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1.
Nat Commun ; 10(1): 3526, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387995

RESUMO

Segmentation of viral genomes into multiple RNAs creates the potential for replication of incomplete viral genomes (IVGs). Here we use a single-cell approach to quantify influenza A virus IVGs and examine their fitness implications. We find that each segment of influenza A/Panama/2007/99 (H3N2) virus has a 58% probability of being replicated in a cell infected with a single virion. Theoretical methods predict that IVGs carry high costs in a well-mixed system, as 3.6 virions are required for replication of a full genome. Spatial structure is predicted to mitigate these costs, however, and experimental manipulations of spatial structure indicate that local spread facilitates complementation. A virus entirely dependent on co-infection was used to assess relevance of IVGs in vivo. This virus grows robustly in guinea pigs, but is less infectious and does not transmit. Thus, co-infection allows IVGs to contribute to within-host spread, but complete genomes may be critical for transmission.


Assuntos
Vírus Defeituosos/patogenicidade , Genoma Viral , Vírus da Influenza A Subtipo H3N2/patogenicidade , Influenza Humana/transmissão , Replicação Viral/genética , Animais , Vírus Defeituosos/genética , Modelos Animais de Doenças , Cães , Evolução Molecular , Feminino , Cobaias , Células HEK293 , Humanos , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/virologia , Funções Verossimilhança , Células Madin Darby de Rim Canino , Modelos Biológicos , RNA Viral/genética , Análise de Célula Única , Carga Viral , Vírion/genética , Eliminação de Partículas Virais/genética
2.
Molecules ; 24(14)2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31319565

RESUMO

Influenza A viruses leading to infectious respiratory diseases cause seasonal epidemics and sometimes periodic global pandemics. Viral polymerase is an attractive target in inhibiting viral replication, and 4'-ethynyladenosine, which has been reported as a highly potent anti-human immunodeficiency virus (HIV) nucleoside derivative, can work as an anti-influenza agent. Herein, we designed and synthesized a 4'-ethynyl-2'-deoxyadenosine 5'-monophosphate analog called EdAP (5). EdAP exhibited potent inhibition against influenza virus multiplication in Madin-Darby canine kidney (MDCK) cells transfected with human α2-6-sialyltransferase (SIAT1) cDNA and did not show any toxicity toward the cells. Surprisingly, this DNA-type nucleic acid analog (5) inhibited the multiplication of influenza A virus, although influenza virus is an RNA virus that does not generate DNA.


Assuntos
Antivirais/farmacologia , Nucleotídeos de Desoxiadenina/farmacologia , Desoxiadenosinas/síntese química , Influenza Humana/tratamento farmacológico , Animais , Antivirais/síntese química , Antivirais/química , Nucleotídeos de Desoxiadenina/síntese química , Nucleotídeos de Desoxiadenina/química , Desoxiadenosinas/química , Desoxiadenosinas/farmacologia , Cães , Células HEK293 , Humanos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/patogenicidade , Influenza Humana/virologia , Células Madin Darby de Rim Canino , Replicação Viral/efeitos dos fármacos
3.
Prensa méd. argent ; 105(6): 361-369, Jul 2019. graf, tab
Artigo em Espanhol | LILACS, BINACIS | ID: biblio-1023787

RESUMO

Influenza is a respiratory disease ocasionated by influenza virus A and B. Is a disease with high morbi-mortality world-wide. Influenza produces an acute febrile respiratory illness with cough, headache and myalgias for 3-4 days, with simptoms that may persist for as long as 2 weeks. There are three types of influenza virsuses: A, B and C, of whom the type a has a higher ability to originate pandemias and is subclassified according to their surface antigens: hemaglutinine (H) and neuraminidase (N). Of the capacity of mutation that has the influenza virus and the consequent expression of different proteins, can modify its virulence. The transmission route is through direct contact with secretetory repirations. The transmission route is through direct contact with secretetory repirations. The incubation period is scant, between 12-72 hs. The aim of this study was to compare the clinical characteristics demographicals and evolutive of pediatric patients hospitalized because by Influenze A: subtypes H1N1 (pdm2009) and H3N2. An observative study was performed, retrospective, using data of hospitalizations of children during the years 2016 and 2017 with influenza A confirmed by laboratory. The study also, aimed to evaluate if the viral subtype constitutes a factor of risk, independent for complicated hospitalization (admission to intensive care and/or development of complications) in hospitalized children. The results obtained in the study are detailed in the paper. In conclusion, both viral subtypes affected mainly to children with risk factors. The viral subtype H1N1 was related with higher severety in hospitalized children. is of most importance to perform preventive works, specially in vulnerable groups, offering a good cover of immunizations. The clinical parameters arae commented (AU)


