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1.
Am J Respir Crit Care Med ; 204(11): 1259-1273, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34469272

RESUMO

Rationale: Type 2 innate lymphoid cells (ILC2s) are significant sources of type 2 cytokines, which are implicated in the pathogenesis of asthma and asthma exacerbations. The role of ILC2s in virus-induced asthma exacerbations is not well characterized. Objectives: To characterize pulmonary ILC responses following experimental rhinovirus challenge in patients with moderate asthma and healthy subjects. Methods: Patients with moderate asthma and healthy subjects were inoculated with rhinovirus-16 and underwent bronchoscopy at baseline and at Day 3, and Day 8 after inoculation. Pulmonary ILC1s and ILC2s were quantified in bronchoalveolar lavage using flow cytometry. The ratio of bronchoalveolar lavage ILC2:ILC1 was assessed to determine their relative contributions to the clinical and immune response to rhinovirus challenge. Measurements and Main Results: At baseline, ILC2s were significantly higher in patients with asthma than in healthy subjects. At Day 8, ILC2s significantly increased from baseline in both groups, which was significantly higher in patients with asthma than in healthy subjects (all comparisons P < 0.05). In healthy subjects, ILC1s increased from baseline at Day 3 (P = 0.001), while in patients with asthma, ILC1s increased from baseline at Day 8 (P = 0.042). Patients with asthma had significantly higher ILC2:ILC1 ratios at baseline (P = 0.024) and Day 8 (P = 0.005). Increased ILC2:ILC1 ratio in patients with asthma correlated with clinical exacerbation severity and type 2 cytokines in nasal mucosal lining fluid. Conclusions: An ILC2-predominant inflammatory profile in patients with asthma was associated with increased severity and duration of rhinovirus infection compared with healthy subjects, supporting the potential role of ILC2s in the pathogenesis of virus-induced asthma exacerbations.


Assuntos
Asma/etiologia , Asma/imunologia , Asma/virologia , Progressão da Doença , Imunidade Inata , Infecções por Picornaviridae/complicações , Fatores de Virulência/imunologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
2.
PLoS Pathog ; 9(8): e1003520, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23935498

RESUMO

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ∼90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo.


Assuntos
Anticorpos Monoclonais Murinos/farmacologia , Imunoglobulina G/farmacologia , Molécula 1 de Adesão Intercelular/imunologia , Infecções por Picornaviridae/imunologia , Pneumonia Viral/imunologia , Rhinovirus/imunologia , Internalização do Vírus/efeitos dos fármacos , Animais , Anticorpos Monoclonais Murinos/imunologia , Quimiocinas/genética , Quimiocinas/imunologia , Células HeLa , Humanos , Imunoglobulina G/imunologia , Molécula 1 de Adesão Intercelular/genética , Células Jurkat , Antígeno-1 Associado à Função Linfocitária/genética , Antígeno-1 Associado à Função Linfocitária/imunologia , Camundongos , Camundongos Transgênicos , Infecções por Picornaviridae/tratamento farmacológico , Infecções por Picornaviridae/genética , Infecções por Picornaviridae/patologia , Pneumonia Viral/dietoterapia , Pneumonia Viral/genética , Pneumonia Viral/patologia , Células Th2/imunologia
3.
Am J Respir Crit Care Med ; 190(12): 1373-82, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25350863

RESUMO

RATIONALE: Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell-derived cytokine IL-33 plays a central role in exacerbation pathogenesis through augmentation of type 2 inflammation. OBJECTIVES: To assess whether rhinovirus induces a type 2 inflammatory response in asthma in vivo and to define a role for IL-33 in this pathway. METHODS: We used a human experimental model of rhinovirus infection and novel airway sampling techniques to measure IL-4, IL-5, IL-13, and IL-33 levels in the asthmatic and healthy airways during a rhinovirus infection. Additionally, we cultured human T cells and type 2 innate lymphoid cells (ILC2s) with the supernatants of rhinovirus-infected bronchial epithelial cells (BECs) to assess type 2 cytokine production in the presence or absence of IL-33 receptor blockade. MEASUREMENTS AND MAIN RESULTS: IL-4, IL-5, IL-13, and IL-33 are all induced by rhinovirus in the asthmatic airway in vivo and relate to exacerbation severity. Further, induction of IL-33 correlates with viral load and IL-5 and IL-13 levels. Rhinovirus infection of human primary BECs induced IL-33, and culture of human T cells and ILC2s with supernatants of rhinovirus-infected BECs strongly induced type 2 cytokines. This induction was entirely dependent on IL-33. CONCLUSIONS: IL-33 and type 2 cytokines are induced during a rhinovirus-induced asthma exacerbation in vivo. Virus-induced IL-33 and IL-33-responsive T cells and ILC2s are key mechanistic links between viral infection and exacerbation of asthma. IL-33 inhibition is a novel therapeutic approach for asthma exacerbations.


