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1.
Arch Virol ; 166(2): 545-557, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33409549

RESUMO

The use of gamma-irradiated influenza A virus (γ-Flu), retains most of the viral structural antigens, represent a promising option for vaccine development. However, despite the high effectiveness of γ-Flu vaccines, the need to incorporate an adjuvant to improve vaccine-mediated protection seems inevitable. Here, we examined the protective efficacy of an intranasal gamma-irradiated HIN1 vaccine co-administered with a plasmid encoding mouse interleukin-28B (mIL-28B) as a novel adjuvant in BALB/c mice. Animals were immunized intranasally three times at one-week intervals with γ-Flu, alone or in combination with the mIL-28B adjuvant, followed by viral challenge with a high lethal dose (10 LD50) of A/PR/8/34 (H1N1) influenza virus. Virus-specific antibody, cellular and mucosal responses, and the balance of cytokines in the spleen IFN-γ, IL-12, and IL-4) and in lung homogenates (IL-6 and IL-10) were measured by ELISA. The lymphoproliferative activity of restimulated spleen cells was also determined by MTT assay. Furthermore, virus production in the lungs of infected mice was estimated using the Madin-Darby canine kidney (MDCK)/hemagglutination assay (HA). Our data showed that intranasal immunization with adjuvanted γ-Flu vaccine efficiently promoted humoral, cellular, and mucosal immune responses and efficiently decreased lung virus titers, all of which are associated with protection against challenge. This combination also reduced IL-6 and IL-10 levels in lung homogenates. The results suggest that IL-28B can enhance the ability of the vaccine to elicit virus-specific immune responses and could potentially be used as an effective adjuvant.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Citocinas/imunologia , Imunidade Celular/imunologia , Imunidade nas Mucosas/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Infecções por Orthomyxoviridae/imunologia , Administração Intranasal/métodos , Animais , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Cães , Feminino , Imunização/métodos , Vacinas contra Influenza/imunologia , Pulmão/imunologia , Pulmão/virologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/virologia , Vacinação/métodos
3.
PLoS One ; 15(12): e0239112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382708

RESUMO

Influenza virus A is a significant agent involved in the outbreak of worldwide epidemics, causing millions of fatalities around the world by respiratory diseases and seasonal illness. Many projects had been conducting to investigate recovered infected patients for therapeutic vaccines that have broad-spectrum activity. With the aid of the computational approach in biology, the designation for a vaccine model is more accessible. We developed an in silico protocol called iBRAB to design a broad-reactive Fab on a wide range of influenza A virus. The Fab model was constructed based on sequences and structures of available broad-spectrum Abs or Fabs against a wide range of H1N1 influenza A virus. As a result, the proposed Fab model followed iBRAB has good binding affinity over 27 selected HA of different strains of H1 influenza A virus, including wild-type and mutated ones. The examination also took by computational tools to fasten the procedure. This protocol could be applied for a fast-designed therapeutic vaccine against different types of threats.


Assuntos
Anticorpos Antivirais/química , Antígenos Virais/química , Desenho de Fármacos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Fragmentos Fab das Imunoglobulinas/química , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/prevenção & controle , Sequência de Aminoácidos , Anticorpos Antivirais/genética , Antígenos Virais/genética , Antígenos Virais/imunologia , Sítios de Ligação , Simulação por Computador , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Fragmentos Fab das Imunoglobulinas/genética , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/biossíntese , Influenza Humana/imunologia , Influenza Humana/virologia , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Termodinâmica
4.
Front Immunol ; 11: 574862, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042157

