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Introduction: Before they can produce their own antibodies, newborns are protected from infections by transplacental transfer of maternal IgG antibodies and after birth through breast milk IgA antibodies. Rhinovirus (RV) infections are extremely common in early childhood, and while RV infections often result in only mild upper respiratory illnesses, they can also cause severe lower respiratory illnesses such as bronchiolitis and pneumonia. Methods: We used high-density peptide arrays to profile infant and maternal antibody reactivity to capsid and full proteome sequences of three human RVs - A16, B52, and C11. Results: Numerous plasma IgG and breast milk IgA RV epitopes were identified that localized to regions of the RV capsid surface and interior, and also to several non-structural proteins. While most epitopes were bound by both IgG and IgA, there were several instances where isotype-specific and RV-specific binding were observed. We also profiled 62 unique RV-C protein loop sequences characteristic of this species' capsid VP1 protein. Discussion: Many of the RV-C loop sequences were highly bound by IgG from one-year-old infants, indicating recent or ongoing active infections, or alternatively, a level of cross-reactivity among homologous RV-C sites.
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Anticorpos Antivirais , Imunoglobulina G , Leite Humano , Rhinovirus , Humanos , Leite Humano/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Feminino , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Lactente , Rhinovirus/imunologia , Imunoglobulina A/imunologia , Imunoglobulina A/sangue , Infecções por Picornaviridae/imunologia , Recém-Nascido , Epitopos/imunologia , Proteínas do Capsídeo/imunologia , AdultoRESUMO
Respiratory viruses are a major trigger of exacerbations in chronic obstructive pulmonary disease (COPD). Airway neutrophilia is a hallmark feature of stable and exacerbated COPD but roles played by neutrophil extracellular traps (NETS) in driving disease pathogenesis are unclear. Here, using human studies of experimentally-induced and naturally-occurring exacerbations we identify that rhinovirus infection induces airway NET formation which is amplified in COPD and correlates with magnitude of inflammation and clinical exacerbation severity. We show that inhibiting NETosis protects mice from immunopathology in a model of virus-exacerbated COPD. NETs drive inflammation during exacerbations through release of double stranded DNA (dsDNA) and administration of DNAse in mice has similar protective effects. Thus, NETosis, through release of dsDNA, has a functional role in the pathogenesis of COPD exacerbations. These studies open up the potential for therapeutic targeting of NETs or dsDNA as a strategy for treating virus-exacerbated COPD.
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Armadilhas Extracelulares , Neutrófilos , Doença Pulmonar Obstrutiva Crônica , Rhinovirus , Armadilhas Extracelulares/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/virologia , Doença Pulmonar Obstrutiva Crônica/patologia , Animais , Humanos , Rhinovirus/imunologia , Camundongos , Neutrófilos/imunologia , Masculino , Feminino , Infecções por Picornaviridae/imunologia , Infecções por Picornaviridae/virologia , Infecções por Picornaviridae/complicações , Camundongos Endogâmicos C57BL , DNA/imunologia , Modelos Animais de Doenças , Pessoa de Meia-Idade , Inflamação/imunologia , Inflamação/virologia , IdosoRESUMO
Wheezing children infected with rhinovirus (RV) have a markedly increased risk of subsequently developing recurrencies and asthma. No previous studies have assessed the association between cytokine response and the severity of acute illness in the first wheezing episode in children infected with RV. Forty-seven children treated both as inpatients and as outpatients infected with RV only, aged 3-23 months, with severe first wheezing episodes were recruited. During acute illness, peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with anti-CD3/anti-CD28 in vitro. A multiplex ELISA was used to quantitatively identify 56 different cytokines. The mean age of the children was 17 months, 74% were males, 79% were hospitalized, and 33% were sensitized. In adjusted analyses, the inpatient group was characterized by decreased expressions of interferon gamma (IFN-γ), interleukin 10 (IL-10), macrophage inflammatory protein 1 alpha (MIP-1α), RANTES (CCL5), and tumor necrosis factor-alpha (TNF-α) and an increased expression of ENA-78 (CXCL5) compared to the outpatient group. The cytokine response profiles from the PBMCs were different between the inpatient and outpatient groups. Our results support that firmly controlled interplay between pro-inflammatory and anti-inflammatory responses are required during acute viral infection to absolve the initial infection leading, to less severe illness.
