furthermore, the crystal structure of NS1 was resolved recently and, remarkably, identified NS1 as a structural paralogue of the RSV matrix protein. Unfortunately, no structural data on NS2 have been published so far. In this review, we briefly describe the PRRs that mount innate immune responses upon RSV infection and provide an overview of the various effector functions of NS1 and NS2. Furthermore, we discuss the ubiquitination effector functions of NS1 and NS2, which are in line with the hypothesis that the NSD shares features with the canonical 26S proteasome.


Assuntos
Imunidade Inata , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Proteínas não Estruturais Virais/metabolismo , Humanos , Infecções por Vírus Respiratório Sincicial/metabolismo , Infecções por Vírus Respiratório Sincicial/virologia , Transdução de Sinais , Ubiquitinação , Replicação Viral
4.
Nat Commun ; 10(1): 4595, 2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31597913

RESUMO

N6-methyladenosine (m6A) is the most prevalent internal modification of mRNAs in most eukaryotes. Here we show that RNAs of human respiratory syncytial virus (RSV) are modified by m6A within discreet regions and that these modifications enhance viral replication and pathogenesis. Knockdown of m6A methyltransferases decreases RSV replication and gene expression whereas knockdown of m6A demethylases has the opposite effect. The G gene transcript contains the most m6A modifications. Recombinant RSV variants expressing G transcripts that lack particular clusters of m6A display reduced replication in A549 cells, primary well differentiated human airway epithelial cultures, and respiratory tracts of cotton rats. One of the m6A-deficient variants is highly attenuated yet retains high immunogenicity in cotton rats. Collectively, our results demonstrate that viral m6A methylation upregulates RSV replication and pathogenesis and identify viral m6A methylation as a target for rational design of live attenuated vaccine candidates for RSV and perhaps other pneumoviruses.


Assuntos
Adenosina/análogos & derivados , Infecções por Vírus Respiratório Sincicial/imunologia , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Replicação Viral/imunologia , Células A549 , Adenosina/genética , Adenosina/imunologia , Adenosina/metabolismo , Animais , Anticorpos Antivirais/imunologia , Feminino , Células HeLa , Humanos , Masculino , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/genética , Vírus Sincicial Respiratório Humano/patogenicidade , Sigmodontinae , Regulação para Cima/imunologia , Vacinas Atenuadas/imunologia , Células Vero , Virulência/genética , Virulência/imunologia , Replicação Viral/genética
5.
BMJ ; 366: l5021, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506273

RESUMO

Human respiratory syncytial virus (RSV) belongs to the recently defined Pneumoviridae family, Orthopneumovirus genus. It is a negative sense, single stranded RNA virus that results in epidemics of respiratory infections that typically peak in the winter in temperate climates and during the rainy season in tropical climates. Generally, one of the two genotypes (A and B) predominates in a single season, alternating annually, although regional variation occurs. RSV is a cause of disease and death in children, older people, and immunocompromised patients, and its clinical effect on adults admitted to hospital is clarified with expanded use of multiplex molecular assays. Among adults, RSV produces a wide range of clinical symptoms including upper respiratory tract infections, severe lower respiratory tract infections, and exacerbations of underlying disease. Here we discuss the latest evidence on the burden of RSV related disease in adults, especially in those with immunocompromise or other comorbidities. We review current therapeutic and prevention options, as well as those in development.


Assuntos
Carga Global da Doença , Infecções por Vírus Respiratório Sincicial/epidemiologia , Vírus Sinciciais Respiratórios/genética , Infecções Respiratórias/epidemiologia , Adulto , Antivirais/uso terapêutico , Epidemias , Genótipo , Humanos , Hospedeiro Imunocomprometido , Imunoglobulinas Intravenosas/uso terapêutico , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/terapia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/patogenicidade , Infecções Respiratórias/imunologia , Infecções Respiratórias/terapia , Infecções Respiratórias/virologia , Ribavirina/uso terapêutico , Estações do Ano
6.
Internist (Berl) ; 60(11): 1146-1150, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31486858

RESUMO

Respiratory syncytial virus (RSV) is worldwide a very important virus leading to infection of the respiratory system. In particular preterm babies, infants and elderly adults are prone to developing severe diseases such as bronchiolitis or pneumonia, which require intensive care and cause increased mortality. Although RSV is rapidly detected, preventive and therapeutic measures are limited. New antivirals are already in clinical trials.