Assuntos
Asma/etiologia , Inflamação/etiologia , Interleucinas/fisiologia , Infecções por Picornaviridae/complicações , Adulto , Asma/fisiopatologia , Asma/virologia , Células Cultivadas , Feminino , Humanos , Inflamação/fisiopatologia , Interleucina-13/fisiologia , Interleucina-33 , Interleucina-4/fisiologia , Interleucina-5/fisiologia , Subpopulações de Linfócitos/fisiologia , Masculino , Infecções por Picornaviridae/fisiopatologia , Rhinovirus , Índice de Gravidade de Doença , Linfócitos T/fisiologia , Células Th2/fisiologia , Carga Viral
4.
Antiviral Res ; 142: 185-192, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28356234

RESUMO

Rhinoviruses (RVs) cause the common cold and are associated with exacerbations of chronic inflammatory respiratory diseases, especially asthma and chronic obstructive pulmonary disease (COPD). We have assessed the antiviral drugs Anaferon for Children (AC) and Ergoferon (containing AC as one of the active pharmaceutical ingredients) in in vitro and in vivo experimental models, in order to evaluate their anti-rhinoviral and immunomodulatory potential. HeLa cells were pretreated with AC, and levels of the interferon-stimulated gene (ISG), 2'-5'-oligoadenylate synthetase 1 (OAS1-A) and viral replication were analyzed. In a mouse model of RV-induced exacerbation of allergic airway inflammation we administered Ergoferon and analyzed its effect on type I (IFN-ß), type II (IFN-γ) and type III (IFN-λ) IFNs induction, cell counts in bronchoalveolar lavage (BAL), cytokine (interleukin (IL)-4; IL-6) and chemokine (CXCL10/IP-10; CXCL1/KC) levels. It was shown that AC increased OAS1-А production and significantly decreased viral replication in vitro. Increased IFNs expression together with reduced neutrophils/lymphocytes recruitment and correlated IL-4/IL-6 declination was demonstrated for Ergoferon in vivo. However, there was no effect on examined chemokines. We conclude that AC and Ergoferon possess effects against RV infection and may have potential as novel therapies against RV-induced exacerbations of asthma.


Assuntos
Anticorpos/farmacologia , Antivirais/imunologia , Antivirais/farmacologia , Infecções por Picornaviridae/tratamento farmacológico , Rhinovirus/efeitos dos fármacos , 2',5'-Oligoadenilato Sintetase/análise , Animais , Asma/imunologia , Asma/virologia , Linhagem Celular , Quimiocinas/metabolismo , Criança , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Inflamação , Interferons/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , Rhinovirus/patogenicidade
5.
EBioMedicine ; 19: 128-138, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28373098

RESUMO

BACKGROUND: Rhinovirus infection is a major cause of asthma exacerbations. OBJECTIVES: We studied nasal and bronchial mucosal inflammatory responses during experimental rhinovirus-induced asthma exacerbations. METHODS: We used nasosorption on days 0, 2-5 and 7 and bronchosorption at baseline and day 4 to sample mucosal lining fluid to investigate airway mucosal responses to rhinovirus infection in patients with allergic asthma (n=28) and healthy non-atopic controls (n=11), by using a synthetic absorptive matrix and measuring levels of 34 cytokines and chemokines using a sensitive multiplex assay. RESULTS: Following rhinovirus infection asthmatics developed more upper and lower respiratory symptoms and lower peak expiratory flows compared to controls (all P<0.05). Asthmatics also developed higher nasal lining fluid levels of an anti-viral pathway (including IFN-γ, IFN-λ/IL-29, CXCL11/ITAC, CXCL10/IP10 and IL-15) and a type 2 inflammatory pathway (IL-4, IL-5, IL-13, CCL17/TARC, CCL11/eotaxin, CCL26/eotaxin-3) (area under curve day 0-7, all P<0.05). Nasal IL-5 and IL-13 were higher in asthmatics at day 0 (P<0.01) and levels increased by days 3 and 4 (P<0.01). A hierarchical correlation matrix of 24 nasal lining fluid cytokine and chemokine levels over 7days demonstrated expression of distinct interferon-related and type 2 pathways in asthmatics. In asthmatics IFN-γ, CXCL10/IP10, CXCL11/ITAC, IL-15 and IL-5 increased in bronchial lining fluid following viral infection (all P<0.05). CONCLUSIONS: Precision sampling of mucosal lining fluid identifies robust interferon and type 2 responses in the upper and lower airways of asthmatics during an asthma exacerbation. Nasosorption and bronchosorption have potential to define asthma endotypes in stable disease and at exacerbation.