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Citocinas , Leucócitos Mononucleares , Infecções por Picornaviridae , Sons Respiratórios , Rhinovirus , Humanos , Masculino , Rhinovirus/imunologia , Feminino , Citocinas/metabolismo , Lactente , Sons Respiratórios/etiologia , Infecções por Picornaviridae/imunologia , Infecções por Picornaviridae/virologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Índice de Gravidade de DoençaRESUMO
Allergic rhinitis (AR) is a global health challenge that particularly affects the quality of life of children. Human rhinovirus (HRV) infection usually causes common cold in the upper respiratory tract (URT) and can also affect airway allergy development, such as asthma exacerbation, but its relationship with AR is poorly understood. The study aimed to gain insight into the characteristics of HRV that is prevalent in AR children and its role in AR severity. A total of 362 children with symptomatic AR were enrolled from southwestern China during 2022-2023, and nasal lavage samples were collected for HRV molecular characterization and cytokine measurement. HRV was detected in 40% of the AR children, with peak detection in autumn. The positive rate was not correlated with whether the subjects were under allergen-specific immunotherapy (AIT). Among the detected HRVs, 42% were species A, 36% were species B, and 22% were species C, involving 21 A genotypes, 6 B genotypes, and 7 C genotypes. HRV positivity was significantly associated with symptom severity (visual analog scale [VAS] score) and elevated levels of local nasal IgE, interleukin-25 (IL-25), IL-4, and CXCL13 in AR children who did not receive antiallergic treatment. All three species of HRV strains (A1B, A21, B27, B70, and C17) had been isolated and were able to infect respiratory epithelial tissue in vitro. Complete genome sequencing showed that the antigenic epitopes of the isolated HRVs had certain variations. Our work reveals the etiological characteristics of URT-HRV in AR children and suggests a role of HRV infection in the pathogenesis of childhood AR. IMPORTANCE: Our study revealed high human rhinovirus (HRV) detection rate in children with allergic rhinitis (AR), and HRV infection (A, B, or C species) is positively associated with the symptom severity in AR children. Elevated nasal IgE, interleukin-25 (IL-25), IL-4, and CXCL13 levels suggest a potential pathogenic mechanism by which HRV infection induces nasal type 2 immune/inflammation responses and local IgE production in AR patients. In addition, etiological analysis found that the main prevalent HRV species in AR children are A and B (~80%), which is different from acute respiratory infection and asthma exacerbation, where species A and C are dominant. The data reveal the distinct species prevalence characteristics of HRV infection in AR. Finally, we isolated all three species of HRV strains from nasal cavity of AR children with varying degrees of antigenic epitope mutations and in vitro infectivity, highlighting the importance of strengthening monitoring and intervention for respiratory HRV infection in AR children.
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Infecções por Picornaviridae , Rinite Alérgica , Rhinovirus , Humanos , Rhinovirus/genética , Rhinovirus/imunologia , Rhinovirus/isolamento & purificação , Rhinovirus/classificação , Criança , Masculino , Feminino , Infecções por Picornaviridae/virologia , Infecções por Picornaviridae/imunologia , Infecções por Picornaviridae/epidemiologia , Pré-Escolar , China/epidemiologia , Rinite Alérgica/virologia , Rinite Alérgica/imunologia , Imunoglobulina E/imunologia , Imunoglobulina E/sangue , Índice de Gravidade de Doença , Citocinas/metabolismo , Citocinas/imunologia , Genótipo , Infecções Respiratórias/virologia , Infecções Respiratórias/imunologia , Adolescente , Filogenia , Resfriado Comum/virologia , Resfriado Comum/imunologia , Resfriado Comum/epidemiologiaRESUMO
All respiratory viruses establish primary infections in the nasal epithelium, where efficient innate immune induction may prevent dissemination to the lower airway and thus minimize pathogenesis. Human coronaviruses (HCoVs) cause a range of pathologies, but the host and viral determinants of disease during common cold versus lethal HCoV infections are poorly understood. We model the initial site of infection using primary nasal epithelial cells cultured at an air-liquid interface (ALI). HCoV-229E, HCoV-NL63, and human rhinovirus-16 are common cold-associated viruses that exhibit unique features in this model: early induction of antiviral interferon (IFN) signaling, IFN-mediated viral clearance, and preferential replication at nasal airway temperature (33 °C) which confers muted host IFN responses. In contrast, lethal SARS-CoV-2 and MERS-CoV encode antagonist proteins that prevent IFN-mediated clearance in nasal cultures. Our study identifies features shared among common cold-associated viruses, highlighting nasal innate immune responses as predictive of infection outcomes and nasally directed IFNs as potential therapeutics.