Assuntos
Antivirais/administração & dosagem , Bronquiolite/diagnóstico , Bronquiolite/prevenção & controle , Infecções por Vírus Respiratório Sincicial/diagnóstico , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vírus Sincicial Respiratório Humano/isolamento & purificação , Adulto , Idoso , Antivirais/uso terapêutico , Bronquiolite/tratamento farmacológico , Bronquiolite/virologia , Bronquiolite Viral/diagnóstico , Bronquiolite Viral/virologia , Humanos , Lactente , Recém-Nascido , Pneumonia/diagnóstico , Pneumonia/virologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/imunologia , Fatores de Risco
7.
PLoS Pathog ; 15(8): e1007963, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31381610

RESUMO

Human respiratory syncytial virus (RSV) is the leading viral cause of acute pediatric lower respiratory tract infections worldwide, with no available vaccine or effective antiviral drug. To gain insight into virus-host interactions, we performed a genome-wide siRNA screen. The expression of over 20,000 cellular genes was individually knocked down in human airway epithelial A549 cells, followed by infection with RSV expressing green fluorescent protein (GFP). Knockdown of expression of the cellular ATP1A1 protein, which is the major subunit of the Na+,K+-ATPase of the plasma membrane, had one of the strongest inhibitory effects on GFP expression and viral titer. Inhibition was not observed for vesicular stomatitis virus, indicating that it was RSV-specific rather than a general effect. ATP1A1 formed clusters in the plasma membrane very early following RSV infection, which was independent of replication but dependent on the attachment glycoprotein G. RSV also triggered activation of ATP1A1, resulting in signaling by c-Src-kinase activity that transactivated epidermal growth factor receptor (EGFR) by Tyr845 phosphorylation. ATP1A1 signaling and activation of both c-Src and EGFR were found to be required for efficient RSV uptake. Signaling events downstream of EGFR culminated in the formation of macropinosomes. There was extensive uptake of RSV virions into macropinosomes at the beginning of infection, suggesting that this is a major route of RSV uptake, with fusion presumably occurring in the macropinosomes rather than at the plasma membrane. Important findings were validated in primary human small airway epithelial cells (HSAEC). In A549 cells and HSAEC, RSV uptake could be inhibited by the cardiotonic steroid ouabain and the digitoxigenin derivative PST2238 (rostafuroxin) that bind specifically to the ATP1A1 extracellular domain and block RSV-triggered EGFR Tyr845 phosphorylation. In conclusion, we identified ATP1A1 as a host protein essential for macropinocytic entry of RSV into respiratory epithelial cells, and identified PST2238 as a potential anti-RSV drug.


Assuntos
Pinocitose , Infecções por Vírus Respiratório Sincicial/complicações , Vírus Sincicial Respiratório Humano/patogenicidade , Infecções Respiratórias/prevenção & controle , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Proteínas Virais/metabolismo , Internalização do Vírus , Células A549 , Cardiotônicos/farmacologia , Digitoxigenina/química , Digitoxigenina/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Células Epiteliais/virologia , Receptores ErbB/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Ouabaína/farmacologia , RNA Interferente Pequeno/genética , Infecções por Vírus Respiratório Sincicial/virologia , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/enzimologia , Sistema Respiratório/virologia , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/virologia , Transdução de Sinais , ATPase Trocadora de Sódio-Potássio/genética , Proteínas Virais/genética
8.
Mol Biol (Mosk) ; 53(4): 541-560, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31397431