RESUMO

It is currently believed that innate immunity is unable to prevent the spread of SARS-CoV-2 from the upper airways to the alveoli of high-risk groups of patients. SARS-CoV-2 replication in ACE-2-expressing pneumocytes can drive the diffuse alveolar injury through the cytokine storm and immunothrombosis by upregulating the transcription of chemokine/cytokines, unlike several other respiratory viruses. Here we report histopathology data obtained in post-mortem lung biopsies of COVID-19, showing the increased density of perivascular and septal mast cells (MCs) and IL-4-expressing cells (n = 6), in contrast to the numbers found in pandemic H1N1-induced pneumonia (n = 10) or Control specimens (n = 10). Noteworthy, COVID-19 lung biopsies showed a higher density of CD117+ cells, suggesting that c-kit positive MCs progenitors were recruited earlier to the alveolar septa. These findings suggest that MC proliferation/differentiation in the alveolar septa might be harnessed by the shift toward IL-4 expression in the inflamed alveolar septa. Future studies may clarify whether the fibrin-dependent generation of the hyaline membrane, processes that require the diffusion of procoagulative plasma factors into the alveolar lumen and the endothelial dysfunction, are preceded by MC-driven formation of interstitial edema in the alveolar septa.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Mastócitos/imunologia , Pneumonia Viral/imunologia , Alvéolos Pulmonares/imunologia , Edema Pulmonar/imunologia , Trombose/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Influenza Humana/patologia , Influenza Humana/virologia , Interleucina-4/imunologia , Masculino , Mastócitos/patologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Proteínas Proto-Oncogênicas c-kit/imunologia , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/virologia , Edema Pulmonar/patologia , Edema Pulmonar/virologia , Trombose/patologia , Trombose/virologia
5.
PLoS Med ; 17(9): e1003225, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32926731

RESUMO

BACKGROUND: Early studies of narcolepsy after AS03-adjuvanted pandemic A/H1N12009 vaccine (Pandemrix) could not define the duration of elevated risk post-vaccination nor the risk in children aged under 5 years who may not present until much older. METHODS/FINDINGS: Clinical information and sleep test results, extracted from hospital notes at 3 large pediatric sleep centers in England between September 2017 and June 2018 for narcolepsy cases aged 4-19 years with symptom onset since January 2009, were reviewed by an expert panel to confirm the diagnosis. Vaccination histories were independently obtained from general practitioners (GPs). The odds of vaccination in narcolepsy cases compared with the age-matched English population was calculated after adjustment for clinical conditions that were indications for vaccination. GP questionnaires were returned for 242 of the 244 children with confirmed narcolepsy. Of these 5 were under 5 years, 118 were 5-11 years, and 119 were 12-19 years old at diagnosis; 39 were vaccinated with Pandemrix before onset. The odds ratio (OR) for onset at any time after vaccination was 1.94 (95% confidence interval [CI] 1.30-2.89), The elevated risk period was restricted to onsets within 12 months of vaccination (OR 6.65 [3.44-12.85]) and was highest within the first 6 months. After one year, ORs were not significantly different from 1 up to 8 years after vaccination. The ORs were similar in under five-year-olds and older ages. The estimated attributable risk was 1 in 34,500 doses. Our study is limited by including cases from only 3 sleep centers, who may differ from cases diagnosed in nonparticipating centers, and by imprecision in defining the centers' catchment population. The potential for biased recall of onset shortly after vaccination in cases aware of the association cannot be excluded. CONCLUSIONS: In this study, we found that vaccine-attributable cases have onset of narcolepsy within 12 months of Pandemrix vaccination. The attributable risk is higher than previously estimated in England because of identification of vaccine-attributable cases with late diagnoses. Absence of a compensatory drop in risk 1-8 years after vaccination suggests that Pandemrix does not trigger onsets in those in whom narcolepsy would have occurred later.


Assuntos
Narcolepsia/etiologia , Polissorbatos/efeitos adversos , Esqualeno/efeitos adversos , Vacinação/efeitos adversos , alfa-Tocoferol/efeitos adversos , Adolescente , Criança , Pré-Escolar , Combinação de Medicamentos , Inglaterra/epidemiologia , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/uso terapêutico , Influenza Humana/epidemiologia , Masculino , Narcolepsia/epidemiologia , Narcolepsia/imunologia , Razão de Chances , Pandemias , Fatores de Risco , Inquéritos e Questionários
7.
Arch Virol ; 165(11): 2503-2512, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32783078

RESUMO

Immunodominance is recognized as a key factor in the antigenic drift of seasonal influenza viruses. In the immunodominance model, each individual in a population predominantly responds to a single epitope among the five antigenic epitopes of the viral hemagglutinin (HA), driving escape mutations one at a time, and sequential mutations in multiple individuals who respond to different epitopes eventually generate a drifted strain with mutations in epitopes that are targeted by a majority of the population. A focused antibody response to the Sa epitope in people born between 1965 and 1979 was believed to contribute to a mutation at HA residue 163 and the first antigenic drift of the 2009 pandemic influenza A H1N1 virus. A serine-to-threonine mutation at HA residue 185 in the Sb epitope emerged in 2010 even before the 163 mutation. We show here that a large fraction of the population in 2010-2011 had responses to the Sb epitope, as shown by 47% of tested sera having altered titers to the S185T mutant. Responses to the Sb epitope showed an age-specific trend similar to that found for the response to Sa epitope in these subjects. Together, the focused responses to Sa and Sb epitopes may have driven the first antigenic drift of the 2009 pandemic H1N1 virus.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Variação Antigênica , Evolução Molecular , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Animais , Cães , Mapeamento de Epitopos , Testes de Inibição da Hemaglutinação , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Proteínas Mutantes/genética , Proteínas Mutantes/imunologia , RNA Viral/genética , Seleção Genética , Análise de Sequência de DNA , Cultura de Vírus
8.
Immunity ; 53(3): 685-696.e3, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32783921