Assuntos
Humanos , Criança , Comorbidade/tendências , Fatores Epidemiológicos , Análise Estatística , Estudos Retrospectivos , Estudos de Coortes , Tamanho da Amostra , Seleção de Pacientes , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H3N2/patogenicidade , Influenza Aviária/complicações , Fatores de Risco
4.
PLoS One ; 14(4): e0214207, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30951544

RESUMO

Respiratory diseases are a major contributor to morbidity and mortality in many tropical countries, including Lao PDR. However, little has been published regarding viral or bacterial pathogens that can contribute to influenza-like illness (ILI) in a community setting. We report on the results of a community-based surveillance that prospectively monitored the incidence of ILI and its causative pathogens in Vientiane capital in Lao PDR. A cohort of 995 households, including 4885 study participants, were followed-up between May 2015 and May 2016. Nasopharyngeal swabs, throat swabs, and sputum specimens were collected from ILI cases identified through active case-finding. Real-Time PCR was used to test nasopharyngeal swabs for 21 respiratory pathogens, while throat and sputum samples were subjected to bacterial culture. Generalized linear mixed models were used to assess potential risk factors for associations with ILI. In total, 548 episodes of ILI were reported among 476 (9.7%) of the study participants and 330 (33.2%) of the study households. The adjusted estimated incidence of ILI within the study area was 10.7 (95%CI: 9.4-11.9) episodes per 100 person-years. ILI was significantly associated with age group (p<0.001), sex (p<0.001), and number of bedrooms (p = 0.04) in multivariate analysis. In 548 nasopharyngeal swabs, the most commonly detected potential pathogens were Streptococcus pneumoniae (17.0%), Staphylococcus aureus (11.3%), influenza A (11.1%; mostly subtype H3N2), rhinovirus (7.5%), and influenza B (8.0%). Streptococci were isolated from 42 (8.6%) of 536 throat swabs, most (27) of which were Lancefield Group G. Co-infections were observed in 132 (24.1%) of the 548 ILI episodes. Our study generated valuable data on respiratory disease burden and patterns of etiologies associated with community-acquired acute respiratory illness Laos. Establishment of a surveillance strategy in Laos to monitor trends in the epidemiology and burden of acute respiratory infections is required to minimize their impact on human health.


Assuntos
Vírus da Influenza A Subtipo H3N2/patogenicidade , Influenza Humana/epidemiologia , Infecções Respiratórias/epidemiologia , Rhinovirus/patogenicidade , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Características da Família , Feminino , Humanos , Lactente , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Influenza Humana/diagnóstico , Influenza Humana/patologia , Influenza Humana/virologia , Laos/epidemiologia , Masculino , Pessoa de Meia-Idade , Faringe/patologia , Faringe/virologia , Reação em Cadeia da Polimerase em Tempo Real , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/patologia , Infecções Respiratórias/virologia
5.
BMC Res Notes ; 12(1): 101, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808400

RESUMO

OBJECTIVE: Influenza is an acute respiratory disease caused by the influenza virus which circulates annually in populations of different species. Madin-Darby Canine Kidney (MDCK) is the most widely utilized cell-line for conducting influenza research. However, the infectivity of various influenza strains in MDCK cells is not equivalent and the productivity of viral propagation is also limited. RESULTS: We tested the functional adequacy of two MDCK-lineage cell lines, conventional MDCK and MDCK/London, were evaluated by assessing their infectivity of different influenza viral strains with focus forming assays and the cellular toxicity caused by influenza infections by lactate dehydrogenase assay. Moreover, the sensitivity of cells in the presence of the antiviral agent ribavirin was assessed by MTT assay. Our results showed that MDCK/London cells efficiently propagate virus across all influenza viruses tested, are comparable to the utility of Mv1Lu cells, and are superior to conventional MDCK cells in replicating virus as indicated by an increase in virus of three to four logs, particularly in H3N2 infection. Also, the MDCK/London cells were more sensitive to the presence of antiviral drug than conventional MDCK cells. In conclusion, MDCK/London cell line could be a better platform for influenza studies and vaccine development.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Vírus da Influenza A Subtipo H9N2 , Células Madin Darby de Rim Canino , Ribavirina/farmacologia , Animais , Pesquisa Biomédica , Cães , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/patogenicidade , Vírus da Influenza A Subtipo H9N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H9N2/patogenicidade
6.
PLoS One ; 14(1): e0210132, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30650117

RESUMO

Interferon-induced transmembrane protein 3 (IFITM3) is a potent antiviral protein that enhances cellular resistance to a variety of pathogens, including influenza virus. Classically defined as an interferon-stimulated gene, expression of IFITM3 on cells is rapidly up-regulated in response to type I and II interferon. Here we found that IFITM3 is rapidly up-regulated by T cells following their activation and this occurred independently of type I and II interferon and the interferon regulatory factors 3 and 7. Up-regulation of IFITM3 on effector T cells protected these cells from virus infection and imparted a survival advantage at sites of virus infection. Our results show that IFITM3 expression on effector T cells is crucial for these cells to mediate their effector function and highlights an interferon independent pathway for the induction of IFITM3 which, if targeted, could be an effective approach to harness the activity of IFITM3 for infection prevention.