RESUMO

The human respiratory syncytial virus (RSV) is one of the most common viral pathogens that affects the lower respiratory tract and could be a reason of bronchiolitis and/or pneumonia. Currently, there are no available effective ways of treating the RSV infection. Attempts to develop preventive vaccine have been unsuccessful. The only therapeutic agent used for RSV treatment is virazole (ribavirin); however, it induces adverse effects. Medications based on neutralizing monoclonal antibodies, such as IGIV (Respigam), palivizumab (Synagis), and MEDI-524 (Numab), are under clinical trials; however, their use will be limited by their high cost. One of the promising approaches for antiviral therapy is the use of natural peptides (defensins and cathelicidins), or their synthetic analogs. The majority of currently described antiviral peptides are developed against the human immunodeficiency virus, the herpes simplex virus, and the influenza virus. At the same time, a body of experimental data evidencing anti-RSV activity of peptides has been accumulated. The main advantages of peptide drugs are their wide spectrum of antiviral activity and low toxicity. However, there are obstacles in implementing peptide-based drugs in clinical practice. Due to their low resistance to the action of serum proteases, most authors consider peptides promising only for local application. Given that RSV affects the epithelium of the respiratory tract, where the protease activity is lower than in the systemic circulation, it is possible to develop locally active peptide drugs, for example, as inhalation forms. Their stability could also be increased by the synthesis of dendrimer peptides and by the development of recombinant peptides as precursor proteins. Anti-RSV peptides can be divided into several groups: (1) attachment and/or fusion blockers; (2) peptides displaying direct virucidal activity, disrupting the viral envelope. Such peptides, which suppress early stages of the viral life cycle, are considered prophylactic agents. However, for several peptides, their immunoregulatory properties have been described, which opens the possibility for therapeutic use. This review summarizes the information on the antiviral properties of such peptides and mechanisms of their action and describes the prospects of the future development of antiviral peptides.


Assuntos
Antivirais/farmacologia , Peptídeos/farmacologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Antivirais/uso terapêutico , Humanos , Peptídeos/uso terapêutico
9.
BMC Infect Dis ; 19(1): 729, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429710

RESUMO

BACKGROUND: No comparison data have been reported on viral and epidemiological profiles of hospitalized children with severe acute respiratory infection (SARI) in Beijing or Shanghai, China. METHODS: We collected 700 nasopharyngeal aspirates (NPA) from hospitalized children with SARI in Beijing (northern China) and Shanghai (southern China). Multiple respiratory viruses (including 15 common viruses) were screened by validated polymerase chain reaction (PCR) or real-time reverse transcription-PCR assays and confirmed by sequencing. Demographic data and the distribution of viral infections were also examined. RESULTS: Of 700 samples, 547 (78.1%) tested positive for viral infections. The picornaviruses (PIC), which included rhinovirus (RV) and enterovirus (EV), were the most common (34.0%), followed by respiratory syncytial virus (RSV) (28.3%), human bocavirus (HBoV) (19.1%), adenovirus (ADV) (13.7%), human coronaviruses (HCoV) (10.7%), influenza A and B (8.9%), parainfluenza virus (PIV 1-3) (7.9%), and human metapneumovirus (HMPV) (5.0%). PIC (RV/EV) and RSV were the most prevalent etiological agents of SARI in both cities. The total and age-matched prevalence of RSV, HCoV, and hMPV among SARI children under 5 years old were significantly higher in Beijing than in Shanghai. Different age and seasonal distribution patterns of the viral infections were found between Beijing and Shanghai. CONCLUSIONS: Viral infection was tested and shown to be the most prevalent etiological agent among children with SARI in either the Beijing or the Shanghai area, while showing different patterns of viral and epidemiological profiles. Our findings provide a better understanding of the roles of geographic location and climate in respiratory viral infections in hospitalized children with SARI.


Assuntos
Infecções Respiratórias/epidemiologia , Infecções Respiratórias/virologia , Infecções por Adenoviridae/epidemiologia , Infecções por Adenoviridae/virologia , Pequim/epidemiologia , Pré-Escolar , China/epidemiologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Influenza Humana/epidemiologia , Influenza Humana/virologia , Masculino , Infecções por Paramyxoviridae/epidemiologia , Infecções por Paramyxoviridae/virologia , Infecções por Parvoviridae/epidemiologia , Infecções por Parvoviridae/virologia , Infecções por Picornaviridae/epidemiologia , Infecções por Picornaviridae/virologia , Prevalência , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/virologia , Infecções por Respirovirus/epidemiologia , Infecções por Respirovirus/virologia
10.
BMC Infect Dis ; 19(1): 613, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299924