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic poses a current world-wide public health threat. However, little is known about its hallmarks compared to other infectious diseases. Here, we report the single-cell transcriptional landscape of longitudinally collected peripheral blood mononuclear cells (PBMCs) in both COVID-19- and influenza A virus (IAV)-infected patients. We observed increase of plasma cells in both COVID-19 and IAV patients and XIAP associated factor 1 (XAF1)-, tumor necrosis factor (TNF)-, and FAS-induced T cell apoptosis in COVID-19 patients. Further analyses revealed distinct signaling pathways activated in COVID-19 (STAT1 and IRF3) versus IAV (STAT3 and NFκB) patients and substantial differences in the expression of key factors. These factors include relatively increase of interleukin (IL)6R and IL6ST expression in COVID-19 patients but similarly increased IL-6 concentrations compared to IAV patients, supporting the clinical observations of increased proinflammatory cytokines in COVID-19 patients. Thus, we provide the landscape of PBMCs and unveil distinct immune response pathways in COVID-19 and IAV patients.


Assuntos
Infecções por Coronavirus/imunologia , Citocinas/imunologia , Influenza Humana/imunologia , Leucócitos Mononucleares/imunologia , Pneumonia Viral/imunologia , Transdução de Sinais/imunologia , Betacoronavirus/imunologia , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Pandemias
9.
Vaccine ; 38(41): 6374-6380, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32798142

RESUMO

The rapid spread of the Coronavirus pandemic and its significant health and social impact urges the search for effective and readily available solutions to mitigate the damages. Thus, evaluating the effectiveness of existing vaccines like Bacillus Calmette-Guérin (BCG) has attracted attention. The aim of this review was evidence synthesis on the effect of BCG vaccine in preventing severe infectious respiratory disease including COVD-19, but not tuberculosis. We considered studies conducted on human participants of any study design from any country setting that were published in Enlgish. We did a systematic literature search in MEDLINE, Scopus and Google scholar databases and a free search on Google. The identified studies were appraised and relevant data were extracted using Joanna Briggs Institute tools. The extracted findings were synthesized with tables and narrative summary. Nine studies met the inclusion criteria. The findings indicated that BCG vaccine has a strong protective effect against both upper and lower acute respiratory tract infections. For instance in countries with universal BCG vaccination policy, the incidence of COVID-19 was lower compared to the counterparts. Addtionally, BCG vaccine was found to protect against infections like lethal influenza A virus, pandemic influenza (H1N1), and other acute respiratory tract infections. BCG improved the human body's immune response involving antigen-specific T cells and memory cells. It also induced adaptive functional reprogramming of mononuclear phagocytes that induce protective effects against different respiratory infections other than tuberculosis. In countries with universal BCG vaccination, the incidence and death from acute respiratory viral infection including COVID - 19 is significantly low. However, there is an urgent need for further evidence from well-designed studies to understand the possible role of BCG vaccination over time and across age groups, its possible benefits in special populations such as health workers and cost-savings related to a policy of universal BCG vaccination.


