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1.
Microbiol Spectr ; 12(7): e0422023, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38864599

RESUMO

The emergence of the COVID-19 pandemic prompted an increased interest in seasonal human coronaviruses. OC43, 229E, NL63, and HKU1 are endemic seasonal coronaviruses that cause the common cold and are associated with generally mild respiratory symptoms. In this study, we identified cell lines that exhibited cytopathic effects (CPE) upon infection by three of these coronaviruses and characterized their viral replication kinetics and the effect of infection on host surface receptor expression. We found that NL63 produced CPE in LLC-MK2 cells, while OC43 produced CPE in MRC-5, HCT-8, and WI-38 cell lines, while 229E produced CPE in MRC-5 and WI-38 by day 3 post-infection. We observed a sharp increase in nucleocapsid and spike viral RNA (vRNA) from day 3 to day 5 post-infection for all viruses; however, the abundance and the proportion of vRNA copies measured in the supernatants and cell lysates of infected cells varied considerably depending on the virus-host cell pair. Importantly, we observed modulation of coronavirus entry and attachment receptors upon infection. Infection with 229E and OC43 led to a downregulation of CD13 and GD3, respectively. In contrast, infection with NL63 and OC43 leads to an increase in ACE2 expression. Attempts to block entry of NL63 using either soluble ACE2 or anti-ACE2 monoclonal antibodies demonstrated the potential of these strategies to greatly reduce infection. Overall, our results enable a better understanding of seasonal coronaviruses infection kinetics in permissive cell lines and reveal entry receptor modulation that may have implications in facilitating co-infections with multiple coronaviruses in humans.IMPORTANCESeasonal human coronavirus is an important cause of the common cold associated with generally mild upper respiratory tract infections that can result in respiratory complications for some individuals. There are no vaccines available for these viruses, with only limited antiviral therapeutic options to treat the most severe cases. A better understanding of how these viruses interact with host cells is essential to identify new strategies to prevent infection-related complications. By analyzing viral replication kinetics in different permissive cell lines, we find that cell-dependent host factors influence how viral genes are expressed and virus particles released. We also analyzed entry receptor expression on infected cells and found that these can be up- or down-modulated depending on the infecting coronavirus. Our findings raise concerns over the possibility of infection enhancement upon co-infection by some coronaviruses, which may facilitate genetic recombination and the emergence of new variants and strains.


Assuntos
Coronavirus Humano 229E , Coronavirus Humano NL63 , Coronavirus Humano OC43 , Internalização do Vírus , Replicação Viral , Humanos , Coronavirus Humano NL63/fisiologia , Coronavirus Humano NL63/genética , Coronavirus Humano 229E/fisiologia , Coronavirus Humano 229E/genética , Coronavirus Humano OC43/fisiologia , Coronavirus Humano OC43/genética , Linhagem Celular , Estações do Ano , Cinética , Receptores Virais/metabolismo , Receptores Virais/genética , Resfriado Comum/virologia , Resfriado Comum/metabolismo , SARS-CoV-2/fisiologia , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , RNA Viral/metabolismo , RNA Viral/genética , Animais , COVID-19/virologia , COVID-19/metabolismo , Coronavirus/fisiologia , Coronavirus/genética
2.
Am J Physiol Renal Physiol ; 325(6): F685-F694, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37795536

RESUMO

The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated angiopoietin-like 4 (ANGPTL4) in podocytes have been crucial in explaining the cardinal manifestations of human minimal change nephrotic syndrome (MCNS). Recently, uncovered genomic defects upstream of ZHX2 induce a ZHX2 hypomorph state that makes podocytes inherently susceptible to mild cytokine storms resulting from a common cold. In ZHX2 hypomorph podocytes, ZHX proteins are redistributed away from normal transmembrane partners like aminopeptidase A (APA) toward alternative binding partners like IL-4Rα. During disease relapse, high plasma soluble IL-4Rα (sIL-4Rα) associated with chronic atopy complements the cytokine milieu of a common cold to displace ZHX1 from podocyte transmembrane IL-4Rα toward the podocyte nucleus. Nuclear ZHX1 induces severe upregulation of ANGPTL4, resulting in incomplete sialylation of part of the ANGPTL4 protein, secretion of hyposialylated ANGPTL4, and hyposialylation-related injury in the glomerulus. This pattern of injury induces many of the classic manifestations of human minimal change disease (MCD), including massive and selective proteinuria, podocyte foot process effacement, and loss of glomerular basement membrane charge. Administration of glucocorticoids reduces ANGPTL4 upregulation, which reduces hyposialylation injury to improve the clinical phenotype. Improving sialylation of podocyte-secreted ANGPTL4 also reduces proteinuria and improves experimental MCD. Neutralizing circulating TNF-α, IL-6, or sIL-4Rα after the induction of the cytokine storm in Zhx2 hypomorph mice reduces albuminuria, suggesting potential new therapeutic targets for clinical trials to prevent MCD relapse. These studies collectively lay to rest prior suggestions of a role of single cytokines or soluble proteins in triggering MCD relapse.