RESUMO

BACKGROUND: The Respiratory Syncytial Virus (RSV) A genotype ON1, which was first detected in Ontario (Canada) in 2010/11, appeared in Germany in 2011/12. Preliminary observations suggested a higher clinical severity in children infected with this new genotype. We investigated spread and disease severity of RSV-A ON1 in pediatric in- and outpatient settings. METHODS: During 2010/11 to 2016/17, clinical characteristics and respiratory samples from children with acute respiratory tract infections (RTI) were obtained from ongoing surveillance studies in 33 pediatric practices (PP), one pediatric hospital ward (PW) and 23 pediatric intensive care units (PICU) in Germany. RSV was detected in the respiratory samples by PCR; genotypes were identified by sequencing. Within each setting, clinical severity markers were compared between RSV-A ON1 and RSV-A non-ON1 genotypes. RESULTS: A total of 603 children with RSV-RTI were included (132 children in PP, 288 in PW, and 183 in PICU). Of these children, 341 (56.6%) were infected with RSV-A, 235 (39.0%) with RSV-B, and one child (0.2%) with both RSV-A and RSV-B; in 26 (4.3%) children, the subtype could not be identified. In the 341 RSV-A positive samples, genotype ON1 was detected in 247 (72.4%), NA1 in 92 (26.9%), and GA5 in 2 children (0.6%). RSV-A ON1, rarely observed in 2011/12, was the predominant RSV-A genotype in all settings by 2012/13 and remained predominant until 2016/17. Children in PP or PW infected with RSV-A ON1 did not show a more severe clinical course of disease compared with RSV-A non-ON1 infections. In the PICU group, hospital stay was one day longer (median 8 days, inter-quartile range (IQR) 7-12 vs. 7 days, IQR 5-9; p = 0.02) and duration of oxygen treatment two days longer (median 6 days, IQR 4-9 vs. 4 days, IQR 2-6; p = 0.03) for children infected with RSV-A ON1. CONCLUSIONS: In children, RSV-A ON1 largely replaced RSV-A non-ON1 genotypes within two seasons and remained the predominant RSV-A genotype in Germany during subsequent seasons. A higher clinical severity of RSV-A ON1 was observed within the group of children receiving PICU treatment, whereas in other settings clinical severity of RSV-A ON1 and non-ON1 genotypes was largely similar.


Assuntos
Infecções por Vírus Respiratório Sincicial/patologia , Vírus Sincicial Respiratório Humano/genética , Infecções Respiratórias/patologia , Pré-Escolar , Feminino , Genótipo , Alemanha/epidemiologia , Hospitais Pediátricos , Humanos , Lactente , Unidades de Terapia Intensiva Pediátrica , Tempo de Internação , Masculino , Filogenia , RNA Viral/metabolismo , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/isolamento & purificação , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/virologia , Estações do Ano , Índice de Gravidade de Doença
11.
Immunol Allergy Clin North Am ; 39(3): 309-319, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31284922

RESUMO

The infant's developing immune response is central to establishing a balanced system that reacts appropriately to infectious stimuli, but does not induce altered disease states with potential long-term sequelae. Respiratory syncytial virus may alter the immune system, affecting future responses. Early infection may have direct effects on the lung itself. Other early life processes contribute to the development of immune responses including assembly of the microbiome, which seems to have a particularly important role for establishing the immune environment. This review covers studies that have set up important paradigms and discusses recent data that direct research toward informative hypotheses.


Assuntos
Asma/etiologia , Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios , Imunidade Adaptativa/genética , Fatores Etários , Animais , Asma/epidemiologia , Suscetibilidade a Doenças , Metabolismo Energético , Epigênese Genética , Microbioma Gastrointestinal/imunologia , Humanos , Imunidade Inata/genética , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/virologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/imunologia
12.
Immunol Allergy Clin North Am ; 39(3): 321-334, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31284923

RESUMO

Severe lower respiratory tract infection in infants and young children is most frequently caused by respiratory syncytial virus (RSV). RSV infects the smallest airways, making breathing difficult and in some infants requiring medical support. Severity is affected by viral dose, infant age, virus genotype, and effectiveness of the innate/adaptive immune responses. Severe disease correlates with later wheezing and asthma in some children. The adaptive immune response is protective but wanes after each infection, likely due to the ability of the RSV NS1/NS2 proteins to inhibit the innate immune response. Several vaccine approaches and candidates are currently in clinical trials.


