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1.
J Clin Immunol ; 43(8): 2011-2021, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37695435

RESUMEN

Autosomal recessive tyrosine kinase 2 (TYK2) deficiency is characterized by susceptibility to mycobacterial and viral infections. Here, we report a 4-year-old female with severe respiratory viral infections, EBV-driven Burkitt-like lymphoma, and infection with the neurotropic Jamestown Canyon virus. A novel, homozygous c.745C > T (p.R249*) variant was found in TYK2. The deleterious effects of the TYK2 lesion were confirmed by immunoblotting; by evaluating functional responses to IFN-α/ß, IL-10, and IL-23; and by assessing its scaffolding effect on the cell surface expression of cytokine receptor subunits. The effects of the mutation could not be pharmacologically circumvented in vitro, suggesting that alternative modalities, such as hematopoietic stem cell transplantation or gene therapy, may be needed. We characterize the first patient from Canada with a novel homozygous mutation in TYK2.


Asunto(s)
Encefalitis Viral , Linfoma , Virosis , Femenino , Humanos , Preescolar , Herpesvirus Humano 4 , TYK2 Quinasa/genética , Mutación/genética
2.
Am J Physiol Lung Cell Mol Physiol ; 314(4): L635-L641, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-29351441

RESUMEN

Cystic fibrosis patients exhibit chronic Pseudomonas aeruginosa respiratory infections and sustained proinflammatory state favoring lung tissue damage and remodeling, ultimately leading to respiratory failure. Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function is associated with MAPK hyperactivation and increased cytokines expression, such as interleukin-8 [chemoattractant chemokine (C-X-C motif) ligand 8 (CXCL8)]. Recently, new therapeutic strategies directly targeting the basic CFTR defect have been developed, and ORKAMBI (Vx-809/Vx-770 combination) is the only Food and Drug Administration-approved treatment for CF patients homozygous for the F508del mutation. Here we aimed to determine the effect of the Vx-809/Vx-770 combination on the induction of the inflammatory response by fully differentiated primary bronchial epithelial cell cultures from CF patients carrying F508del mutations, following exposure to P. aeruginosa exoproducts. Our data unveiled that CFTR functional rescue with Vx-809/Vx-770 drastically reduces CXCL8 (as well as CXCL1 and CXCL2) transcripts and p38 MAPK phosphorylation in response to P. aeruginosa exposure through a CFTR-dependent mechanism. These results suggest that ORKAMBI has anti-inflammatory properties that could decrease lung inflammation and contribute to the observed beneficial impact of this treatment in CF patients.


Asunto(s)
Aminofenoles/uso terapéutico , Aminopiridinas/uso terapéutico , Benzodioxoles/uso terapéutico , Bronquios/inmunología , Fibrosis Quística/tratamiento farmacológico , Células Epiteliales/inmunología , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/aislamiento & purificación , Quinolonas/uso terapéutico , Bronquios/efectos de los fármacos , Bronquios/patología , Células Cultivadas , Agonistas de los Canales de Cloruro/uso terapéutico , Fibrosis Quística/inmunología , Fibrosis Quística/microbiología , Fibrosis Quística/patología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Humanos , Interleucina-8/metabolismo , Mutación , Infecciones por Pseudomonas/inmunología , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/patología
5.
Biochem Biophys Res Commun ; 483(2): 829-833, 2017 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-28062182

RESUMEN

Chronic bacterial infections in cystic fibrosis lung disease are often characterized by Pseudomonas aeruginosa biofilms that are regulated by bacterial intercellular signals termed quorum sensing (QS), such as N-(3-oxododecanoyl)-l-homoserine lactone (3OC12-HSL). This study reports that biofilm-derived exoproducts decrease the transcriptional activity of the anti-oxidant response element in bronchial epithelial cells. In a live co-culture assay of BEAS-2B cells and P. aeruginosa biofilm, the QS molecule 3OC12-HSL was an important but not sole contributor to the inhibition of basal NRF2 luciferase reporter activity. Moreover, biofilm-derived exoproducts and 3OC12-HSL decrease the expression of endogenous antioxidant response element-regulated genes hemeoxygenase-1 (HO-1) and NAD(P)H Quinone Dehydrogenase-1 (NQO-1) while they increase IL-8 expression. As previously reported, IL-8 expression is partially dependent on p38 MAPK activity, but the inhibitory effect of biofilm QS molecules on HO-1 and NQO-1 expression occurs independently of this protein kinase. Finally, the transfection of CFTRdelF508 but not its wild type counterpart decreases basal, planktonic PsaDM and sulforaphane-driven NRF2 luciferase reporter activity in BEAS-2B cells. Therefore, the presence of quorum sensing molecules derived from bacterial biofilms lowers the transcriptional activity of the anti-oxidant response element, which may contribute to the establishment of chronic bacterial infections, especially in the presence of mutated CFTR. Increasing NRF2 activity may thus be a promising strategy to potentiate anti-biofilm activity in cystic fibrosis lung disease.