Assuntos
Influenza Humana/imunologia , Ativação Linfocitária/imunologia , Proteínas de Membrana/imunologia , Linfócitos T/imunologia , Transferência Adotiva/métodos , Animais , Células Cultivadas , Modelos Animais de Doenças , Cães , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza A Subtipo H3N2/patogenicidade , Influenza Humana/virologia , Fator Regulador 3 de Interferon/genética , Fator Regulador 7 de Interferon/genética , Interferons/metabolismo , Células Madin Darby de Rim Canino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Linfócitos T/metabolismo , Linfócitos T/transplante
7.
BMC Infect Dis ; 19(1): 42, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30630435

RESUMO

BACKGROUND: Influenza is a global infectious disease with a large burden of illness and high healthcare costs. Those who experience greater burden of disease include younger and older people, and pregnant women. Although there are known age and sex susceptibilities, little is known about how the interaction of age and sex may affect a population's vulnerability to infection with different subtypes of influenza virus. METHODS: Laboratory-confirmed cases of influenza notified between 1 January 2009 and 31 December 2015 obtained from the Australian Government National Notifiable Diseases Surveillance System Influenza Public Data Set were analysed by age, sex and virus subtype. Age standardised notification rates per 100,000 population were calculated separately for females and males and used to generate female-to-male ratios with 95% confidence intervals for influenza A and B, and for virus subtypes A(H1N1)pdm09 and A(H3N2). RESULTS: 334,560 notifications for influenza A (all notifications), A(H1N1)pmd09, A(H3N2) and B subtypes from a total of 335,414 influenza notifications were analysed. Male notification rates were significantly higher for the 0 to 4 years old age group regardless of virus type or subtype; and higher for those aged 0 to 14 years and those 85 years and older for influenza types A and B and subtype A(H1N1)pdm09. Female notification rates were significantly higher for A(H1N1)pdm09 in those aged 15 to 54 years, for Type A and sub-type A(H3N2) in those aged 15 to 69 years, and for Influenza B in those aged 20 to 74 years. CONCLUSIONS: We observed a female dominance in notification rates throughout the adult age groups, which could possibly be related to health seeking behaviours. However, differences in health seeking behaviours cannot explain the variations observed across virus subtypes in the particular age groups with higher female notifications. Depending on their age, females may be more susceptible to certain subtypes of influenza virus. These observations suggest that there is an interaction between age and sex on susceptibility to influenza infection which varies by the subtype of the virus. The inclusion of pregnancy and menopausal status in surveillance data may assist development of targeted public health approaches during the emergence of new subtypes of influenza virus. Targeted vaccination campaigns may need to take into consideration specific age and sex groups who have a greater susceptibility to influenza infection as well as those who experience a greater burden of illness.


Assuntos
Influenza Humana/epidemiologia , Influenza Humana/virologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Criança , Pré-Escolar , Suscetibilidade a Doenças , Feminino , Humanos , Programas de Imunização , Lactente , Recém-Nascido , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H3N2/patogenicidade , Masculino , Pessoa de Meia-Idade , Gravidez , Adulto Jovem
8.
Transbound Emerg Dis ; 66(2): 842-851, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30520554

RESUMO

H3N2 canine influenza virus (CIV) originated from avian species and emerged in dogs in Asia around 2005 where it became enzootic before reaching the USA in 2015. To investigate the key aspects of the evolution of H3N2 CIV regarding its emergence and adaptation in the canine host, we conducted an extensive analysis of all publicly available H3N2 CIV sequences spanning a 10-year period. We believe that H3N2 AIVs transferred to canines around 2002-2004. Furthermore, H3N2 CIVs could be divided into seven major clades with strong geographic clustering and some changed sites evidence of adaptive evolution. Most notably, the dN/dS of each H3N2 CIVs segment was higher than the correspondent of H3N2 AIVs and the U content of HA and NA was increasing over time, suggesting the idea that this avian-origin virus may be gradually adapting to the host. Our results provide a framework to elucidate a general mechanism for emergence of novel influenza viruses.