Assuntos
Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/fisiologia , Antígenos Virais/química , Antígenos Virais/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Infecções por Vírus Respiratório Sincicial/diagnóstico , Infecções por Vírus Respiratório Sincicial/imunologia , Índice de Gravidade de Doença , Proteínas Virais/química , Proteínas Virais/imunologia , Vacinas Virais , Montagem de Vírus
13.
Nat Commun ; 10(1): 3273, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332169

RESUMO

Severe respiratory syncytial virus (RSV) infection is a major cause of morbidity and mortality in infants <2 years-old. Here we describe that high-fiber diet protects mice from RSV infection. This effect was dependent on intestinal microbiota and production of acetate. Oral administration of acetate mediated interferon-ß (IFN-ß) response by increasing expression of interferon-stimulated genes in the lung. These effects were associated with reduction of viral load and pulmonary inflammation in RSV-infected mice. Type 1 IFN signaling via the IFN-1 receptor (IFNAR) was essential for acetate antiviral activity in pulmonary epithelial cell lines and for the acetate protective effect in RSV-infected mice. Activation of Gpr43 in pulmonary epithelial cells reduced virus-induced cytotoxicity and promoted antiviral effects through IFN-ß response. The effect of acetate on RSV infection was abolished in Gpr43-/- mice. Our findings reveal antiviral effects of acetate involving IFN-ß in lung epithelial cells and engagement of GPR43 and IFNAR.


Assuntos
Acetatos/farmacologia , Interferon Tipo I/metabolismo , Microbiota , Receptores Acoplados a Proteínas-G/metabolismo , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Células A549 , Acetatos/metabolismo , Animais , Linhagem Celular , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/virologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Polimorfismo de Nucleotídeo Único , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia , Receptor de Interferon alfa e beta/genética , Receptores Acoplados a Proteínas-G/genética , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/virologia , Células Vero , Carga Viral/efeitos dos fármacos , Carga Viral/genética
14.
BMC Public Health ; 19(1): 807, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31234829

RESUMO

BACKGROUND: Human metapneumovirus (HMPV) have similar symptoms to those caused by the respiratory syncytial virus (RSV). The modes of transmission and dynamics of time series data still remain poorly understood. Climatic factors have long been suspected to be implicated in impacting on the number of cases for these epidemics. Currently, only a few models satisfactorily capture the dynamics of time series data of these two viruses. Our objective was to assess the presence of influence of high incidences between the viruses and to ascertain whether higher incidences of one virus are influenced by the other. METHODS: In this study, we used a negative binomial model to investigate the relationship between RSV and HMPV while adjusting for climatic factors. We specifically aimed at establishing the heterogeneity in the autoregressive effect to account for the influence between these viruses. RESULTS: In this study, our findings showed that RSV incidence contributed to the severity of HMPV incidence. This was achieved through comparison of 12 models with different structures, including those with and without interaction between climatic factors. The models with climatic factors out-performed those without. CONCLUSIONS: The study has improved our understanding of the dynamics of RSV and HMPV in relation to climatic cofactors thereby setting a platform to devise better intervention measures to combat the epidemics. We conclude that preventing and controlling RSV infection subsequently reduces the incidence of HMPV.


Assuntos
Metapneumovirus , Modelos Estatísticos , Infecções por Paramyxoviridae/epidemiologia , Vigilância da População/métodos , Infecções por Vírus Respiratório Sincicial/epidemiologia , Vírus Sincicial Respiratório Humano , Teorema de Bayes , Clima , Epidemias , Feminino , Humanos , Incidência , Quênia/epidemiologia , Masculino , Infecções por Paramyxoviridae/virologia , Infecções por Vírus Respiratório Sincicial/virologia
15.
Emerg Infect Dis ; 25(7): 1408-1411, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31211675

RESUMO

Homelessness has not previously been identified as a risk factor for respiratory syncytial virus (RSV) infection. We conducted an observational study at an urban safety-net hospital in Washington, USA, during 2012-2017. Hospitalized adults with RSV were more likely to be homeless, and several clinical outcome measures were worse with RSV than with influenza.


Assuntos
Pessoas em Situação de Rua , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios , Estudos de Casos e Controles , Feminino , Hospitalização , Humanos , Masculino , Razão de Chances , Vigilância da População , Estudos Retrospectivos , Fatores Socioeconômicos , Washington/epidemiologia
16.
Arch Virol ; 164(9): 2231-2241, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177351