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Resfriado Comum , Imunidade Inata , Interferons , Mucosa Nasal , SARS-CoV-2 , Transdução de Sinais , Humanos , Mucosa Nasal/virologia , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Interferons/metabolismo , Interferons/imunologia , Resfriado Comum/imunologia , Resfriado Comum/virologia , Transdução de Sinais/imunologia , SARS-CoV-2/imunologia , Replicação Viral , Rhinovirus/imunologia , Coronavirus Humano 229E/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Células Epiteliais/virologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavirus Humano NL63/imunologiaRESUMO
Rhinoviruses (RV) are the major cause of chronic obstructive pulmonary disease and are associated with exacerbation development as well as community-acquired pneumonia in children, leading to substantial morbidity, mortality, and hospital admission. Here we have examined how changes at the amino terminal of the conserved VP4 epitope of different RV serotypes may affect pulmonary cytokine and chemokine responses and disease severity. Samples positive for rhinovirus were used for genetic characterization, followed by profiling gene expression of pulmonary Th1 and Th2 cytokines/chemokines by RT-PCR arrays. Genetic sequencing and homology 3D modeling revealed changes at the amino terminal of the conserved viral protein 4 (VP4) epitope in the RV-A101 serotype, especially serine at several positions that are important for interactive binding with the host immune cells. We found dysregulation of pulmonary gene expression of Th1- and Th2-related cytokines and chemokines in RV-A 101 and RV-C 8 pneumonia patients. These findings might contribute to a better understanding of RV immunity and the potential mechanisms underlying the pathogenesis of severe RV infections, but further functional studies are needed to confirm the causal relationship.
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Rhinovirus , Humanos , Rhinovirus/genética , Rhinovirus/imunologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/química , Citocinas/imunologia , Citocinas/genética , Feminino , Masculino , Infecções por Picornaviridae/imunologia , Infecções por Picornaviridae/genética , Infecções por Picornaviridae/virologia , Células Th2/imunologiaRESUMO
En el contexto de la pandemia de COVID-19, a partir de 2020, la Unidad Centinela de Enfermedades Tipo Influenza (UC-ETI) (Santa Fe, Argentina) integró la vigilancia clínica y por laboratorio de SARS-CoV-2 y rinovirus (HRV) a la habitual vigilancia de influenza y otros virus respiratorios (OVR). El objetivo de este estudio transversal y retrospectivo fue describir las características clínico-epidemiológicas de casos de ETI de la ciudad de Santa Fe, con diagnóstico de HRV confirmado durante 2020-2021, en el marco de la UC-ETI. Del total de 600 casos de ETI cuyas muestras fueron analizadas, más del 50,0% fueron mujeres; y la mayor proporción se concentró en el grupo de 15 a 39 años (40,2%). El 33,7% registró al menos una comorbilidad o factor de riesgo, siendo la hipertensión arterial, asma, diabetes, obesidad y EPOC las más frecuentes. Además de fiebre y tos, los signos/síntomas predominantes fueron odinofagia, mialgia y cefalea. El porcentaje de positividad fue de 41,3% en 2020, 27,8% en 2021 y 35,5% en 2020-2021. De las muestras positivas del bienio (213), 59,0% fue SARS-CoV-2, 40,0% HRV y 1,0% OVR. La mayor proporción de diagnósticos positivos de SARS-CoV-2 se concentró en pacientes de 15 años y más, y la de HRV en menores de 15. Los periodos en los que predominó la circulación de HRV no lo hizo la de SARS-CoV-2, y viceversa. El aporte a la carga real de las infecciones virales respiratorias y su impacto en la salud pública destaca la importancia de sostener la vigilancia de HRV