Assuntos
Doenças do Cão/virologia , Vírus da Influenza A Subtipo H3N2/genética , Influenza Aviária/transmissão , Infecções por Orthomyxoviridae/veterinária , Animais , Ásia , Aves , Cães , Genoma Viral , Especificidade de Hospedeiro , Humanos , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Vírus da Influenza A Subtipo H3N2/patogenicidade , Influenza Aviária/virologia , Mutação , Infecções por Orthomyxoviridae/virologia , Filogenia , Seleção Genética , Proteínas Virais/genética
9.
PLoS Pathog ; 14(12): e1007417, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30507946

RESUMO

Genetic reassortment between influenza A viruses (IAVs) facilitate emergence of pandemic strains, and swine are proposed as a "mixing vessel" for generating reassortants of avian and mammalian IAVs that could be of risk to mammals, including humans. However, how a transmissible reassortant emerges in swine are not well understood. Genomic analyses of 571 isolates recovered from nasal wash samples and respiratory tract tissues of a group of co-housed pigs (influenza-seronegative, avian H1N1 IAV-infected, and swine H3N2 IAV-infected pigs) identified 30 distinct genotypes of reassortants. Viruses recovered from lower respiratory tract tissues had the largest genomic diversity, and those recovered from turbinates and nasal wash fluids had the least. Reassortants from lower respiratory tracts had the largest variations in growth kinetics in respiratory tract epithelial cells, and the cold temperature in swine nasal cells seemed to select the type of reassortant viruses shed by the pigs. One reassortant in nasal wash samples was consistently identified in upper, middle, and lower respiratory tract tissues, and it was confirmed to be transmitted efficiently between pigs. Study findings suggest that, during mixed infections of avian and swine IAVs, genetic reassortments are likely to occur in the lower respiratory track, and tissue tropism is an important factor selecting for a transmissible reassortant.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Infecções por Orthomyxoviridae , Recombinação Genética/genética , Tropismo Viral , Animais , Coinfecção , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/patogenicidade , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/transmissão , Vírus Reordenados/genética , Vírus Reordenados/patogenicidade , Infecções Respiratórias/virologia , Suínos
10.
PLoS One ; 13(12): e0208028, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30507951

RESUMO

BACKGROUND AND AIM: The majority of seasonal influenza vaccines are trivalent, containing two A virus strains (H1N1 and H3N2) and one B virus strain. The co-circulation of two distinct lineages of B viruses can lead to mismatch between the influenza B virus strain recommended for the trivalent seasonal vaccine and the circulating B virus. This has led some manufacturers to produce quadrivalent influenza vaccines containing one strain from each B lineage in addition to H1N1 and H3N2 strains. However, it is also important to know whether vaccines containing a single influenza B strain can provide cross-protectivity against viruses of the antigenically distinct lineage. The aim of this study was to assess in naïve ferrets the potential cross-protective activity of trivalent live attenuated influenza vaccine (T-LAIV) against challenge with a heterologous wild-type influenza B virus belonging to the genetically different lineage and to compare this activity with effectiveness of quadrivalent LAIV (Q-LAIV) in the ferret model. METHODS AND RESULTS: Ferrets were vaccinated with either one dose of trivalent LAIV containing B/Victoria or B/Yamagata lineage virus, or quadrivalent LAIV (containing both B lineages), or placebo. They were then challenged with B/Victoria or B/Yamagata lineage wild-type virus 28 days after vaccination. The ferrets were monitored for clinical signs and morbidity. Nasal swabs and lung tissue samples were analyzed for the presence of challenge virus. Antibody response to vaccination was assessed by routine hemagglutination inhibition assay. All LAIVs tested were found to be safe and effective against wild-type influenza B viruses based on clinical signs, and virological and histological data. The absence of interference between vaccine strains in trivalent and quadrivalent vaccine formulations was confirmed. Trivalent LAIVs were shown to have the potential to be cross-protective against infection with genetically different influenza B/Victoria and B/Yamagata lineages. CONCLUSIONS: In this ferret model, quadrivalent vaccine provided higher protection to challenge against both B/Victoria and B/Yamagata lineage viruses. However, T-LAIV provided some cross-protection in the case of a mismatch between circulating and vaccine type B strains. Notably, B/Victoria-based T-LAIV was more protective compared to B/Yamagata-based T-LAIV.


Assuntos
Proteção Cruzada/imunologia , Imunogenicidade da Vacina , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Vacinação/métodos , Administração Intranasal , Animais , Anticorpos Antivirais/sangue , Proteção Cruzada/genética , Modelos Animais de Doenças , Feminino , Furões , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza A Subtipo H3N2/patogenicidade , Vírus da Influenza B/genética , Vírus da Influenza B/imunologia , Vírus da Influenza B/patogenicidade , Vacinas contra Influenza/administração & dosagem , Influenza Humana/sangue , Influenza Humana/imunologia , Influenza Humana/virologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia
11.
PLoS One ; 13(11): e0207007, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30412605