RESUMO

Viral persistence alters cellular antiviral activities. Nitric oxide (NO), a highly reactive free radical and a potent antiviral molecule, can inhibit replication of RNA and DNA viruses, but its production and effect during viral persistence are largely unknown. NO synthesis is stimulated in epithelial cells during acute infection with respiratory syncytial virus (RSV) and interferes with viral replication. In this study, we compared the levels of production of NO and expression of its regulatory enzymes, inducible nitric oxide synthase (NOS II) and arginase 1 (Arg-1), during acute and persistent RSV infection in a macrophage cell line to investigate their role in the control and maintenance of viral infection. We observed that NO and NOS II mRNA were induced at higher levels in acutely infected macrophages than in persistently infected macrophages, while the kinetics of NOS II protein expression were similar in both types of infected cultures, except that its disappearance was delayed during acute infection. Thus, NOS II was inducible and expressed at high levels during persistent infection, but production of NO was low relative to acute infection. This was not associated with a lack of enzymatic activity but instead was due to constitutive expression of the Arg-1 enzyme at the mRNA and protein levels, suggesting that arginase restricts availability of L-arginine as a substrate for NOS II to synthesize NO. This hypothesis was supported by showing that arginase enzymatic activity was inhibited in persistently RSV-infected cells by Nω-hydroxy-nor-L-arginine, increasing L-arginine availability in conditioned medium and producing increased levels of nitrites, concurrently with a significant reduction in virus genome replication, implying that Arg-1 overexpression contributes to the maintenance of the RSV genome in the host in persistent infection.


Assuntos
Arginase/metabolismo , Óxido Nítrico/metabolismo , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/fisiologia , Arginase/genética , Arginina/metabolismo , Regulação para Baixo , Humanos , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Nitritos/metabolismo , Infecções por Vírus Respiratório Sincicial/enzimologia , Infecções por Vírus Respiratório Sincicial/genética , Vírus Sincicial Respiratório Humano/genética , Replicação Viral
17.
Curr Med Sci ; 39(3): 363-370, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31209804

RESUMO

Respiratory syncytial virus (RSV) infection is the primary cause of respiratory disease in infants. The formalin-inactivated RSV (FI-RSV) vaccine resulted in an enhanced respiratory disease (ERD) in infants upon natural RSV infection, which is a major obstacle for development of safe and efficacious vaccines. Excessive and uncontrolled Th immune responses could be involved in the ERD. Agonists of TLRs are used as adjuvants to guide the type of immune response induced by vaccines. We evaluated the impact of lipopolysaccharide (LPS), the agonist of TLR4, on ERD as the adjuvant of FI-RSV. The results showed that LPS remarkably inhibited FI-RSV-enhanced lung inflammation, mucus production, airway inflammatory cell infiltration, and inflammatory cytokines following RSV challenge. Interestingly, LPS inhibited both Th2 and Th17 type cytokines in lungs of FI-RSV-immunized mice following RSV challenge, without an increase in the Th1 type cytokines, suggesting a controlled immune response. In contrast, Pam3Cys and Poly(I:C), the agonist of TLR1/2 or TLR3, partly inhibited FI-RSV-enhanced lung inflammation. Pam3Cys inhibited Th17 type cytokine IL-17, but promoted both Th1 and Th2 type cytokines. Poly(I:C) inhibited Th2 and Th17 type cytokines, but promoted Th1 type cytokines. In addition, LPS promoted IgG and IgG2a antibody production, which might provide protection from RSV challenge. These results suggest that LPS inhibits ERD without impairment in antibody production and protection, and the mechanism appears to be related with regulation of Th responses induced by FI-RSV.


Assuntos
Adjuvantes Imunológicos/farmacologia , Anticorpos Antivirais/biossíntese , Lipopolissacarídeos/farmacologia , Pneumonia/prevenção & controle , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Animais , Feminino , Formaldeído , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Lipoproteínas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/etiologia , Pneumonia/imunologia , Pneumonia/patologia , Poli I-C/farmacologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/patologia , Infecções por Vírus Respiratório Sincicial/virologia , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vírus Sinciciais Respiratórios/imunologia , Vírus Sinciciais Respiratórios/patogenicidade , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/virologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/virologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/virologia , Receptor 2 Toll-Like/agonistas , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Receptor 3 Toll-Like/agonistas , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/imunologia , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Vacinação , Vacinas de Produtos Inativados
18.
Virology ; 534: 1-13, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31163351