Asunto(s)
Elementos de Respuesta Antioxidante , Factor 2 Relacionado con NF-E2/metabolismo , Pseudomonas aeruginosa/patogenicidad , Percepción de Quorum/fisiología , 4-Butirolactona/análogos & derivados , 4-Butirolactona/metabolismo , Biopelículas , Línea Celular , Fibrosis Quística/microbiología , Células Epiteliales/metabolismo , Células Epiteliales/microbiología , Regulación de la Expresión Génica , Hemo-Oxigenasa 1/genética , Homoserina/análogos & derivados , Homoserina/metabolismo , Humanos , Interleucina-8/genética , Pulmón/metabolismo , Pulmón/microbiología , Pulmón/patología , NAD(P)H Deshidrogenasa (Quinona)/genética , Factor 2 Relacionado con NF-E2/genética , Infecciones por Pseudomonas/metabolismo , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/patología , Pseudomonas aeruginosa/metabolismo
6.
Biochem Biophys Res Commun ; 482(4): 645-650, 2017 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-27865842

RESUMEN

Niemann-Pick disease (NPD) type B is a rare autosomal recessive disease characterized by variable levels of impairment in sphingomyelin phosphodiesterase 1 (SMPD1) activity. Lung involvement is the most important prognostic factor in NPD-B, with recurrent respiratory infections starting in infancy being the major cause of morbidity and mortality. We hypothesized that decreased SMPD1 activity impaired airway epithelium host defense response. SMPD1 activity was reduced using inducible shRNA. Surprisingly, decreasing SMPD1 activity by 50%, resulted in increased neutrophil recruitment, both at baseline and in response to bacterial stimulation. This correlated with elevated levels of cytokine mRNA shown to contribute to neutrophil recruitment in unstimulated (e.g. IL-8 and GRO-α) and infected cells (e.g. IL-8, GRO-α, GM-CSF and CCL20). Instead of preventing the host defence responses, decreased SMPD1 activity results in an inflammatory response even in the absence of infection. Moreover, decreasing SMPD1 activity resulted in a pro-oxidative shift. Accordingly, expression of an inactive mutant, SMPD1[L225P] but not the WT enzyme increased activation of the antioxidant transcription factor NRF2. Therefore, decreasing SMPD1 activity by 50% in airway epithelial cells, the equivalent of the loss of one allele, results in the accumulation of oxidants that activates NRF2 and a concomitant increased cytokine production as well as neutrophil recruitment. This can result in a chronic inflammatory state that impairs host defence similar to scenarios observe in other chronic inflammatory lung disease such as Chronic Obstructive Pulmonary Disease or Cystic Fibrosis.


Asunto(s)
Citocinas/inmunología , Factor 2 Relacionado con NF-E2/inmunología , Infiltración Neutrófila , Enfermedad de Niemann-Pick Tipo B/inmunología , Mucosa Respiratoria/inmunología , Esfingomielina Fosfodiesterasa/inmunología , Bronquios/citología , Bronquios/inmunología , Bronquios/patología , Línea Celular , Humanos , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/inmunología , Especies Reactivas de Oxígeno/inmunología , Mucosa Respiratoria/citología , Mucosa Respiratoria/patología
7.
Int J Cancer ; 136(6): 1341-50, 2015 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-25082668

