RESUMO
Influenza A viruses (IAVs) are common pathogens of birds that occasionally establish endemic infections in mammals. The processes and mechanisms that result in IAV mammalian adaptation are poorly understood. The viral nonstructural 1 (NS1) protein counteracts the interferon (IFN) response, a central component of the host species barrier. We characterized the NS1 proteins of equine influenza virus (EIV), a mammalian IAV lineage of avian origin. We showed that evolutionarily distinct NS1 proteins counteract the IFN response using different and mutually exclusive mechanisms: while the NS1 proteins of early EIVs block general gene expression by binding to cellular polyadenylation-specific factor 30 (CPSF30), NS1 proteins from more evolved EIVs specifically block the induction of IFN-stimulated genes by interfering with the JAK/STAT pathway. These contrasting anti-IFN strategies are associated with two mutations that appeared sequentially and were rapidly selected for during EIV evolution, highlighting the importance of evolutionary processes in immune evasion mechanisms during IAV adaptation.IMPORTANCE Influenza A viruses (IAVs) infect certain avian reservoir species and occasionally transfer to and cause epidemics of infections in some mammalian hosts. However, the processes by which IAVs gain the ability to efficiently infect and transmit in mammals remain unclear. H3N8 equine influenza virus (EIV) is an avian-origin virus that successfully established a new lineage in horses in the early 1960s and is currently circulating worldwide in the equine population. Here, we analyzed the molecular evolution of the virulence factor nonstructural protein 1 (NS1) and show that NS1 proteins from different time periods after EIV emergence counteract the host innate immune response using contrasting strategies, which are associated with two mutations that appeared sequentially during EIV evolution. The results shown here indicate that the interplay between virus evolution and immune evasion plays a key role in IAV mammalian adaptation.
Assuntos
Adaptação Fisiológica/genética , Adaptação Fisiológica/imunologia , Evolução Molecular , Evasão da Resposta Imune , Vírus da Influenza A/genética , Vírus da Influenza A/imunologia , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Linhagem Celular , Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Citocinas/metabolismo , Cães , Regulação Viral da Expressão Gênica , Vetores Genéticos , Células HEK293 , Cavalos , Especificidade de Hospedeiro , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Vírus da Influenza A Subtipo H3N8/imunologia , Vírus da Influenza A/patogenicidade , Interferon beta , Interferons/metabolismo , Janus Quinases , Células Madin Darby de Rim Canino , Mutação , Infecções por Orthomyxoviridae/virologia , Domínios e Motivos de Interação entre Proteínas , Fator de Transcrição STAT1/metabolismo , Alinhamento de Sequência , Transcriptoma , Proteínas não Estruturais Virais/química , Fatores de Virulência , Replicação Viral/genéticaRESUMO
The potential threat of another influenza virus pandemic stimulates discussion on how to prepare for such an event. The most reasonable prophylactic approach appears to be the use of effective vaccines. Since influenza and other negative-stranded RNA viruses are amenable to genetic manipulation using transfection by plasmids, it is possible to outline new reverse genetics-based approaches for vaccination against influenza viruses. We suggest three approaches. First, we use a plasmid-only rescue system that allows the rapid generation of high-yield recombinant vaccine strains. Second, we propose developing second-generation live influenza virus vaccines by constructing an attenuated master strain with deletions in the NS1 protein, which acts as an interferon antagonist. Third, we suggest the use of Newcastle disease virus recombinants expressing influenza virus haemagglutinin proteins of pandemic (epizootic) strains as novel vaccine vectors for use in animals and possibly humans.
Assuntos
Vírus da Influenza A/genética , Vacinas contra Influenza/genética , Plasmídeos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Vírus da Doença de Newcastle/genética , Recombinação Genética , Proteínas não Estruturais Virais/genéticaRESUMO
There is increasing interest in the health-related quality of life (HRQOL) of patients with chronic oedema. Studies in this area have tended to be exploratory and little work has examined the potential for HRQOL as a treatment outcome indicator in this context. This study aimed to ascertain whether or not conservative treatment for lymphoedema results in a measurable change in HRQOL, using the Nottingham Health Profile Part 1 (NHP-1) as the study instrument. Thirty-four patients participated. The patients received a range of conservative treatments. The participants completed the NHP-1 prior to treatment and 4 weeks after completion of the initial treatment phase. The overall post-treatment NHP-1 scores were significantly lower than the overall pre-treatment scores (z = 3.1 and p < 0.01), indicating an improvement in the HRQOL. The greatest change in a single dimension was in physical mobility (z = 2.3 and p < 0.05). The change in limb volume was not associated with a change in any NHP-1 subscale. A significant correlation was found between an improvement in skin condition and an improvement in scores on the 'pain' subscale (r = 0.53 and P < 0.01). It is concluded that the NHP-1 was useful in the assessment of the 'physical' domains of HRQOL in this context, but was less useful with regard to psychological and emotional domains.
Assuntos
Linfedema/enfermagem , Qualidade de Vida , Inquéritos e Questionários , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Inglaterra , Feminino , Humanos , Linfedema/etiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Estatísticas não Paramétricas , Resultado do TratamentoRESUMO
This paper reports findings from the pilot stage of a longitudinal descriptive study of problems experienced by day-patients undergoing chemotherapy treatment with the Day Ward, Worthing Hospital. Unlike the majority of studies in this field, this study allows documentation of all side-effects perceived by the patient as important, and is designed to follow the progress in incidence and severity of each problem through the treatment course. Preliminary findings show some 100 side-effects have been identified, with different problems being most troublesome for each treatment regime. Full data are provided. The study emphasises the importance of regime-specific data both in formulating clinical practice and in the provision of patient education.