Assuntos
Resfriado Comum , Nefrose Lipoide , Síndrome Nefrótica , Podócitos , Camundongos , Humanos , Animais , Nefrose Lipoide/tratamento farmacológico , Podócitos/metabolismo , Resfriado Comum/metabolismo , Proteinúria/metabolismo , Membrana Basal Glomerular/metabolismo , Recidiva , Síndrome Nefrótica/genética , Síndrome Nefrótica/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Homeodomínio/metabolismo
3.
Front Immunol ; 12: 731968, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34733277

RESUMO

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.


Assuntos
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 Viral
4.
Front Immunol ; 12: 731846, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34691038

RESUMO

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.


Assuntos
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 Sinais
5.
Commun Biol ; 4(1): 921, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34326461

RESUMO

Retinoic acid-inducible gene I (RIG-I) senses viral RNA and instigates an innate immune signaling cascade to induce type I interferon expression. Currently, the regulatory mechanisms controlling RIG-I activation remain to be fully elucidated. Here we show that the FAK family kinase-interacting protein of 200 kDa (FIP200) facilitates RIG-I activation. FIP200 deficiency impaired RIG-I signaling and increased host susceptibility to RNA virus infection. In vivo studies further demonstrated FIP200 knockout mice were more susceptible to RNA virus infection due to the reduced innate immune response. Mechanistic studies revealed that FIP200 competed with the helicase domain of RIG-I for interaction with the two tandem caspase activation and recruitment domains (2CARD), thereby facilitating the release of 2CARD from the suppression status. Furthermore, FIP200 formed a dimer and facilitated 2CARD oligomerization, thereby promoting RIG-I activation. Taken together, our study defines FIP200 as an innate immune signaling molecule that positively regulates RIG-I activation.


Assuntos
Proteínas Relacionadas à Autofagia/genética , Resfriado Comum/prevenção & controle , Coronavirus Humano OC43/fisiologia , Proteína DEAD-box 58/genética , Infecções por Rhabdoviridae/prevenção & controle , Vírus da Estomatite Vesicular Indiana/fisiologia , Células A549 , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Chlorocebus aethiops , Resfriado Comum/metabolismo , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/prevenção & controle , Proteína DEAD-box 58/metabolismo , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Células RAW 264.7 , Infecções por Rhabdoviridae/metabolismo , Células Vero , Estomatite Vesicular/metabolismo , Estomatite Vesicular/prevenção & controle
6.
BMC Complement Med Ther ; 21(1): 112, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33827515

RESUMO

BACKGROUND: Elderberry has traditionally been used to prevent and treat respiratory problems. During the COVID-19 pandemic, there has been interest in elderberry supplements to treat or prevent illness, but also concern that elderberry might overstimulate the immune system and increase the risk of 'cytokine storm'. We aimed to determine benefits and harms of elderberry for the prevention and treatment of viral respiratory infections, and to assess the relationship between elderberry supplements and negative health impacts associated with overproduction of pro-inflammatory cytokines. METHODS: We conducted a systematic review and searched six databases, four research registers, and two preprint sites for studies. Two reviewers independently assessed studies for inclusion, extracted data from studies, assessed risk of bias using Cochrane tools, and evaluated certainty of estimates using GRADE. Outcomes included new illnesses and the severity and duration of illness. RESULTS: We screened 1187 records and included five randomized trials on elderberry for the treatment or prevention of viral respiratory illness. We did not find any studies linking elderberry to clinical inflammatory outcomes. However, we found three studies measuring production of cytokines ex vivo after ingestion of elderberry. Elderberry may not reduce the risk of developing the common cold; it may reduce the duration and severity of colds, but the evidence is uncertain. Elderberry may reduce the duration of influenza but the evidence is uncertain. Compared to oseltamivir, an elderberry-containing product may be associated with a lower risk of influenza complications and adverse events. We did not find evidence on elderberry and clinical outcomes related to inflammation. However, we found evidence that elderberry has some effect on inflammatory markers, although this effect may decline with ongoing supplementation. One small study compared elderberry to diclofenac (a nonsteroidal anti-inflammatory drug) and provided some evidence that elderberry is as effective or less effective than diclofenac in cytokine reduction over time. CONCLUSIONS: Elderberry may be a safe option for treating viral respiratory illness, and there is no evidence that it overstimulates the immune system. However, the evidence on both benefits and harms is uncertain and information from recent and ongoing studies is necessary to make firm conclusions.