Assuntos
Vacina BCG/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Mycobacterium bovis/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Anticorpos Antivirais/imunologia , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/prevenção & controle , Tuberculose Pulmonar/prevenção & controle , Vacinação
10.
PLoS One ; 15(8): e0237218, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760143

RESUMO

Influenza is an infectious respiratory illness caused by influenza viruses. Despite yearly updates, the efficacy of influenza vaccines is significantly curtailed by the virus antigenic drift and antigenic shift. These constant changes to the influenza virus make-up also challenge the development of a universal flu vaccine, which requires conserved antigenic regions shared by influenza viruses of different subtypes. We propose that it is possible to bypass these challenges by the development of an influenza vaccine based on conserved proteins delivered in an adjuvanted nanoparticle system. In this study, we generated influenza nanoparticle constructs using trimethyl chitosan nanoparticles (TMC nPs) as the carrier of recombinant influenza hemagglutinin subunit 2 (HA2) and nucleoprotein (NP). The purified HA2 and NP recombinant proteins were encapsulated into TMC nPs to form HA2-TMC nPs and NP-TMC nPs, respectively. Primary human intranasal epithelium cells (HNEpCs) were used as an in vitro model to measure immunity responses. HA2-TMC nPs, NP-TMC nPs, and HA2-NP-TMC nPs (influenza nanoparticle constructs) showed no toxicity in HNEpCs. The loading efficiency of HA2 and NP into the TMC nPs was 97.9% and 98.5%, respectively. HA2-TMC nPs and NP-TMC nPs more efficiently delivered HA2 and NP proteins to HNEpCs than soluble HA2 and NP proteins alone. The induction of various cytokines and chemokines was more evident in influenza nanoparticle construct-treated HNEpCs than in soluble protein-treated HNEpCs. In addition, soluble factors secreted by influenza nanoparticle construct-treated HNEpCs significantly induced MoDCs maturation markers (CD80, CD83, CD86 and HLA-DR), as compared to soluble factors secreted by protein-treated HNEpCs. HNEpCs treated with the influenza nanoparticle constructs significantly reduced influenza virus replication in an in vitro challenge assay. The results indicate that TMC nPs can be used as influenza vaccine adjuvants and carriers capable of delivering HA2 and NP proteins to HNEpCs.


Assuntos
Adjuvantes Imunológicos/farmacologia , Quitosana/farmacologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/farmacologia , Influenza Humana/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Animais , Linhagem Celular , Células Cultivadas , Quitosana/administração & dosagem , Cães , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/administração & dosagem , Glicoproteínas de Hemaglutininação de Vírus da Influenza/farmacologia , Humanos , Vacinas contra Influenza/administração & dosagem , Influenza Humana/imunologia , Células Madin Darby de Rim Canino , Nanopartículas/administração & dosagem , Proteínas do Nucleocapsídeo , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Proteínas de Ligação a RNA/administração & dosagem , Proteínas de Ligação a RNA/farmacologia , Proteínas do Core Viral/administração & dosagem , Proteínas do Core Viral/farmacologia
12.
PLoS One ; 15(7): e0236172, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726321

RESUMO

There are several broadly neutralizing monoclonal antibodies that neutralize influenza viruses with different mechanisms from traditional polyclonal antibodies induced by vaccination. CT149, which is one of the broadly neutralizing antibodies, was also previously reported to neutralize group 2 and some of group 1 influenza viruses (13 out of 13 tested group 2 viruses and 5 out of 11 group 1 viruses). In this study, we developed another antibody with the aim of compensating partial coverage of CT149 against group 1 influenza viruses. CT120 was screened among different antibody candidates and mixed with CT149. Importantly, although the binding sites of CT120 and CT149 are close to each other, the two antibodies do not interfere. The mixture of CT120 and CT149, which we named as CT-P27, showed broad efficacy by neutralizing 37 viruses from 11 different subtypes, of both group 1 and 2 influenza A viruses. Moreover, CT-P27 showed in vivo therapeutic efficacy, long prophylactic potency, and synergistic effect with oseltamivir in influenza virus-challenged mouse models. Our findings provide a novel therapeutic opportunity for more efficient treatment of influenza.


Assuntos
Anticorpos Monoclonais/farmacocinética , Anticorpos Neutralizantes/farmacologia , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Especificidade de Anticorpos/imunologia , Antígenos Virais/imunologia , Hemaglutinação/imunologia , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Camundongos , Testes de Neutralização , Vacinação
13.
PLoS One ; 15(7): e0234827, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645112