RESUMO

Environmental signals mediated via the aryl hydrocarbon receptor (AHR) shape the developing immune system and influence immune function. Developmental exposure to AHR binding chemicals causes persistent changes in CD4+ and CD8+ T cell responses later in life, including dampened clonal expansion and differentiation during influenza A virus (IAV) infection. Naïve T cells require activation by dendritic cells (DCs), and AHR ligands modulate the function of DCs from adult organisms. Yet, the consequences of developmental AHR activation by exogenous ligands on DCs later in life has not been examined. We report here that early life activation of AHR durably reduces the ability of DC to activate naïve IAV-specific CD8+ T cells; however, activation of naïve CD4+ T cells was not impaired. Also, DCs from developmentally exposed offspring migrated more poorly than DCs from control dams in both in vivo and ex vivo assessments of DC migration. Conditional knockout mice, which lack Ahr in CD11c lineage cells, suggest that dampened DC emigration is intrinsic to DCs. Yet, levels of chemokine receptor 7 (CCR7), a key regulator of DC trafficking, were generally unaffected. Gene expression analyses reveal changes in Lrp1, Itgam, and Fcgr1 expression, and point to alterations in genes that regulate DC migration and antigen processing and presentation as being among pathways disrupted by inappropriate AHR signaling during development. These studies establish that AHR activation during development causes long-lasting changes to DCs, and provide new information regarding how early life environmental cues shape immune function later in life.


Assuntos
Células Dendríticas/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Envelhecimento , Animais , Células da Medula Óssea/citologia , Antígeno CD11c/genética , Antígeno CD11c/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Movimento Celular , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/metabolismo , Vírus da Influenza A Subtipo H3N2/patogenicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/genética , Receptores CCR7/metabolismo
12.
Nat Commun ; 9(1): 4418, 2018 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-30356117

RESUMO

The response to respiratory viruses varies substantially between individuals, and there are currently no known molecular predictors from the early stages of infection. Here we conduct a community-based analysis to determine whether pre- or early post-exposure molecular factors could predict physiologic responses to viral exposure. Using peripheral blood gene expression profiles collected from healthy subjects prior to exposure to one of four respiratory viruses (H1N1, H3N2, Rhinovirus, and RSV), as well as up to 24 h following exposure, we find that it is possible to construct models predictive of symptomatic response using profiles even prior to viral exposure. Analysis of predictive gene features reveal little overlap among models; however, in aggregate, these genes are enriched for common pathways. Heme metabolism, the most significantly enriched pathway, is associated with a higher risk of developing symptoms following viral exposure. This study demonstrates that pre-exposure molecular predictors can be identified and improves our understanding of the mechanisms of response to respiratory viruses.


Assuntos
Expressão Gênica/genética , Voluntários Saudáveis , Heme/metabolismo , Humanos , Vírus da Influenza A Subtipo H1N2/imunologia , Vírus da Influenza A Subtipo H1N2/patogenicidade , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza A Subtipo H3N2/patogenicidade , Vírus Sinciciais Respiratórios/imunologia , Vírus Sinciciais Respiratórios/patogenicidade , Rhinovirus/imunologia , Rhinovirus/patogenicidade
13.
Vaccine ; 36(41): 6117-6123, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30190121

RESUMO

BACKGROUND: Influenza vaccination is the most effective intervention to prevent influenza virus infections. Vaccine effectiveness (VE) can vary due to factors such as matching between vaccine strains and prevailing strains, age and other characteristics of the vaccine recipients. OBJECTIVE: To evaluate influenza VE against medically-attended illness in different age groups and against specific influenza types/subtypes in Hong Kong. METHODS: A test-negative study was conducted from December 2014 through August 2017 in 20 outpatient clinics. Patients at least 6 months of age presenting with at least two symptoms of acute respiratory illness, ARI (fever ≥37.8 °C, cough, sore throat, runny nose, headache, myalgia and phlegm) within 72 h of onset were tested for influenza virus by reverse transcription polymerase chain reaction (PCR). Vaccination history was assessed by self-report or medical records at the clinics. VE against medically-attended illness was estimated using conditional logistic regression for influenza PCR result versus vaccination history, matching by calendar time and adjusting for age, age-squared, sex, and chronic medical illness. Additional analyses examined VE by age group and by influenza type/subtype. RESULTS: We enrolled 2566 patients, of whom 1118 (43.6%) tested positive for influenza A or B virus by PCR. Test-positive subjects were generally older, more likely to present with one of the symptoms of ARI, and less likely to receive vaccination against influenza. VE estimates for influenza A(H1N1), A(H3N2), B/Yamagata and B/Victoria were 61.6% (95% confidence interval, CI: 21.8%, 81.1%), 26.4% (95% CI: -1.3%, 46.6%), 67.0% (95% CI: 25.9%, 85.3%), 60.4% (95% CI: 0.3%, 84.3%), respectively. Estimates of VE by age group were generally higher in adults aged 50-64 and lower among children and older adults. CONCLUSIONS: VE against medically-attended influenza was moderate in Hong Kong, confirming the impact of influenza vaccination in reducing disease burden. The reduced VE for influenza A(H3N2) is a continuing concern.