Assuntos
Tratamento Farmacológico da COVID-19 , Resfriado Comum/tratamento farmacológico , Citocinas/metabolismo , Influenza Humana/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Sambucus , COVID-19/metabolismo , Resfriado Comum/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/prevenção & controle , Influenza Humana/metabolismo , Pandemias , SARS-CoV-2
7.
Front Immunol ; 12: 793517, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34975898

RESUMO

EphA2 receptor and its ephrin ligands are involved in virus infection, epithelial permeability, and chemokine secretion. We hypothesized that ephrinA1/ephA2 signaling participates in rhinovirus (RV)-induced antiviral immune response in sinonasal mucosa of patients with chronic rhinosinusitis (CRS). Therefore, we investigated the expression of ephrinA1/ephA2 in normal and inflamed sinonasal mucosa and evaluated whether they regulate chemokine secretion and the production of antiviral immune mediators including interferons (IFNs) in RV-infected human primary sinonasal epithelial cells. For this purpose, the expression and distribution of ephrinA1/ephA2 in sinonasal mucosa were evaluated with RT-qPCR, immunofluorescence, and western blot. Their roles in chemokine secretion and the production of antiviral immune mediators such as type I and III IFNs, and interferon stimulated genes were evaluated by stimulating ephA2 with ephrinA1 and inactivating ephA2 with ephA2 siRNA or inhibitor in cells exposed to RV and poly(I:C). We found that ephrinA1/ephA2 were expressed in normal mucosa and their levels increased in inflamed sinonasal mucosa of CRS patients. RV infection or poly(I:C) treatment induced chemokine secretion which were attenuated by blocking the action of ephA2 with ephA2 siRNA or inhibitor. The production of antiviral immune mediators enhanced by rhinovirus or poly (I:C) is increased by blocking ephA2 compared with that of cells stimulated by either rhinovirus or poly(I:C) alone. In addition, blocking ephA2 attenuated RV replication in cultured cells. Taken together, these results describe a novel role of ephrinA1/ephA2 signaling in antiviral innate immune response in sinonasal epithelium, suggesting their participation in RV-induced development and exacerbations of CRS.


Assuntos
Resfriado Comum/metabolismo , Efrina-A1/metabolismo , Células Epiteliais/metabolismo , Mucosa Nasal/metabolismo , Receptor EphA2/metabolismo , Rinite/metabolismo , Rhinovirus/patogenicidade , Sinusite/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Doença Crônica , Resfriado Comum/imunologia , Resfriado Comum/virologia , Citocinas/metabolismo , Efrina-A1/genética , Efrina-A2/genética , Efrina-A2/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/virologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/imunologia , Mucosa Nasal/virologia , Poli I-C/farmacologia , Receptor EphA2/genética , Rinite/imunologia , Rhinovirus/crescimento & desenvolvimento , Rhinovirus/imunologia , Transdução de Sinais , Sinusite/imunologia , Replicação Viral
8.
Complement Ther Med ; 45: 50-56, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31331582

RESUMO

BACKGROUND: So-Cheong-Ryong-Tang (SCRT), also known as Xiao-Qing-Long-Tang or Sho-seiryo-to, is a mixed herbal formula that is used to treat allergic rhinitis, bronchitis, allergic asthma, and common cold in traditional Korean medicine. OBJECTIVE: To assess the efficacy and safety of the SCRT for the treatment of allergic rhinitis. METHODS: We conducted a double-blind, randomized, placebo-controlled, parallel-group, multicenter study of Korean adults with perennial allergic rhinitis. The trial consisted of a 4-week oral administration of SCRT or placebo, with two visits at 2-week intervals, and an 8-week follow-up period, with two visits at 4-week intervals. The primary outcome was a change in the total nasal symptoms score. The secondary outcomes included changes in the Rhinoconjunctivitis Quality of Life Questionnaire score, total serum immunoglobulin E (IgE), cytokines levels, and nasal endoscopy index. RESULTS: SCRT improved nasal symptoms and quality of life in patients with PAR after 4 weeks medication, and these effects did not last 8 weeks after the end of medication. The level of serum IgE, eosinophil counts, and cytokines did not alter after medication. Nasal endoscopy index did not show significant difference. No serious AEs and safety assessment changes were observed in this trial. CONCLUSION: SCRT is an effective and safe medication for patients with chronic, perennial, and moderate to severe AR. A clinical study with a >4-week period of medication use, and more participants for immune material test is needed to investigate the long-term efficacy of SCRT in relieving the symptoms of nasal obstruction and identifying the underlying mechanisms of action and indications for traditional Korean medicine.