In the context of the COVID-19 pandemic, in 2020, the influenza-like illness Sentinel Unit (ILI-SU) (Santa Fe, Argentina), integrated clinical and laboratory surveillance of SARS-CoV-2 and Rhinovirus (HRV) to the usual surveillance of Influenza and other respiratory viruses (ORV). The objective of this cross-sectional and retrospective study was to describe the clinical-epidemiological characteristics of ILI cases of Santa Fe city, who had a confirmed HRV diagnosis during 2020-2021, by the ILI-SU. Of a total of 600 ILI cases whose samples were analyzed, more than 50.0% were women; and the highest proportion was concentrated in the group between 15 and 39 years of age (40.2%). 33.7% of the cases registered at least one comorbidity or risk factor, among which arterial hypertension, asthma, diabetes, obesity and COPD were the most frequent. In addition to fever and cough, the predominant signs/symptoms were sore throat, myalgia and headache. The percentage of positivity was 41.3% in 2020, 27.8% in 2021, and 35.5% in 2020-2021. Of the biennium positive samples (213), 59.0% were SARS-CoV-2, 40.0% HRV, and 1.0% ORV. The highest proportion of SARS-CoV-2 positive diagnoses were concentrated in patients 15 years of age and older, while the highest proportion of HRV positive diagnoses were concentrated in patients under 15 years of age. The periods in which the circulation of HRV predominated did not predominated SARS-CoV-2, and vice versa. The contribution to the real burden of respiratory viral infections and its impact on public health, highlight the importance of sustaining HRV surveillance
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Humanos , Masculino , Feminino , Rhinovirus/imunologia , Síndrome Respiratória Aguda Grave/epidemiologia , COVID-19/epidemiologiaRESUMO
Human rhinoviruses (HRVs) are small non-enveloped RNA viruses that belong to the Enterovirus genus within the Picornaviridae family and are known for causing the common cold. Though symptoms are generally mild in healthy individuals, the economic burden associated with HRV infection is significant. A vaccine could prevent disease. The Vero-cell-based viral vaccine platform technology was considered for such vaccine development. Unfortunately, most HRV strains are unable to propagate on Vero cells due to a lack of the major receptor of HRV group A and B, intercellular adhesion molecule (ICAM1, also known as CD54). Therefore, stable human ICAM1 expressing Vero cell clones were generated by transfecting the ICAM1 gene in Vero cells and selecting clones that overexpressed ICAM1 on the cell surface. Cell banks were made and expression of ICAM1 was stable for at least 30 passages. The Vero_ICAM1 cells and parental Vero cells were infected with four HRV prototypes, B14, A16, B37 and A57. Replication of all four viruses was detected in Vero_ICAM1, but not in the parental Vero cells. Altogether, Vero cells expressing ICAM1 could efficiently propagate the tested HRV strains. Therefore, ICAM1-expressing cells could be a useful tool for the development and future production of polyvalent HRV vaccines or other viruses that use ICAM1 as a receptor.