RESUMO

BACKGROUND: The most important factor influencing maternal vaccination uptake is healthcare professional (HCP) recommendation. However, where data are available, one-third of pregnant women remain unvaccinated despite receiving a recommendation. Therefore, it is essential to understand the significance of other factors and distinguish between vaccines administered routinely and during outbreaks. This is the first systematic review and meta-analysis (PROSPERO: CRD 42019118299) to examine the strength of the relationships between identified factors and maternal vaccination uptake. METHODS: We searched MEDLINE, Embase Classic & Embase, PsycINFO, CINAHL Plus, Web of Science, IBSS, LILACS, AfricaWideInfo, IMEMR, and Global Health databases for studies reporting factors that influence maternal vaccination. We used random-effects models to calculate pooled odds ratios (OR) of being vaccinated by vaccine type. FINDINGS: We screened 17,236 articles and identified 120 studies from 30 countries for inclusion. Of these, 49 studies were eligible for meta-analysis. The odds of receiving a pertussis or influenza vaccination were ten to twelve-times higher among pregnant women who received a recommendation from HCPs. During the 2009 influenza pandemic an HCP recommendation increased the odds of antenatal H1N1 vaccine uptake six times (OR 6.76, 95% CI 3.12-14.64, I2 = 92.00%). Believing there was potential for vaccine-induced harm had a negative influence on seasonal (OR 0.22, 95% CI 0.11-0.44 I2 = 84.00%) and pandemic influenza vaccine uptake (OR 0.16, 95% CI 0.09-0.29, I2 = 89.48%), reducing the odds of being vaccinated five-fold. Combined with our qualitative analysis the relationship between the belief in substantial disease risk and maternal seasonal and pandemic influenza vaccination uptake was limited. CONCLUSIONS: The effect of an HCP recommendation during an outbreak, whilst still powerful, may be muted by other factors. This requires further research, particularly when vaccines are novel. Public health campaigns which centre on the protectiveness and safety of a maternal vaccine rather than disease threat alone may prove beneficial.


Assuntos
Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Gestantes/psicologia , Vacinação/psicologia , Adulto , Tomada de Decisões , Feminino , Pessoal de Saúde/psicologia , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Razão de Chances , Gravidez , Inquéritos e Questionários
14.
Nat Commun ; 11(1): 3418, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32647286

RESUMO

The emergence and spread of antiviral drug-resistant viruses have been a worldwide challenge and a great concern for patient care. We report A4 antibody specifically recognizing and binding to the mutant I223R/H275Y neuraminidase and prove the applicability of A4 antibody for direct detection of antiviral multidrug-resistant viruses in various sensing platforms, including naked-eye detection, surface-enhanced Raman scattering-based immunoassay, and lateral flow system. The development of the A4 antibody enables fast, simple, and reliable point-of-care assays of antiviral multidrug-resistant influenza viruses. In addition to current influenza virus infection testing methods that do not provide information on the antiviral drug-resistance of the virus, diagnostic tests for antiviral multidrug-resistant viruses will improve clinical judgment in the treatment of influenza virus infections, avoid the unnecessary prescription of ineffective drugs, and improve current therapies.


Assuntos
Anticorpos Antivirais/imunologia , Resistência a Múltiplos Medicamentos/imunologia , Farmacorresistência Viral/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Mutação/genética , Neuraminidase/genética , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/química , Afinidade de Anticorpos/imunologia , Antígenos Virais/metabolismo , Líquidos Corporais/virologia , Análise Mutacional de DNA , Cães , Epitopos/química , Epitopos/imunologia , Humanos , Vírus da Influenza A Subtipo H1N1/enzimologia , Vírus da Influenza A Subtipo H3N2/enzimologia , Células Madin Darby de Rim Canino , Simulação de Acoplamento Molecular , Imagem Óptica , Ligação Proteica , Análise Espectral Raman
15.
PLoS Pathog ; 16(7): e1008671, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32614923

RESUMO

Viral infection outcomes are governed by the complex and dynamic interplay between the infecting virus population and the host response. It is increasingly clear that both viral and host cell populations are highly heterogeneous, but little is known about how this heterogeneity influences infection dynamics or viral pathogenicity. To dissect the interactions between influenza A virus (IAV) and host cell heterogeneity, we examined the combined host and viral transcriptomes of thousands of individual cells, each infected with a single IAV virion. We observed complex patterns of viral gene expression and the existence of multiple distinct host transcriptional responses to infection at the single cell level. We show that human H1N1 and H3N2 strains differ significantly in patterns of both viral and host anti-viral gene transcriptional heterogeneity at the single cell level. Our analyses also reveal that semi-infectious particles that fail to express the viral NS can play a dominant role in triggering the innate anti-viral response to infection. Altogether, these data reveal how patterns of viral population heterogeneity can serve as a major determinant of antiviral gene activation.