Assuntos
Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/uso terapêutico , Rinite Alérgica Perene/tratamento farmacológico , Adulto , Asma/tratamento farmacológico , Asma/metabolismo , Resfriado Comum/tratamento farmacológico , Resfriado Comum/metabolismo , Citocinas/metabolismo , Método Duplo-Cego , Feminino , Humanos , Masculino , Medicina Tradicional Coreana/métodos , Fitoterapia/métodos , Qualidade de Vida , Rinite Alérgica Perene/metabolismo , Resultado do Tratamento
9.
Proc Natl Acad Sci U S A ; 114(25): 6515-6520, 2017 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-28584098

RESUMO

Exposure to parental separation or divorce during childhood has been associated with an increased risk for physical morbidity during adulthood. Here we tested the hypothesis that this association is primarily attributable to separated parents who do not communicate with each other. We also examined whether early exposure to separated parents in conflict is associated with greater viral-induced inflammatory response in adulthood and in turn with increased susceptibility to viral-induced upper respiratory disease. After assessment of their parents' relationship during their childhood, 201 healthy volunteers, age 18-55 y, were quarantined, experimentally exposed to a virus that causes a common cold, and monitored for 5 d for the development of a respiratory illness. Monitoring included daily assessments of viral-specific infection, objective markers of illness, and local production of proinflammatory cytokines. Adults whose parents lived apart and never spoke during their childhood were more than three times as likely to develop a cold when exposed to the upper respiratory virus than adults from intact families. Conversely, individuals whose parents were separated but communicated with each other showed no increase in risk compared with those from intact families. These differences persisted in analyses adjusted for potentially confounding variables (demographics, current socioeconomic status, body mass index, season, baseline immunity to the challenge virus, affectivity, and childhood socioeconomic status). Mediation analyses were consistent with the hypothesis that greater susceptibility to respiratory infectious illness among the offspring of noncommunicating parents was attributable to a greater local proinflammatory response to infection.


Assuntos
Resfriado Comum/etiologia , Adulto , Índice de Massa Corporal , Resfriado Comum/metabolismo , Citocinas/metabolismo , Divórcio , Feminino , Humanos , Masculino , Pais , Infecções Respiratórias/etiologia , Fatores de Risco , Classe Social
10.
Brain Behav Immun ; 53: 255-261, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26778776

RESUMO

The immunosuppressive effects of glucocorticoids (GCs) are well-established. However, whether the net effect of GC-elicited alterations in immune function is sufficient to influence a clinically relevant outcome in healthy adults has yet to be shown. The aim of the present study was to investigate whether inter-individual differences in basal salivary cortisol production are associated with increased risk and severity of infection and subsequent illness following experimental exposure to a virus that causes the common cold. The present analyses combine archival data from three viral-challenge studies. Participants were 608 healthy adults, aged 18 to 55 years (49.2% female; 65.8% white), who each completed a three-day saliva collection protocol; was subsequently exposed to a virus that causes the common cold; and monitored for 5 days for objective signs of infection (presence of challenge virus in nasal secretions) and clinical illness (mucus weight, mucociliary clearance time). Basal cortisol production (operationalized as the calculated area-under-the-curve averaged across the 3 days) showed a graded association with infection risk, with those producing higher levels of cortisol being at greater risk. Cortisol also showed a continuous association with duration of viral shedding, an indicator of viral replication and continuing infection, such that higher cortisol concentrations predicted more days of shedding. Cortisol was not, however, related to severity of objective illness. These findings are the first to demonstrate in healthy adults an association between basal cortisol production and an objectively measured and clinically relevant infectious disease outcome.