RESUMO

Alum adjuvanted formalin-inactivated respiratory syncytial virus (RSV) vaccination resulted in enhanced respiratory disease in young children upon natural infection. Here, we investigated the adjuvant effects of monophosphoryl lipid A (MPL) and oligodeoxynucleotide CpG (CpG) on vaccine-enhanced respiratory disease after fusion (F) protein prime vaccination and RSV challenge in infant and adult mouse models. Combination CpG + MPL adjuvant in RSV F protein single dose priming of infant and adult age mice was found to promote the induction of IgG2a isotype antibodies and neutralizing activity, and lung viral clearance after challenge. CpG + MPL adjuvanted F protein (Fp) priming of infant and adult age mice was effective in avoiding lung histopathology, in reducing interleukin-4+ CD4 T cells and cellular infiltration of monocytes and neutrophils after RSV challenge. This study suggests that combination CpG and MPL adjuvant in RSV subunit vaccination might contribute to priming protective immune responses and preventing inflammatory RSV disease after infection.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Pulmão/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vírus Sincicial Respiratório Humano/imunologia , Proteínas Virais de Fusão/administração & dosagem , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Humanos , Pulmão/patologia , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/imunologia , Oligodesoxirribonucleotídeos/administração & dosagem , Oligodesoxirribonucleotídeos/imunologia , Infecções por Vírus Respiratório Sincicial/patologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Infecções por Vírus Respiratório Sincicial/virologia , Vacinas contra Vírus Sincicial Respiratório/genética , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sincicial Respiratório Humano/genética , Vírus Sincicial Respiratório Humano/fisiologia , Vacinação , Proteínas Virais de Fusão/genética , Proteínas Virais de Fusão/imunologia
19.
Diagn Microbiol Infect Dis ; 95(1): 55-58, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31160164

RESUMO

Respiratory syncytial virus (RSV) causes acute respiratory infections. Rapid RSV diagnosis has an impact on patient management. In a newly developed molecular assay, named reverse transcription strand invasion based amplification (RT-SIBA) RSV assay, RSV RNA is reverse transcribed to cDNA and amplified and detected under isothermal reaction conditions. The performance of this assay was evaluated. Respiratory samples that tested positive (n = 81) or negative (n = 61) for RSV with the multiplex RT-PCR Anyplex II RV16 Detection Kit (Anyplex) were analyzed with the RT-SIBA assay. Discordant samples were tested with the GeneXpert Flu/RSV XC assay. Consistent results in at least 2 of the 3 methods were defined as reference standard. The RT-SIBA assay yielded a negative result for the 61 negative samples and a positive result in 71/81 (85.5%) of the Anyplex positive samples. After a resolution of discordant samples, the positive and negative percent agreement of the RT-SIBA assay were 92% and 100%, respectively. The RT-SIBA assay is a rapid molecular assay for the detection of RSV with good performance in clinical specimens.


Assuntos
Infecções por Vírus Respiratório Sincicial/diagnóstico , Vírus Sincicial Respiratório Humano/genética , Infecções Respiratórias/diagnóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa/normas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular/normas , Nasofaringe/virologia , RNA Viral/genética , Infecções por Vírus Respiratório Sincicial/virologia , Infecções Respiratórias/virologia , Sensibilidade e Especificidade , Fatores de Tempo , Adulto Jovem
20.
Nat Commun ; 10(1): 2218, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101811

RESUMO

RSV infection is typically associated with secondary bacterial infection. We hypothesise that the local airway immune response to RSV has incidental antibacterial effects. Using coordinated proteomics and metagenomics analysis we simultaneously analysed the microbiota and proteomes of the upper airway and determined direct antibacterial activity in airway secretions of RSV-infected children. Here, we report that the airway abundance of Streptococcus was higher in samples collected at the time of RSV infection compared with samples collected one month later. RSV infection is associated with neutrophil influx into the airway and degranulation and is marked by overexpression of proteins with known antibacterial activity including BPI, EPX, MPO and AZU1. Airway secretions of children infected with RSV, have significantly greater antibacterial activity compared to RSV-negative controls. This RSV-associated, neutrophil-mediated antibacterial response in the airway appears to act as a regulatory mechanism that modulates bacterial growth in the airways of RSV-infected children.


Assuntos
Infecções Bacterianas/imunologia , Neutrófilos/imunologia , Mucosa Respiratória/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Infecções Bacterianas/microbiologia , Degranulação Celular/imunologia , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Quênia , Metagenômica/métodos , Microbiota/imunologia , Proteômica/métodos , Mucosa Respiratória/citologia , Mucosa Respiratória/microbiologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/isolamento & purificação , Streptococcus/imunologia , Streptococcus/isolamento & purificação
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