Assuntos
Asma/imunologia , Brônquios/imunologia , Citocinas/imunologia , Mucosa Nasal/imunologia , Infecções por Picornaviridae/imunologia , Rhinovirus , Adulto , Asma/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/virologia , Carga Viral , Adulto Jovem
7.
PLoS One ; 9(4): e91119, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24690886

RESUMO

Human embryonic stem cell-derived endothelial cells (hESC-EC), as well as other stem cell derived endothelial cells, have a range of applications in cardiovascular research and disease treatment. Endothelial cells sense Gram-negative bacteria via the pattern recognition receptors (PRR) Toll-like receptor (TLR)-4 and nucleotide-binding oligomerisation domain-containing protein (NOD)-1. These pathways are important in terms of sensing infection, but TLR4 is also associated with vascular inflammation and atherosclerosis. Here, we have compared TLR4 and NOD1 responses in hESC-EC with those of endothelial cells derived from other stem cells and with human umbilical vein endothelial cells (HUVEC). HUVEC, endothelial cells derived from blood progenitors (blood outgrowth endothelial cells; BOEC), and from induced pluripotent stem cells all displayed both a TLR4 and NOD1 response. However, hESC-EC had no TLR4 function, but did have functional NOD1 receptors. In vivo conditioning in nude rats did not confer TLR4 expression in hESC-EC. Despite having no TLR4 function, hESC-EC sensed Gram-negative bacteria, a response that was found to be mediated by NOD1 and the associated RIP2 signalling pathways. Thus, hESC-EC are TLR4 deficient but respond to bacteria via NOD1. This data suggests that hESC-EC may be protected from unwanted TLR4-mediated vascular inflammation, thus offering a potential therapeutic advantage.


Assuntos
Células Endoteliais/metabolismo , Células Endoteliais/microbiologia , Haemophilus influenzae/fisiologia , Células-Tronco Embrionárias Humanas/citologia , Células-Tronco Embrionárias Humanas/microbiologia , Proteína Adaptadora de Sinalização NOD1/metabolismo , Animais , Células Endoteliais/citologia , Técnicas de Silenciamento de Genes , Infecções por Haemophilus/microbiologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/microbiologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , RNA Interferente Pequeno/metabolismo , Ratos Nus , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Transplante de Células-Tronco , Receptor 4 Toll-Like/metabolismo
8.
Antiviral Res ; 95(3): 193-201, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22742898

RESUMO

Rhinoviruses (RVs) are ubiquitous human respiratory viruses, the major cause of common colds, acute exacerbations of asthma and other respiratory diseases. The development of antibodies to RV following primary infection is poorly understood and there is currently no RV vaccine available. We therefore used mouse models of intranasal RV infection and immunisation to determine the induction, magnitude and specificity of antibody responses. Strong cross-serotype RV-specific IgG responses in serum and bronchoalveolar lavage were induced towards the RV capsid protein VP1. IgA responses were weaker, requiring two infections to generate detectable RV-specific binding. Similarly two or more RV infections were necessary to induce neutralising antibodies. Immunisation strategies boosted homotypic as well as inducing cross-serotype neutralising IgG responses. We conclude that VP1 based antigens combined with adjuvants may permit successful antibody-mediated vaccine design and development.


Assuntos
Anticorpos Antivirais/sangue , Reações Cruzadas , Infecções por Picornaviridae/imunologia , Rhinovirus/imunologia , Proteínas Virais/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/análise , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/análise , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Feminino , Imunoglobulina A/análise , Imunoglobulina A/sangue , Imunoglobulina G/análise , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos BALB C , Vacinas Virais/administração & dosagem
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