Assuntos
Resfriado Comum/fisiopatologia , Hidrocortisona/metabolismo , Saliva/metabolismo , Adulto , Resfriado Comum/etiologia , Resfriado Comum/metabolismo , Resfriado Comum/virologia , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Depuração Mucociliar , Fatores de Risco , Estresse Psicológico/fisiopatologia , Estresse Psicológico/virologia
11.
PLoS Genet ; 11(4): e1005111, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25874939

RESUMO

Rhinovirus (RV) is the most prevalent human respiratory virus and is responsible for at least half of all common colds. RV infections may result in a broad spectrum of effects that range from asymptomatic infections to severe lower respiratory illnesses. The basis for inter-individual variation in the response to RV infection is not well understood. In this study, we explored whether host genetic variation is associated with variation in gene expression response to RV infections between individuals. To do so, we obtained genome-wide genotype and gene expression data in uninfected and RV-infected peripheral blood mononuclear cells (PBMCs) from 98 individuals. We mapped local and distant genetic variation that is associated with inter-individual differences in gene expression levels (eQTLs) in both uninfected and RV-infected cells. We focused specifically on response eQTLs (reQTLs), namely, genetic associations with inter-individual variation in gene expression response to RV infection. We identified local reQTLs for 38 genes, including genes with known functions in viral response (UBA7, OAS1, IRF5) and genes that have been associated with immune and RV-related diseases (e.g., ITGA2, MSR1, GSTM3). The putative regulatory regions of genes with reQTLs were enriched for binding sites of virus-activated STAT2, highlighting the role of condition-specific transcription factors in genotype-by-environment interactions. Overall, we suggest that the 38 loci associated with inter-individual variation in gene expression response to RV-infection represent promising candidates for affecting immune and RV-related respiratory diseases.


Assuntos
Resfriado Comum/genética , Loci Gênicos , Variação Genética , Transcriptoma , 2',5'-Oligoadenilato Sintetase/genética , 2',5'-Oligoadenilato Sintetase/metabolismo , Adulto , Resfriado Comum/metabolismo , Feminino , Perfilação da Expressão Gênica , Interação Gene-Ambiente , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Humanos , Integrina alfa2/genética , Integrina alfa2/metabolismo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Transcrição STAT2/genética , Fator de Transcrição STAT2/metabolismo , Receptores Depuradores Classe A/genética , Receptores Depuradores Classe A/metabolismo
12.
Clin Exp Allergy ; 44(12): 1484-93, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25109477

RESUMO

BACKGROUND: Asthma exacerbations contribute to significant morbidity, mortality and healthcare utilization. Furthermore, viral infections are associated with asthma exacerbations by mechanisms that are not fully understood. OBJECTIVE: The aim of this analysis was to determine whether cytokine patterns in patients with colds could identify risks for subsequent asthma exacerbations. METHODS: We analysed cytokine levels in nasal lavage fluid (NLF) in 59 subjects (46 with asthma) with acute upper respiratory symptoms and after symptomatic resolution. Analyte choice was based on potential relevance to asthma exacerbations: antiviral (IFN-α, IFN-ß, IFN-γ, IFN-λ1, IP-10, TRAIL), cell recruiting (G-CSF, IL-1ß, IL-8, MCP-1, MCP-3, TNF-α), polarizing (CXCL13, IL-10, IL-13, IL-17, TSLP), and injury remodelling (fibronectin, IL-33, MMP-9, VEGF). RESULTS: The overall cytokine response induced during viral infections was not different between asthmatic and non-asthmatic individuals for a wide array of cytokines. However, mean levels of VEGF, TNF-α and IL-1ß were 1.7-, 5.1- and 4.7-fold higher in samples from asthma subjects who exacerbated in the first 3 weeks of the cold compared with those who did not exacerbate (P = 0.006, 0.01, 0.048, respectively). Using receiver operating characteristic curve-defined thresholds, high VEGF and TNF-α levels predicted a shorter time-to-exacerbation after NLF sampling (25% exacerbation rate: 3 vs. 45 days, and 3 vs. 26 days; P = 0.03, 0.04, respectively). CONCLUSION AND CLINICAL RELEVANCE: Although they produce similar cytokine responses to viral infection as non-asthmatics, asthmatics with higher levels of VEGF and TNF-α in NLF obtained during acute cold phases predicted subsequent asthma exacerbations in this cohort of patients with mild-to-moderate disease. In the future, stratifying the risk of an asthma exacerbation by cytokine profile may aid the targeting of personalized treatment and intervention strategies.