Assuntos
Vacinas contra Influenza/uso terapêutico , Influenza Humana/prevenção & controle , Feminino , Hong Kong , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza A Subtipo H3N2/patogenicidade , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Masculino
14.
PLoS Pathog ; 14(9): e1007291, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30208108

RESUMO

To escape immune recognition in previously infected hosts, viruses evolve genetically in immunologically important regions. The host's immune system responds by generating new memory cells recognizing the mutated viral strains. Despite recent advances in data collection and analysis, it remains conceptually unclear how epidemiology, immune response, and evolutionary factors interact to produce the observed speed of evolution and the incidence of infection. Here we establish a general and simple relationship between long-term cross-immunity, genetic diversity, speed of evolution, and incidence. We develop an analytic method fusing the standard epidemiological susceptible-infected-recovered approach and the modern virus evolution theory. The model includes the factors of strain selection due to immune memory cells, random genetic drift, and clonal interference effects. We predict that the distribution of recovered individuals in memory serotypes creates a moving fitness landscape for the circulating strains which drives antigenic escape. The fitness slope (effective selection coefficient) is proportional to the reproductive number in the absence of immunity R0 and inversely proportional to the cross-immunity distance a, defined as the genetic distance of a virus strain from a previously infecting strain conferring 50% decrease in infection probability. Analysis predicts that the evolution rate increases linearly with the fitness slope and logarithmically with the genomic mutation rate and the host population size. Fitting our analytic model to data obtained for influenza A H3N2 and H1N1, we predict the annual infection incidence within a previously estimated range, (4-7)%, and the antigenic mutation rate of Ub = (5 - 8) ⋅ 10(-4) per transmission event per genome. Our prediction of the cross-immunity distance of a = (14 - 15) aminoacid substitutions agrees with independent data for equine influenza.


Assuntos
Antígenos Virais/genética , Evolução Molecular , Vírus da Influenza A/genética , Vírus da Influenza A/imunologia , Substituição de Aminoácidos , Animais , Deriva Genética , Genoma Viral , Doenças dos Cavalos/imunologia , Doenças dos Cavalos/virologia , Cavalos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Memória Imunológica , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza A Subtipo H3N2/patogenicidade , Vírus da Influenza A/patogenicidade , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Influenza Humana/virologia , Modelos Genéticos , Modelos Imunológicos , Mutação , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/veterinária , Infecções por Orthomyxoviridae/virologia , Processos Estocásticos
15.
J Infect Chemother ; 24(11): 873-880, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30100400

RESUMO

The 2016/17 influenza season in Japan was characterized by a predominance of influenza A (H3N2) activity; with H3N2 accounting for 85% of all detected influenza virus infections. We assessed the vaccine effectiveness (VE) of an inactivated quadrivalent influenza vaccine (IIV4) in adult patients, using a test-negative case-control design study based on the results of a rapid influenza diagnostic test (RIDT). Between November 2016 and March 2017, a total of 1048 adult patients were enrolled: including 363 RIDT positive for influenza A, 9 RIDT-positive for influenza B, and 676 RIDT-negative. During the 2016/17 season, the overall adjusted VE was 28.8% (95% confidence interval [CI]: 6.3-46%). The adjusted VE against influenza A was 27.4% (95%CI: 4.4-45%). The VE against influenza B could not be estimated because of the very low number of influenza B patients. Twenty-nine patients were hospitalized due to influenza-associated illness-during the present study, all of whom were infected with influenza A virus. The adjusted VE, determined using a case-control study, for preventing hospitalization for influenza A infection was 72.6% (95%CI: 30.7-89.1%). In addition, the VE for preventing hospitalization of influenza patients with comorbidities was 78.2% (95%CI: 41.1-92%). Our study showed that, during the 2016/17season, IIV4 was effective for preventing both the onset of influenza and influenza-associated hospitalization.


Assuntos
Hospitalização/estatística & dados numéricos , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Vacinas contra Influenza/uso terapêutico , Influenza Humana/prevenção & controle , Vacinação/estatística & dados numéricos , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Vírus da Influenza A Subtipo H3N2/patogenicidade , Influenza Humana/diagnóstico , Influenza Humana/epidemiologia , Influenza Humana/virologia , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estações do Ano , Resultado do Tratamento , Adulto Jovem
16.
Hum Gene Ther ; 29(9): 1044-1055, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30062926