Assuntos
Regulação Viral da Expressão Gênica/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Influenza Humana/imunologia , Influenza Humana/virologia , Células A549 , Humanos , Imunidade Inata/imunologia , Proteínas não Estruturais Virais/imunologia
16.
Viruses ; 12(6)2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32599823

RESUMO

The respiratory Influenza A Viruses (IAVs) and emerging zoonotic viruses such as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pose a significant threat to human health. To accelerate our understanding of the host-pathogen response to respiratory viruses, the use of more complex in vitro systems such as normal human bronchial epithelial (NHBE) cell culture models has gained prominence as an alternative to animal models. NHBE cells were differentiated under air-liquid interface (ALI) conditions to form an in vitro pseudostratified epithelium. The responses of well-differentiated (wd) NHBE cells were examined following infection with the 2009 pandemic Influenza A/H1N1pdm09 strain or following challenge with the dsRNA mimic, poly(I:C). At 30 h postinfection with H1N1pdm09, the integrity of the airway epithelium was severely impaired and apical junction complex damage was exhibited by the disassembly of zona occludens-1 (ZO-1) from the cell cytoskeleton. wdNHBE cells produced an innate immune response to IAV-infection with increased transcription of pro- and anti-inflammatory cytokines and chemokines and the antiviral viperin but reduced expression of the mucin-encoding MUC5B, which may impair mucociliary clearance. Poly(I:C) produced similar responses to IAV, with the exception of MUC5B expression which was more than 3-fold higher than for control cells. This study demonstrates that wdNHBE cells are an appropriate ex-vivo model system to investigate the pathogenesis of respiratory viruses.


Assuntos
Vírus da Influenza A Subtipo H1N1/fisiologia , Influenza Humana/virologia , Mucosa Respiratória/citologia , Mucosa Respiratória/virologia , Animais , Brônquios/citologia , Brônquios/virologia , Células Cultivadas , Quimiocinas/metabolismo , Citocinas/metabolismo , Cães , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/epidemiologia , Junções Intercelulares , Células Madin Darby de Rim Canino , Modelos Biológicos , Mucina-5AC/metabolismo , Pandemias , Cultura de Vírus
17.
Trends Biotechnol ; 38(9): 943-947, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32600777

RESUMO

Vaccine solutions rarely reach the public until after an outbreak abates; an Ebola vaccine was approved 5 years after peak outbreak and SARS, MERS, and Zika vaccines are still in clinical development. Despite massive leaps forward in rapid science, other regulatory bottlenecks are hamstringing the global effort for pandemic vaccines.


Assuntos
Infecções por Coronavirus/prevenção & controle , Aprovação de Drogas/organização & administração , Doença pelo Vírus Ebola/prevenção & controle , Influenza Humana/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais/biossíntese , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Vacinas contra Ebola/administração & dosagem , Vacinas contra Ebola/biossíntese , Ebolavirus/efeitos dos fármacos , Ebolavirus/imunologia , Ebolavirus/patogenicidade , Europa (Continente)/epidemiologia , Saúde Global/tendências , Regulamentação Governamental , Doença pelo Vírus Ebola/epidemiologia , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/virologia , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/biossíntese , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Influenza Humana/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/imunologia , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/epidemiologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/prevenção & controle , Síndrome Respiratória Aguda Grave/virologia , Estados Unidos/epidemiologia , Vacinas Virais/administração & dosagem , Zika virus/efeitos dos fármacos , Zika virus/imunologia , Zika virus/patogenicidade , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/prevenção & controle , Infecção por Zika virus/virologia
18.
Nat Med ; 26(8): 1240-1246, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32601336

RESUMO

The conserved region of influenza hemagglutinin (HA) stalk (or stem) has gained attention as a potent target for universal influenza vaccines1-5. Although the HA stalk region is relatively well conserved, the evolutionarily dynamic nature of influenza viruses6 raises concerns about the possible emergence of viruses carrying stalk escape mutation(s) under sufficient immune pressure. Here we show that immune pressure on the HA stalk can lead to expansion of escape mutant viruses in study participants challenged with a 2009 H1N1 pandemic influenza virus inoculum containing an A388V polymorphism in the HA stalk (45% wild type and 55% mutant). High level of stalk antibody titers was associated with the selection of the mutant virus both in humans and in vitro. Although the mutant virus showed slightly decreased replication in mice, it was not observed in cell culture, ferrets or human challenge participants. The A388V mutation conferred resistance to some of the potent HA stalk broadly neutralizing monoclonal antibodies (bNAbs). Co-culture of wild-type and mutant viruses in the presence of either a bNAb or human serum resulted in rapid expansion of the mutant. These data shed light on a potential obstacle for the success of HA-stalk-targeting universal influenza vaccines-viral escape from vaccine-induced stalk immunity.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/genética , Seleção Genética/genética , Animais , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Antivirais/genética , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/farmacologia , Sequência Conservada/genética , Reações Cruzadas/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vacinas contra Influenza/genética , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Camundongos , Seleção Genética/imunologia
19.
Nat Commun ; 11(1): 3624, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681036