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Molécula 1 de Adesão Intercelular , Infecções por Picornaviridae , Rhinovirus , Células Vero , Vacinas Virais , Animais , Humanos , Chlorocebus aethiops , Enterovirus/genética , Enterovirus/imunologia , Infecções por Enterovirus/genética , Infecções por Enterovirus/imunologia , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/imunologia , Infecções por Picornaviridae/genética , Infecções por Picornaviridae/imunologia , Rhinovirus/genética , Rhinovirus/imunologia , Células Vero/imunologia , Vacinas Virais/imunologiaRESUMO
The mechanisms explaining excess morbidity and mortality in respiratory infections among males are poorly understood. Innate immune responses are critical in protection against respiratory virus infections. We hypothesised that innate immune responses to respiratory viruses may be deficient in males. We stimulated peripheral blood mononuclear cells from 345 participants at age 16 years in a population-based birth cohort with three live respiratory viruses (rhinoviruses A16 and A1, and respiratory syncytial virus) and two viral mimics (R848 and CpG-A, to mimic responses to SARS-CoV-2) and investigated sex differences in interferon (IFN) responses. IFN-α responses to all viruses and stimuli were 1.34-2.06-fold lower in males than females (P = 0.018 - < 0.001). IFN-ß, IFN-γ and IFN-induced chemokines were also deficient in males across all stimuli/viruses. Healthcare records revealed 12.1% of males and 6.6% of females were hospitalized with respiratory infections in infancy (P = 0.017). In conclusion, impaired innate anti-viral immunity in males likely results in high male morbidity and mortality from respiratory virus infections.
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Imidazóis/imunologia , Imunidade Inata , Oligodesoxirribonucleotídeos/imunologia , Infecções por Picornaviridae/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Rhinovirus/imunologia , Adolescente , Coorte de Nascimento , Estudos de Coortes , Feminino , Humanos , Interferons/imunologia , Interferons/metabolismo , Leucócitos Mononucleares/imunologia , Masculino , Infecções por Picornaviridae/mortalidade , Infecções por Picornaviridae/virologia , Infecções por Vírus Respiratório Sincicial/mortalidade , Infecções por Vírus Respiratório Sincicial/virologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/mortalidade , Infecções Respiratórias/virologia , SARS-CoV-2 , Fatores SexuaisRESUMO
Introduction: Air pollution is a risk factor for respiratory infections and asthma exacerbations. We previously reported impaired Type-I and Type-III interferons (IFN-ß/λ) from airway epithelial cells of preschool children with asthma and/or atopy. In this study we analyzed the association between rhinovirus-induced IFN-ß/λ epithelial expression and acute exposure to the principal outdoor air pollutants in the same cohort. Methods: We studied 34 children (17asthmatics/17non-asthmatics) undergoing fiberoptic bronchoscopy for clinical indications. Bronchial epithelial cells were harvested by brushing, cultured and experimentally infected with Rhinovirus Type 16 (RV16). RV16-induced IFN-ß and λ expression was measured by quantitative real time PCR, as was RV16vRNA. The association between IFNs and the mean exposure to PM10, SO2 and NO2 in the day preceding bronchoscopy was evaluated using a Generalized Linear Model (GLM) with Gamma distribution. Results: Acute exposure to PM10 and NO2 was negatively associated to RV16-induced IFNß mRNA. For each increase of 1ug/m3 of NO2 we found a significative decrease of 2.3x103 IFN-ß mRNA copies and for each increase of 1ug/m3 of PM10 a significative decrease of 1x103 IFN-ß mRNA copies. No significant associations were detected between IFN-λ mRNA and NO2 nor PM10. Increasing levels of NO2 (but not PM10) were found to be associated to increased RV16 replication. Conclusions: Short-term exposure to high levels of NO2 and PM10 is associated to a reduced IFN-ß expression by the airway epithelium, which may lead to increased viral replication. These findings suggest a potential mechanism underlying the link between air pollution, viral infections and asthma exacerbations.