RESUMO

Influenza A H3N2 viruses circulate globally, leading to substantial morbidity and mortality. Commercially available, antigen-matched influenza vaccines must be updated frequently to match dynamic sequence variability in immune epitopes, especially within viral influenza A H3N2 hemagglutinin (H3). In an effort to create comprehensive immune responses against H3N2, four micro-consensus antigens were designed to mimic the sequence and antigenic diversity of H3. Synthetic plasmid DNA constructs were developed to express each micro-consensus immunogen and combined into a multi-antigen DNA vaccine cocktail, pH3HA. Facilitated delivery of pH3HA via intramuscular electroporation in mice induced comprehensive, potent humoral responses against diverse seasonal H3N2 viruses that circulated between 1968 and the present. Vaccination with pH3HA also induced an antigen-specific cellular cytokine response. Mice immunized with pH3HA were protected against lethal challenge using two distinct H3N2 viruses, highlighting the heterologous protection afforded by synthetic micro-consensus immunogens. These findings warrant further study of the DNA vaccine micro-consensus platform for broad protection against influenza viruses.


Assuntos
Vírus da Influenza A Subtipo H3N2/imunologia , Vacinas contra Influenza/administração & dosagem , Influenza Humana/imunologia , Vacinas de DNA/administração & dosagem , Animais , Anticorpos Antivirais/imunologia , DNA/imunologia , Humanos , Vírus da Influenza A Subtipo H3N2/patogenicidade , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Camundongos , Camundongos Endogâmicos BALB C , Vacinação/métodos , Vacinas de DNA/imunologia
17.
PLoS Biol ; 16(8): e2004974, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30125272

RESUMO

Human immunity influences the evolution and impact of influenza strains. Because individuals are infected with multiple influenza strains during their lifetime, and each virus can generate a cross-reactive antibody response, it is challenging to quantify the processes that shape observed immune responses or to reliably detect recent infection from serological samples. Using a Bayesian model of antibody dynamics at multiple timescales, we explain complex cross-reactive antibody landscapes by inferring participants' histories of infection with serological data from cross-sectional and longitudinal studies of influenza A/H3N2 in southern China and Vietnam. We find that individual-level influenza antibody profiles can be explained by a short-lived, broadly cross-reactive response that decays within a year to leave a smaller long-term response acting against a narrower range of strains. We also demonstrate that accounting for dynamic immune responses alongside infection history can provide a more accurate alternative to traditional definitions of seroconversion for the estimation of infection attack rates. Our work provides a general model for quantifying aspects of influenza immunity acting at multiple timescales based on contemporary serological data and suggests a two-armed immune response to influenza infection consistent with competitive dynamics between B cell populations. This approach to analysing multiple timescales for antigenic responses could also be applied to other multistrain pathogens such as dengue and related flaviviruses.


Assuntos
Anticorpos Antivirais/sangue , Imunidade Humoral , Vírus da Influenza A Subtipo H3N2/imunologia , Influenza Humana/epidemiologia , Linfócitos B/imunologia , Linfócitos B/virologia , Teorema de Bayes , China/epidemiologia , Reações Cruzadas , Estudos Transversais , Humanos , Soros Imunes/química , Vírus da Influenza A Subtipo H3N2/crescimento & desenvolvimento , Vírus da Influenza A Subtipo H3N2/patogenicidade , Vacinas contra Influenza/administração & dosagem , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Estudos Longitudinais , Fatores de Tempo , Vacinação/estatística & dados numéricos , Vietnã/epidemiologia
18.
PLoS One ; 13(7): e0199167, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30044776

RESUMO

Lactoperoxidase (LPO) is an enzyme found in several exocrine secretions including the airway surface liquid producing antimicrobial substances from mainly halide and pseudohalide substrates. Although the innate immune function of LPO has been documented against several microbes, a detailed characterization of its mechanism of action against influenza viruses is still missing. Our aim was to study the antiviral effect and substrate specificity of LPO to inactivate influenza viruses using a cell-free experimental system. Inactivation of different influenza virus strains was measured in vitro system containing LPO, its substrates, thiocyanate (SCN-) or iodide (I-), and the hydrogen peroxide (H2O2)-producing system, glucose and glucose oxidase (GO). Physiologically relevant concentrations of the components of the LPO/H2O2/(SCN-/I-) antimicrobial system were exposed to twelve different strains of influenza A and B viruses in vitro and viral inactivation was assessed by determining plaque-forming units of non-inactivated viruses using Madin-Darby canine kidney cells (MDCK) cells. Our data show that LPO is capable of inactivating all influenza virus strains tested: H1N1, H1N2 and H3N2 influenza A viruses (IAV) and influenza B viruses (IBV) of both, Yamagata and Victoria lineages. The extent of viral inactivation, however, varied among the strains and was in part dependent on the LPO substrate. Inactivation of H1N1 and H1N2 viruses by LPO showed no substrate preference, whereas H3N2 influenza strains were inactivated significantly more efficiently when iodide, not thiocyanate, was the LPO substrate. Although LPO-mediated inactivation of the influenza B strains tested was strain-dependent, it showed slight preference towards thiocyanate as the substrate. The results presented here show that the LPO/H2O2/(SCN-/I-) cell-free, in vitro experimental system is a functional tool to study the specificity, efficiency and the molecular mechanism of action of influenza inactivation by LPO. These studies tested the hypothesis that influenza strains are all susceptible to the LPO-based antiviral system but exhibit differences in their substrate specificities. We propose that a LPO-based antiviral system is an important contributor to anti-influenza virus defense of the airways.