RESUMEN

Surgery is required for the curative treatment of lung cancer but is associated with high rates of postoperative pneumonias predominantly caused by gram negative bacteria. Recent evidence suggests that these severe infectious complications may decrease long term survival after hospital discharge via cancer recurrence, but the mechanism is unclear. Lung cancer cells have recently been demonstrated to express Toll-like receptors (TLR) that mediate pathogen recognition. We hypothesized that incubation of non-small cell lung cancer (NSCLC) cells with heat-inactivated Escherichia coli can augment cancer cell adhesion, migration and metastasis via TLR4 signaling. Incubation of murine and human NSCLC cells with E. coli increased in vitro cell adhesion to collagen I, collagen IV and fibronectin, and enhanced in vitro migration. Using hepatic intravital microscopy, we demonstrated that NSCLC cells have increased in vivo adhesion to hepatic sinusoids after coincubation with gram negative bacteria. These enhanced cell adhesion and migration phenotypes following incubation with E. coli were attenuated at three levels: inhibition of TLR4 (Eritoran), p38 MAPK (BIRB0796) and ERK1/2 phosphorylation (PD184352). Incubation of murine NSCLC cells in vitro with E. coli prior to intrasplenic injection significantly augmented formation of in vivo hepatic metastases 2 weeks later. This increase was abrogated by NSCLC TLR4 blockade using Eritoran. TLR4 represents a potential therapeutic target to help prevent severe postoperative infection driven cancer metastasis.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/secundario , Escherichia coli/patogenicidad , Neoplasias Pulmonares/patología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Receptor Toll-Like 4/fisiología , Animales , Adhesión Celular , Línea Celular Tumoral , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Fosforilación
8.
J Infect Dis ; 207(10): 1544-55, 2013 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-23402824

RESUMEN

Biofilm microcolonies of Pseudomonas aeruginosa chronically infect the airways of patients with cystic fibrosis and fuel ongoing destructive inflammation, yet the impact of the switch from planktonic to biofilm growth on host responses is poorly understood. We report that in airway epithelial cells a threshold of p38α mitogen-activated protein kinase (MAPK) activation was required to trigger neutrophil recruitment, which is influenced by extrinsic and intrinsic factors. Planktonic P. aeruginosa diffusible material (PsaDM) induced stronger p38α MAPK activation as compared to biofilm PsaDM. Biofilm PsaDM activated p38α MAPK in a Toll-like receptor-independent fashion via the lasI/lasR quorum-sensing system, but this activation was insufficient to recruit neutrophils. However, in airway epithelial cells from patients with cystic fibrosis with hypersensitivity to injurious stimuli, biofilm PsaDM activated p38α MAPK strongly enough to recruit neutrophils, which can contribute to lung injury.


Asunto(s)
Biopelículas/crecimiento & desarrollo , Células Epiteliales/inmunología , Inmunidad Innata , Proteína Quinasa 14 Activada por Mitógenos/inmunología , Pseudomonas aeruginosa/inmunología , Pseudomonas aeruginosa/patogenicidad , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Biopsia , Células Cultivadas , Fibrosis Quística/inmunología , Fibrosis Quística/microbiología , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/microbiología , Humanos , Immunoblotting , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , FN-kappa B/metabolismo , Mucosa Nasal/citología , Infiltración Neutrófila , Neutrófilos/metabolismo , Neutrófilos/microbiología , Plancton/metabolismo , Percepción de Quorum , Sistema Respiratorio/citología , Sistema Respiratorio/enzimología , Sistema Respiratorio/inmunología , Sistema Respiratorio/microbiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transactivadores/genética , Transactivadores/metabolismo
9.
J Exp Med ; 221(2)2024 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-38175961

RESUMEN

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only in three, IFN-α2 plus IFN-ω in five, and IFN-α2, IFN-ω plus IFN-ß in two; IFN-ω only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-α2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-ω in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-α2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-ω only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-ω and/or IFN-α2.