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Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Asma/metabolismo , Células Epiteliais/efeitos dos fármacos , Interferon beta/metabolismo , Pulmão/efeitos dos fármacos , Asma/diagnóstico , Asma/imunologia , Asma/virologia , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Resfriado Comum/imunologia , Resfriado Comum/metabolismo , Resfriado Comum/virologia , Progressão da Doença , Exposição Ambiental/efeitos adversos , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Feminino , Interações Hospedeiro-Patógeno , Humanos , Interferon beta/genética , Itália , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , Masculino , Óxido Nítrico/toxicidade , Material Particulado/toxicidade , Rhinovirus/crescimento & desenvolvimento , Rhinovirus/imunologia , Dióxido de Enxofre/toxicidade , Replicação ViralRESUMO
The majority of asthma exacerbations in children are caused by Rhinovirus (RV), a positive sense single stranded RNA virus of the Picornavirus family. The host has developed virus defense mechanisms that are mediated by the upregulation of interferon-activated signaling. However, the virus evades the immune system by inducing immunosuppressive cytokines and surface molecules like programmed cell death protein 1 (PD-1) and its ligand (PD-L1) on immunocompetent cells. Initially, RV infects epithelial cells, which constitute a physiologic mucosal barrier. Upon virus entrance, the host cell immediately recognizes viral components like dsRNA, ssRNA, viral glycoproteins or CpG-DNA by host pattern recognition receptors (PRRs). Activation of toll like receptors (TLR) 3, 7 and 8 within the endosome and through MDA-5 and RIG-I in the cytosol leads to the production of interferon (IFN) type I and other antiviral agents. Every cell type expresses IFNAR1/IFNAR2 receptors thus allowing a generalized antiviral activity of IFN type I resulting in the inhibition of viral replication in infected cells and preventing viral spread to non-infected cells. Among immune evasion mechanisms of the virus, there is downregulation of IFN type I and its receptor as well as induction of the immunosuppressive cytokine TGF-ß. TGF-ß promotes viral replication and is associated with induction of the immunosuppression signature markers LAP3, IDO and PD-L1. This article reviews the recent advances on the regulation of interferon type I expression in association with RV infection in asthmatics and the immunosuppression induced by the virus.
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Asma/virologia , Resfriado Comum/virologia , Evasão da Resposta Imune , Pulmão/virologia , Rhinovirus/imunologia , Imunidade Adaptativa , Animais , Asma/imunologia , Asma/metabolismo , Asma/fisiopatologia , Resfriado Comum/imunologia , Resfriado Comum/metabolismo , Resfriado Comum/fisiopatologia , Citocinas/metabolismo , Progressão da Doença , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Hospedeiro Imunocomprometido , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/fisiopatologia , Rhinovirus/patogenicidade , Transdução de SinaisRESUMO
Human rhinovirus (RV) is the most common cause of upper respiratory infections and exacerbations of asthma. In this work, we selected 14 peptides (6 from RV A and 8 from RV C) encompassing potential CD4 T cell epitopes. Peptides were selected for being highly conserved in RV A and C serotypes and predicted to bind to multiple human leukocyte antigen class II (HLA II) molecules. We found positive T cell recall responses by interferon gamma (IFNγ)-ELISPOT assays to eight peptides, validating seven of them (three from RV A and four from RV C) as CD4 T cell epitopes through intracellular cytokine staining assays. Additionally, we verified their promiscuous binding to multiple HLA II molecules by quantitative binding assays. According to their experimental HLA II binding profile, the combination of all these seven epitopes could be recognized by >95% of the world population. We actually determined IFNγ responses to a pool encompassing these CD4 T cell epitopes by intracellular cytokine staining, finding positive responses in 29 out of 30 donors. The CD4 T cell epitopes identified in this study could be key to monitor RV infections and to develop peptide-based vaccines against most RV A and C serotypes.
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Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Fragmentos de Peptídeos/imunologia , Infecções por Picornaviridae/imunologia , Rhinovirus/imunologia , Proteínas Virais/imunologia , Adulto , Feminino , Humanos , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Infecções por Picornaviridae/virologia , Rhinovirus/isolamento & purificação , Adulto JovemRESUMO
We used mass cytometry to extensively characterize bronchoalveolar lavage macrophages before and two days after in vivo rhinovirus 16 infection in a heterogeneous population of healthy and asthma/COPD subjects. Multivariate partial least squares discriminant analysis revealed distinct clusters of alveolar macrophages before versus after the virus, suggesting changes in overall phenotype.