Assuntos
Antivirais/farmacologia , Influenza Humana/tratamento farmacológico , Lactoperoxidase/química , Orthomyxoviridae/efeitos dos fármacos , Animais , Antivirais/química , Sistema Livre de Células/efeitos dos fármacos , Cães , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/patogenicidade , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/patogenicidade , Influenza Humana/virologia , Compostos de Iodo/química , Compostos de Iodo/metabolismo , Compostos de Iodo/farmacologia , Lactoperoxidase/metabolismo , Células Madin Darby de Rim Canino , Orthomyxoviridae/patogenicidade , Especificidade por Substrato , Tiocianatos/química , Tiocianatos/metabolismo , Tiocianatos/farmacologia
19.
Vaccine ; 36(33): 4993-5001, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30017144

RESUMO

BACKGROUND: While the 2015-2016 influenza season in the northern hemisphere was dominated by A(H1N1)pdm09 and B/Victoria viruses, in Beijing, China, there was also significant circulation of influenza A(H3N2) virus. In this report we estimate vaccine effectiveness (VE) against influenza A(H3N2) and other circulating viruses, and describe further characteristics of the 2015-2016 influenza season in Beijing. METHODS: We estimated VE of the 2015-2016 trivalent inactivated vaccine (TIV) against laboratory-confirmed influenza virus infection using the test-negative study design. The effect of prior vaccination on current VE was also examined. RESULTS: Of 11,000 eligible patients included in the study, 2969 (27.0%) were influenza positive. Vaccination coverage was 4.2% in both cases and controls. Adjusted VE against all influenza was 8% (95% CI: -16% to 27%): 18% (95% CI: -38% to 52%) for influenza A(H1N1)pdm09, 54% (95% CI: 16% to 74%) for influenza A(H3N2), and -8% (95% CI: -40% to 18%) for influenza B/Victoria. The overall VE for receipt of 2015-2016 vaccination only, 2014-2015 vaccination only, and vaccinations in both seasons was -15% (95% CI: -63% to 19%), -25% (95% CI: -78% to 13%), and 18% (95% CI: -11% to 40%), respectively. CONCLUSIONS: Overall the 2015-2016 TIV was protective against influenza infection in Beijing, with higher VE against the A(H3N2) viruses compared to A(H1N1)pdm09 and B viruses.


Assuntos
Vírus da Influenza A Subtipo H3N2/patogenicidade , Vacinas contra Influenza/uso terapêutico , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Adolescente , Adulto , Pequim , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Vírus da Influenza A Subtipo H3N2/classificação , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Vaccine ; 36(32 Pt B): 4910-4918, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30037481

RESUMO

Transmission of influenza virus between susceptible hosts mediates spread of infection in the population and can occur via direct-contact or airborne routes. Mathematical models suggest that vaccines that reduce viral transmission from infected individuals could substantially reduce viral spread in an epidemic or pandemic, even if they do not completely protect against infection. Vaccines targeting conserved nucleoprotein (A/NP) and matrix 2 (M2) antigens of influenza virus do not completely prevent infection upon influenza virus challenge, but reduce viral replication, morbidity, and mortality. Using a mouse model of influenza virus transmission, we have previously shown that immunization with recombinant adenovirus vectors expressing the combination of A/NP and M2 can reduce viral transmission to unimmunized contacts. Here we demonstrate that transmission reduction is more effective when mice are immunized against A/NP and M2 intranasally than via the intramuscular route. We show that immunization against the combination of A/NP and M2 is more effective at reducing transmission than either antigen alone, with a clear hierarchy of effectiveness (A/NP + M2 > A/NP > M2). Transmission reduction is seen to a similar degree under both direct-contact and airborne transmission conditions. Finally, using seroconversion as an indicator of infection, we show that immunizing contact mice against A/NP and M2 prevents a significant fraction (∼50%) from becoming infected under direct-contact conditions. These findings suggest that when strain-matched vaccines are unavailable, conserved antigen vaccines could not only reduce severity of disease in vaccinated individuals but also limit the spread of virus during influenza epidemics or pandemics.


Assuntos
Antígenos Virais/imunologia , Vacinas contra Influenza/uso terapêutico , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Adenoviridae/genética , Animais , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza A Subtipo H3N2/patogenicidade , Vacinas contra Influenza/imunologia , Camundongos , Vacinação/métodos
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