Asunto(s)
COVID-19 , Interferón Tipo I , Niño , Humanos , Interferón-alfa , Autoanticuerpos
10.
Biochem Biophys Res Commun ; 441(3): 689-692, 2013 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-24513215

RESUMEN

Excessive inflammation and Pseudomonas aeruginosa infection are two major characteristics of cystic fibrosis (CF) lung disease. In this manuscript, we describe a novel mechanism of ERK1/ERK2 activation and CXCL8 expression in AECs lacking functional CFTR. In both non-CF and CF airway epithelial cells (AECs), the protein kinase TPL2 is required for ERK1/ERK2 MAPK activation. However, we have found that EGFR is strongly phosphorylated in the airway epithelium of CF lung and contributes to ERK1/ERK2 MAPK activation in CF AECs exposed to P. aeruginosa diffusible material (PsaDM). Moreover, PsaDM stimulates the expression of the EGFR pro-ligand HB-EGF more strongly, and in a sustained manner, in CF AECs compared to non-CF cells. Finally, although both non-CF and CF AECs expresses CXCL8 in response to PsaDM, the levels of CXCL8 are higher and EGFR plays a more important role in regulating CXCL8 synthesis in CF AECs. Together, our finding shows that in addition to the TLR-mediated TPL2 activation of ERK1/ERK2, an additional pathway contributing to ERK1/ERK2 activation is triggered by infection of CF AECs: the EGFR signalling pathway. This second pathway may contribute to excessive inflammation observed in CF.

11.
Biochem Biophys Res Commun ; 441(3): 689-92, 2013 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-24404585

RESUMEN

Excessive inflammation and Pseudomonas aeruginosa infection are two major characteristics of cysticfibrosis (CF) lung disease. In this manuscript, we describe a novel mechanism of ERK1/ERK2 activationand CXCL8 expression in airway epithelial cells (AECs) lacking functional CFTR. In both non-CF and CFAECs, the protein kinase TPL2 is required for ERK1/ERK2 MAPK activation. However, we have found that EGFR is strongly phosphorylated in the airway epithelium of CF lung and contributes to ERK1/ERK2 MAPK activation in CF AECs exposed to P. aeruginosa diffusible material (PsaDM). Moreover, PsaDM stimulates the expression of the EGFR pro-ligand HB-EGF more strongly, and in a sustained manner, in CF AECs compared to non-CF cells. Finally, although both non-CF and CF AECs expresses CXCL8 in response to PsaDM, the levels of CXCL8 are higher and EGFR plays a more important role in regulating CXCL8 synthesis in CF AECs. Together, our finding shows that in addition to the TLR-mediated TPL2 activation of ERK1/ERK2, an additional pathway contributing to ERK1/ERK2 activation is triggered by infection of CF AECs: the EGFR signaling pathway. This second pathway may contribute to excessive inflammation observed in CF.


Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/enzimología , Fibrosis Quística/microbiología , Receptores ErbB/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Infecciones por Pseudomonas/enzimología , Pseudomonas aeruginosa , Mucosa Respiratoria/enzimología , Línea Celular , Fibrosis Quística/genética , Activación Enzimática , Humanos , Sistema de Señalización de MAP Quinasas , Proteína Quinasa 1 Activada por Mitógenos/biosíntesis , Proteína Quinasa 3 Activada por Mitógenos/biosíntesis , Infecciones por Pseudomonas/genética , Mucosa Respiratoria/microbiología , Eliminación de Secuencia
12.
J Immunol ; 184(8): 4531-7, 2010 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-20228195

RESUMEN

Neutrophilic inflammation plays an important role in lung tissue destruction occurring in many chronic pulmonary diseases. Neutrophils can be recruited to sites of inflammation via the action of the cytokine IL-17. In this study, we report that IL-17RA and IL-17RC mRNA expression is significantly increased in asthmatic bronchoscopic biopsies and that these receptors are not only expressed on epithelial and inflammatory cells but also on endothelial cells. IL-17 potently stimulates lung microvascular endothelial cells to produce chemoattractants (CXCL8 and derivatives of the 5-lipoxygenase pathway) that selectively drive neutrophil but not lymphocyte chemotaxis. Moreover, IL-17 promotes endothelial activation by inducing the expression of endothelial adhesion markers (E-selectin, VCAM-1, and ICAM-1) in a p38 MAPK-dependent manner. This increased expression of adhesion molecules stimulates the trans-endothelial migration of neutrophils, as well as the transmigration of HT-29 colon carcinoma cells, suggesting a further role in promoting lung metastasis. Finally, IL-17 increased neutrophil adhesion to the endothelium in vivo as determined by intravital microscopy of mice cremaster muscle. Overall, our results demonstrate that IL-17 is a potent activator of the endothelium in vivo leading to neutrophil infiltration. Therefore, preventing neutrophil recruitment by blocking the action of IL-17 on endothelial cells may prove to be highly beneficial in diseases in which neutrophilic inflammation plays a key role.