Assuntos
Asma/diagnóstico , Asma/etiologia , Resfriado Comum/complicações , Resfriado Comum/metabolismo , Líquido da Lavagem Nasal , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Citocinas/metabolismo , Progressão da Doença , Feminino , Humanos , Masculino , Líquido da Lavagem Nasal/imunologia , Curva ROC
15.
J Diet Suppl ; 10(3): 171-83, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23927572

RESUMO

Strenuous exercise, such as running a marathon, is known to suppress mucosal immunity for up to 24 hr, which can increase the risk of developing an upper respiratory tract infection (URTI) and reduced performance capacity (Allgrove JE, Geneen L, Latif S, Gleeson M. Influence of a fed or fasted state on the s-IgA response to prolonged cycling in active men and women. Int J Sport Nutr Exerc Metab. 2009;19(3):209-221; Barrett B, Locken K, Maberry R, Schwamman J, Brown R, Bobula J, Stauffacher EA. The Wisconsin Upper Respiratory Symptom Survey (WURSS): a new research instrument for assessing the common cold. J Fam Pract. 2002;51(3):265; Carpenter KC, Breslin WL, Davidson T, Adams A, McFarlin BK. Baker's yeast beta glucan supplementation increases monocytes and cytokines post-exercise: implications for infection risk? Br J Nutr. 2012;1-9). While many dietary interventions have been used to combat postexercise immune suppression, most have been ineffective. The key purpose of this study was to determine if baker's yeast ß-glucan (BG) could positively affect the immune system of individuals undergoing intense exercise stress using two experiments. In the first (E1; N = 182 men and women), BG was compared to placebo supplementation for the incidence of URTI symptoms for 28 days postmarathon. In the second (E2; N = 60 men and women) changes in salivary immunoglobulin A (IgA) were evaluated after 50-min of strenuous cycling when participants had been supplemented for 10 days with either BG (250 mg/day) or placebo (rice flour). For E1, subjects reported URTI symptoms using a daily health log. For E2, saliva was collected prior to, immediately, and 2-hr postexercise using a salivette. Data for E1 and E2 were analyzed using separate analyses of variance (ANOVAs) with repeated measures (p < .05). In E1, BG was associated with a 37% reduction in the number of cold/flu symptom days postmarathon compared to placebo (p = .026). In E2, BG was associated with a 32% increase in salivary IgA (p = .048) at 2 hr after exercise compared to placebo. In summary, the present study demonstrates that BG may reduce URTI symptomatic days and improve mucosal immunity (salivary IgA) postexercise.


Assuntos
Resfriado Comum/tratamento farmacológico , Suplementos Nutricionais , Exercício Físico/fisiologia , Imunoglobulina A/metabolismo , Influenza Humana/tratamento farmacológico , Estresse Fisiológico/imunologia , beta-Glucanas/uso terapêutico , Adolescente , Adulto , Análise de Variância , Ciclismo/fisiologia , Resfriado Comum/complicações , Resfriado Comum/imunologia , Resfriado Comum/metabolismo , Feminino , Humanos , Sistema Imunitário/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Influenza Humana/complicações , Influenza Humana/imunologia , Influenza Humana/metabolismo , Masculino , Pessoa de Meia-Idade , Mucosa/efeitos dos fármacos , Mucosa/imunologia , Mucosa/metabolismo , Esforço Físico/fisiologia , Corrida/fisiologia , Saccharomyces cerevisiae/química , Saliva/imunologia , Saliva/metabolismo , Adulto Jovem , beta-Glucanas/farmacologia
16.
Proc Natl Acad Sci U S A ; 109(16): 5995-9, 2012 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-22474371

RESUMO

We propose a model wherein chronic stress results in glucocorticoid receptor resistance (GCR) that, in turn, results in failure to down-regulate inflammatory response. Here we test the model in two viral-challenge studies. In study 1, we assessed stressful life events, GCR, and control variables including baseline antibody to the challenge virus, age, body mass index (BMI), season, race, sex, education, and virus type in 276 healthy adult volunteers. The volunteers were subsequently quarantined, exposed to one of two rhinoviruses, and followed for 5 d with nasal washes for viral isolation and assessment of signs/symptoms of a common cold. In study 2, we assessed the same control variables and GCR in 79 subjects who were subsequently exposed to a rhinovirus and monitored at baseline and for 5 d after viral challenge for the production of local (in nasal secretions) proinflammatory cytokines (IL-1ß, TNF-α, and IL-6). Study 1: After covarying the control variables, those with recent exposure to a long-term threatening stressful experience demonstrated GCR; and those with GCR were at higher risk of subsequently developing a cold. Study 2: With the same controls used in study 1, greater GCR predicted the production of more local proinflammatory cytokines among infected subjects. These data provide support for a model suggesting that prolonged stressors result in GCR, which, in turn, interferes with appropriate regulation of inflammation. Because inflammation plays an important role in the onset and progression of a wide range of diseases, this model may have broad implications for understanding the role of stress in health.