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Resfriado Comum/imunologia , Macrófagos Alveolares/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Ensaios Clínicos como Assunto , Humanos , Fenótipo , Rhinovirus/imunologiaRESUMO
Coinfection by heterologous viruses in the respiratory tract is common and can alter disease severity compared to infection by individual virus strains. We previously found that inoculation of mice with rhinovirus (RV) 2 days before inoculation with a lethal dose of influenza A virus [A/Puerto Rico/8/34 (H1N1) (PR8)] provides complete protection against mortality. Here, we extended that finding to a second lethal respiratory virus, pneumonia virus of mice (PVM), and analyzed potential mechanisms of RV-induced protection. RV completely prevented mortality and weight loss associated with PVM infection. Major changes in host gene expression upon PVM infection were delayed compared to PR8. RV induced earlier recruitment of inflammatory cells, which were reduced at later times in RV-inoculated mice. Findings common to both virus pairs included the upregulated expression of mucin-associated genes and dampening of inflammation-related genes in mice that were inoculated with RV before lethal virus infection. However, type I interferon (IFN) signaling was required for RV-mediated protection against PR8 but not PVM. IFN signaling had minor effects on PR8 replication and contributed to controlling neutrophilic inflammation and hemorrhagic lung pathology in RV/PR8-infected mice. These findings, combined with differences in virus replication levels and disease severity, suggest that the suppression of inflammation in RV/PVM-infected mice may be due to early, IFN-independent suppression of viral replication, while that in RV/PR8-infected mice may be due to IFN-dependent modulation of immune responses. Thus, a mild upper respiratory viral infection can reduce the severity of a subsequent severe viral infection in the lungs through virus-dependent mechanisms. IMPORTANCE Respiratory viruses from diverse families cocirculate in human populations and are frequently detected within the same host. Although clinical studies suggest that infection by multiple different respiratory viruses may alter disease severity, animal models in which we can control the doses, timing, and strains of coinfecting viruses are critical to understanding how coinfection affects disease severity. Here, we compared gene expression and immune cell recruitment between two pairs of viruses (RV/PR8 and RV/PVM) inoculated sequentially in mice, both of which result in reduced severity compared to lethal infection by PR8 or PVM alone. Reduced disease severity was associated with suppression of inflammatory responses in the lungs. However, differences in disease kinetics and host and viral gene expression suggest that protection by coinfection with RV may be due to distinct molecular mechanisms. Indeed, we found that antiviral cytokine signaling was required for RV-mediated protection against lethal infection by PR8 but not PVM.
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Coinfecção/imunologia , Interações Hospedeiro-Patógeno , Interferon Tipo I/imunologia , Infecções por Picornaviridae/imunologia , Rhinovirus/imunologia , Rhinovirus/patogenicidade , Animais , Coinfecção/virologia , Feminino , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Vírus da Influenza A/imunologia , Vírus da Influenza A/patogenicidade , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Vírus da Pneumonia Murina/imunologia , Vírus da Pneumonia Murina/patogenicidade , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Pneumovirus/imunologia , Infecções por Pneumovirus/prevenção & controle , Índice de Gravidade de Doença , Transcriptoma , Replicação ViralRESUMO
Allergen exposure and rhinovirus (RV) infections are common triggers of acute wheezing exacerbations in early childhood. The identification of such trigger factors is difficult but may have therapeutic implications. Increases of IgE and IgG in sera, were shown against allergens and the N-terminal portion of the VP1 proteins of RV species, respectively, several weeks after allergen exposure or RV infection. Hence, increases in VP1-specific IgG and in allergen-specific IgE may serve as biomarkers for RV infections or allergen exposure. The MeDALL-allergen chip containing comprehensive panels of allergens and the PreDicta RV chip equipped with VP1-derived peptides, representative of three genetic RV species, were used to measure allergen-specific IgE levels and RV-species-specific IgG levels in sera obtained from 120 preschool children at the time of an acute wheezing attack and convalescence. Nearly 20% of the children (22/120) showed specific IgE sensitizations to at least one of the allergen molecules on the MeDALL chip. For 87% of the children, increases in RV-specific IgG could be detected in the follow-up sera. This percentage of RV-specific IgG increases was equal in IgE-positive and -negative children. In 10% of the children, increases or de novo appearances of IgE sensitizations indicative of allergen exposure could be detected. Our results suggest that, in the majority of preschool children, RV infections trigger wheezing attacks, but, in addition, allergen exposure seems to play a role as a trigger factor. RV-induced wheezing attacks occur in IgE-sensitized and non-IgE-sensitized children, indicating that allergic sensitization is not a prerequisite for RV-induced wheeze.