RESUMO

TRIM family proteins play integral roles in the innate immune response to virus infection. MG53 (TRIM72) is essential for cell membrane repair and is believed to be a muscle-specific TRIM protein. Here we show human macrophages express MG53, and MG53 protein expression is reduced following virus infection. Knockdown of MG53 in macrophages leads to increases in type I interferon (IFN) upon infection. MG53 knockout mice infected with influenza virus show comparable influenza virus titres to wild type mice, but display increased morbidity accompanied by more accumulation of CD45+ cells and elevation of IFNß in the lung. We find that MG53 knockdown results in activation of NFκB signalling, which is linked to an increase in intracellular calcium oscillation mediated by ryanodine receptor (RyR). MG53 inhibits IFNß induction in an RyR-dependent manner. This study establishes MG53 as a new target for control of virus-induced morbidity and tissue injury.


Assuntos
Influenza Humana/imunologia , Interferon beta/metabolismo , Proteínas de Membrana/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Animais , Sinalização do Cálcio/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Humanos , Imunidade Inata , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/virologia , Interferon beta/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , RNA Interferente Pequeno , Transdução de Sinais/imunologia , Proteínas com Motivo Tripartido/genética
20.
HLA ; 96(3): 277-298, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32475052

RESUMO

We report detailed peptide-binding affinities between 438 HLA Class I and Class II proteins and complete proteomes of seven pandemic human viruses, including coronaviruses, influenza viruses and HIV-1. We contrast these affinities with HLA allele frequencies across hundreds of human populations worldwide. Statistical modelling shows that peptide-binding affinities classified into four distinct categories depend on the HLA locus but that the type of virus is only a weak predictor, except in the case of HIV-1. Among the strong HLA binders (IC50 ≤ 50), we uncovered 16 alleles (the top ones being A*02:02, B*15:03 and DRB1*01:02) binding more than 1% of peptides derived from all viruses, 9 (top ones including HLA-A*68:01, B*15:25, C*03:02 and DRB1*07:01) binding all viruses except HIV-1, and 15 (top ones A*02:01 and C*14:02) only binding coronaviruses. The frequencies of strongest and weakest HLA peptide binders differ significantly among populations from different geographic regions. In particular, Indigenous peoples of America show both higher frequencies of strongest and lower frequencies of weakest HLA binders. As many HLA proteins are found to be strong binders of peptides derived from distinct viral families, and are hence promiscuous (or generalist), we discuss this result in relation to possible signatures of natural selection on HLA promiscuous alleles due to past pathogenic infections. Our findings are highly relevant for both evolutionary genetics and the development of vaccine therapies. However they should not lead to forget that individual resistance and vulnerability to diseases go beyond the sole HLA allelic affinity and depend on multiple, complex and often unknown biological, environmental and other variables.


Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por HIV/epidemiologia , Antígenos HLA/química , Influenza Humana/epidemiologia , Pandemias , Peptídeos/química , Pneumonia Viral/epidemiologia , Síndrome Respiratória Aguda Grave/epidemiologia , Proteínas Virais/química , África/epidemiologia , América/epidemiologia , Sequência de Aminoácidos , Ásia/epidemiologia , Austrália/epidemiologia , Betacoronavirus/genética , Betacoronavirus/imunologia , Biologia Computacional , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Europa (Continente)/epidemiologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/imunologia , Antígenos HLA/classificação , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/imunologia , Subtipo H7N9 do Vírus da Influenza A/genética , Subtipo H7N9 do Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Influenza Humana/virologia , Cinética , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Peptídeos/genética , Peptídeos/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Ligação Proteica , Vírus da SARS/genética , Vírus da SARS/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia , Proteínas Virais/genética , Proteínas Virais/imunologia
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