Assuntos
Suscetibilidade a Doenças/metabolismo , Inflamação/metabolismo , Receptores de Glucocorticoides/metabolismo , Estresse Psicológico/metabolismo , Adulto , Doença Crônica , Resfriado Comum/metabolismo , Resfriado Comum/psicologia , Resfriado Comum/virologia , Citocinas/metabolismo , Suscetibilidade a Doenças/psicologia , Feminino , Humanos , Hidrocortisona/sangue , Inflamação/psicologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Modelos Psicológicos , Líquido da Lavagem Nasal/virologia , Quarentena/métodos , Rhinovirus/isolamento & purificação , Fatores de Risco , Estresse Psicológico/psicologia , Adulto Jovem
17.
BMC Med Genet ; 12: 39, 2011 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-21410962

RESUMO

BACKGROUND: Uteroglobin-Related Protein 1 (UGRP1) is a secretoglobulin protein which has been suggested to play a role in lung inflammation and allergic diseases. UGRP1 has also been shown to be an important pneumoprotein, with diagnostic potential as a biomarker of lung damage. Previous genetic studies evaluating the association between variations on UGRP1 and allergic phenotypes have yielded mixed results. The aim of this present study was to identify genetic polymorphisms in UGRP1 and investigate if they were associated with asthma and allergic rhinitis in the Singapore Chinese population. METHODS: Resequencing of the UGRP1 gene was conducted on 40 randomly selected individuals from Singapore of ethnic Chinese origin. The polymorphisms identified were then tagged and genotyped in a population of 1893 Singapore Chinese individuals. Genetic associations were evaluated in this population comparing 795 individuals with allergic rhinitis, 718 with asthma (of which 337 had both asthma and allergic rhinitis) and 717 healthy controls with no history of allergy or allergic diseases. RESULTS: By resequencing the UGRP1 gene within our population, we identified 11 novel and 16 known single nucleotide polymorphisms (SNPs). TagSNPs were then genotyped, revealing a significant association between rs7726552 and allergic rhinitis (Odds Ratio: 0.81, 95% Confidence Interval: 0.66-0.98, P = 0.039). This association remained statistically significant when it was analyzed genotypically or when stratified according to haplotypes. When variations on UGRP1 were evaluated against asthma, no association was observed. CONCLUSION: This study documents the association between polymorphisms in UGRP1 and allergic rhinitis, suggesting a potential role in its pathogenesis.


Assuntos
Asma/genética , Resfriado Comum , Rinite Alérgica Perene/genética , Uteroglobina/genética , Povo Asiático/etnologia , Asma/metabolismo , Estudos de Casos e Controles , Mapeamento Cromossômico , Resfriado Comum/genética , Resfriado Comum/metabolismo , Genótipo , Humanos , Pulmão/metabolismo , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Secretoglobinas , Singapura/epidemiologia
18.
J Aerosol Med Pulm Drug Deliv ; 24(3): 137-47, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21361786

RESUMO

BACKGROUND: Exhaled breath studies suggest that humans exhale fine particles during tidal breathing, but little is known of their physical origin in the respiratory system during health or disease. METHODS: Particles generated by 3 healthy and 16 human rhinovirus (HRV)-infected subjects were counted using an optical particle counter with nominal diameter-size bins ranging between 0.3 and 10 µm. Data were collected from HRV-infected subjects during tidal breathing. In addition, data from healthy subjects were collected during coughs, swallows, tidal breathing, and breathing to total lung capacity (TLC) and residual volume (RV). Using general additive models, we graphed exhaled particle concentration versus airflow during exhalation. Exhaled particles were collected from expired air on gelatin filters and analyzed for HRV via quantitative PCR. RESULTS: HRV-infected subjects exhaled from 0.1 to 7200 particles per liter of exhaled air during tidal breathing (geometric mean = 32 part/L). A small fraction (24%) of subjects exhaled most (81%) of the particles measured and 82% of particles detected were 0.300-0.499 µm. Minute ventilation, maximum airflow during exhalation, and forced expiratory volume 1 second (FEV(1) % predicted) were positively correlated with particle production. No human rhinovirus was detected in exhaled breath samples. Three healthy subjects exhaled less than 100 particles per liter of exhaled air during tidal breathing and increased particle concentrations more with exhalation to RV than with coughing, swallowing, or rapid exhalation. CONCLUSIONS: Submicron particles were detected in the exhaled breath of healthy and HRV-infected subjects. Particle concentrations were correlated with airflow during the first half of exhalation, and peaked at the end of exhalation, indicating both lower and upper airways as particle sources. The effect of breathing maneuver suggested a major contribution from lower airways, probably the result of opening collapsed small airways and alveoli.