Assuntos
Alérgenos/imunologia , Anticorpos Antivirais/imunologia , Infecções por Picornaviridae/imunologia , Sons Respiratórios/imunologia , Rhinovirus/imunologia , Alérgenos/genética , Antígenos Virais/genética , Antígenos Virais/imunologia , Pré-Escolar , Feminino , Humanos , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Lactente , Masculino , Análise em Microsséries , Infecções por Picornaviridae/virologia , Rhinovirus/genética , Rhinovirus/fisiologiaRESUMO
BACKGROUND: While programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) antagonists have improved the prognosis for many patients with melanoma, around 60% fail therapy. PVSRIPO is a non-neurovirulent rhinovirus:poliovirus chimera that facilitates an antitumor immune response following cell entry via the poliovirus receptor CD155, which is expressed on tumor and antigen-presenting cells. Preclinical studies show that oncolytic virus plus anti-PD-1 therapy leads to a greater antitumor response than either agent alone, warranting clinical investigation. METHODS: An open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (American Joint Committee on Cancer V.7 stage IIIB, IIIC, or IV) was performed. Eligible patients had disease progression on anti-PD-1 and V-raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen activated protein kinase kinase (MEK) inhibitors (if BRAF mutant). The primary objective was to characterize the safety and tolerability of PVSRIPO. Twelve patients in four cohorts received a total of 1, 2 or 3 injections of PVSRIPO monotherapy, with 21 days between injections. RESULTS: PVSRIPO injections were well tolerated with no serious adverse events (SAEs) or dose-limiting toxicities (DLTs) reported. All adverse events (AEs) were grade (G) 1 or G2 (G1 pruritus most common at 58%); all but two PVSRIPO-treatment related AEs were localized to the injected or adjacent lesions (n=1 G1 hot flash, n=1 G1 fatigue). Four out of 12 patients (33%) achieved an objective response per immune-related response criteria (two observations, 4 weeks apart), including 4/6 (67%) who received three injections. In the four patients with in-transit disease, a pathological complete response (pCR) was observed in two (50%) patients. Following study completion, 11/12 patients (92%) reinitiated immune checkpoint inhibitor-based therapy, and 6/12 patients (50%) remained without progression at a median follow-up time of 18 months. CONCLUSION: Intratumoral PVSRIPO was well tolerated. Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients>5 lesions), intratumoral PVSRIPO showed promising antitumor activity, with pCR in injected as well as non-injected lesions in select patients. TRIAL REGISTRATION NUMBER: NCT03712358.
Assuntos
Melanoma/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos/patogenicidade , Poliovirus/patogenicidade , Rhinovirus/patogenicidade , Neoplasias Cutâneas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , North Carolina , Terapia Viral Oncolítica/efeitos adversos , Vírus Oncolíticos/imunologia , Poliovirus/imunologia , Rhinovirus/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/virologia , Fatores de Tempo , Resultado do TratamentoRESUMO
Antibodies are a critical immune correlate of protection for rhinoviruses, particularly those antibodies found in the secretory compartment. For nonenveloped viruses such as rhinoviruses, antibody binding to regions of the icosahedral capsid can neutralise infections by a number of different mechanisms. The purpose of this review is to address the neutralising mechanisms of antibodies to rhinoviruses that would help progress vaccine development. At least five mechanisms of antibody neutralisation have been identified which depend to some extent on the antibody binding footprints upon the capsid. The most studied mechanisms are virion aggregation, inhibition of attachment to cells, and stabilisation or destabilisation of the capsid structure. Newer mechanisms of degradation inside the cell through cytoplasmic antibody detection or outside by phagocytosis rely on what might have been previously considered as non-neutralising antibodies. We discuss these various approaches of antibody interference of rhinoviruses and offer suggestions as to how these could influence vaccine design.