Assuntos
Testes Respiratórios , Resfriado Comum/metabolismo , Rhinovirus , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/análise
19.
Med Res Rev ; 31(1): 42-92, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19714577

RESUMO

As the major etiological agent of the common cold, human rhinoviruses (HRV) cause millions of lost working and school days annually. Moreover, clinical studies proved an association between harmless upper respiratory tract infections and more severe diseases e.g. sinusitis, asthma, and chronic obstructive pulmonary disease. Both the medicinal and socio-economic impact of HRV infections and the lack of antiviral drugs substantiate the need for intensive antiviral research. A common structural feature of the approximately 100 HRV serotypes is the icosahedrally shaped capsid formed by 60 identical copies of viral capsid proteins VP1-4. The capsid protects the single-stranded, positive sense RNA genome of about 7,400 bases in length. Both structural as well as nonstructural proteins produced during the viral life cycle have been identified as potential targets for blocking viral replication at the step of attachment, entry, uncoating, RNA and protein synthesis by synthetic or natural compounds. Moreover, interferon and phytoceuticals were shown to protect host cells. Most of the known inhibitors of HRV replication were discovered as a result of empirical or semi-empirical screening in cell culture. Structure-activity relationship studies are used for hit optimization and lead structure discovery. The increasing structural insight and molecular understanding of viral proteins on the one hand and the advent of innovative computer-assisted technologies on the other hand have facilitated a rationalized access for the discovery of small chemical entities with antirhinoviral (anti-HRV) activity. This review will (i) summarize existing structural knowledge about HRV, (ii) focus on mechanisms of anti-HRV agents from synthetic and natural origin, and (iii) demonstrate strategies for efficient lead structure discovery.


Assuntos
Antivirais/química , Resfriado Comum/virologia , Rhinovirus/efeitos dos fármacos , Proteínas Virais/antagonistas & inibidores , Antivirais/farmacologia , Proteínas do Capsídeo/antagonistas & inibidores , Proteínas do Capsídeo/metabolismo , Resfriado Comum/metabolismo , Genoma Viral , Humanos , RNA Viral/genética , Rhinovirus/metabolismo , Rhinovirus/patogenicidade , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
20.
Expert Opin Drug Saf ; 9(2): 233-42, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20001764

RESUMO

IMPORTANCE OF THE FIELD: Over-the-counter (OTC) cough and cold medications have been used widely for years and continue to be a preferred choice for temporary relief of symptoms of upper respiratory tract infections in children. These medications are being placed under extraordinary scrutiny in the pediatric population due to the lack of conclusive evidence about their therapeutic efficacy and increased reports of associations with serious adverse events and even mortality. AREAS COVERED IN THIS REVIEW: A PubMed search was conducted to identify articles published up to August 2009 describing the efficacy and safety of OTC cough and cold medications in children. The objective was to provide an overview of the relevant literature and regulatory history and to comment on the available data on this important topic. WHAT THE READER WILL GAIN: The paper provides a detailed up-to-date review of the key efficacy and safety studies published on the subject. In addition, the reader is presented with an overview of the regulatory history and recent developments surrounding the use of OTC cough and cold medications in children in the US. TAKE HOME MESSAGE: This review confirms the lack of efficacy of OTC cough and cold products in children and reaffirms that although the overall incidence of related serious adverse events is low, such events continue to occur. The conclusions in this paper support a recommendation that OTC cough and cold medications should not be given to infants and very young children. Furthermore, additional research is needed to evaluate the safety and efficacy of these medicines in the broader pediatric population.


Assuntos
Antitussígenos/efeitos adversos , Resfriado Comum/tratamento farmacológico , Tosse/tratamento farmacológico , Medicamentos sem Prescrição/efeitos adversos , Medicamentos sem Prescrição/uso terapêutico , Fatores Etários , Antitussígenos/farmacocinética , Antitussígenos/uso terapêutico , Criança , Resfriado Comum/metabolismo , Resfriado Comum/mortalidade , Tosse/metabolismo , Tosse/mortalidade , Humanos , Medicamentos sem Prescrição/farmacocinética , Resultado do Tratamento
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