Asunto(s)
Endotelio Vascular/inmunología , Endotelio Vascular/metabolismo , Mediadores de Inflamación/fisiología , Interleucina-17/fisiología , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/fisiología , Adulto , Animales , Asma/inmunología , Asma/metabolismo , Asma/patología , Células Cultivadas , Endotelio Vascular/enzimología , Endotelio Vascular/patología , Células HT29 , Humanos , Inflamación/enzimología , Inflamación/inmunología , Inflamación/patología , Interleucina-17/biosíntesis , Interleucina-8/biosíntesis , Células Jurkat , Sistema de Señalización de MAP Quinasas/inmunología , Masculino , Ratones , Neutrófilos/enzimología , Neutrófilos/patología
13.
J Allergy Clin Immunol ; 127(4): 1046-53.e1-2, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21345484

RESUMEN

BACKGROUND: Migration of airway smooth muscle cells (ASMCs) might contribute to increased airway smooth muscle mass in asthma. T(H)17 cells and T(H)17-associated cytokines are involved in the pathogenesis of asthma and might also contribute to airway remodeling. OBJECTIVE: We sought to explore the possibility that migration of ASMCs might contribute to airway remodeling through the action of T(H)17-related cytokines. METHODS: The effect of exogenous T(H)17 cytokines on ex vivo human ASMC migration was investigated by using a chemotaxis assay. The involvement of signaling pathways, including p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 MAPK, nuclear factor κB, and phosphoinositide 3-kinase, was also examined. RESULTS: We demonstrated that IL-17A, IL-17F, and IL-22 promote migration in a dose-dependent manner. We further demonstrated that ASMCs express receptors for IL-17RA, IL-17RC, and IL-22R1. Using mAbs directed against these receptors, we confirmed that T(H)17-associated cytokine-induced migration was dependent on selective receptor activation. Moreover, IL-17A and IL-17F exert their effects through signaling pathways that are distinct from those used by IL-22. The p38 MAPK inhibitor BIRB0796 inhibited the migration induced by IL-17A and IL-17F. PS1145, an inhibitor of nuclear factor κB, abolished the IL-22-induced migration. CONCLUSION: These data raise the possibility that T(H)17-associated cytokines promote human ASMC migration in vivo and suggest an important new mechanism for the promotion of airway remodeling in asthma.


Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/fisiología , Movimiento Celular/fisiología , Citocinas/metabolismo , Miocitos del Músculo Liso/citología , Células Th17/metabolismo , Asma/inmunología , Asma/metabolismo , Asma/fisiopatología , Separación Celular , Citocinas/inmunología , Citometría de Flujo , Humanos , Miocitos del Músculo Liso/metabolismo , Transducción de Señal/fisiología , Células Th17/inmunología
14.
Lancet Healthy Longev ; 3(3): e166-e175, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35224524

RESUMEN

BACKGROUND: The use of COVID-19 vaccines has been prioritised to protect the most vulnerable-notably, older people. Because of fluctuations in vaccine availability, strategies such as delayed second dose and heterologous prime-boost have been used. However, the effectiveness of these strategies in frail, older people are unknown. We aimed to assess the antigenicity of mRNA-based COVID-19 vaccines in frail, older people in a real-world setting, with a rationed interval dosing of 16 weeks between the prime and boost doses. METHODS: This prospective observational cohort study was done across 12 long-term care facilities of the Montréal Centre-Sud - Integrated University Health and Social Services Centre in Montréal, Québec, Canada. Under a rationing strategy mandated by the provincial government, adults aged 65 years and older residing in long-term care facilities in Québec, Canada, with or without previously documented SARS-CoV-2 infection, were administered homologous or heterologous mRNA vaccines, with an extended 16-week interval between doses. All older residents in participating long-term care facilities who received two vaccine doses were eligible for inclusion in this study. Participants were enrolled from Dec 31, 2020, to Feb 16, 2021, and data were collected up to June 9, 2021. Clinical data and blood samples were serially collected from participants at the following timepoints: at baseline, before the first dose; 4 weeks after the first dose; 6-10 weeks after the first dose; 16 weeks after the first dose, up to 2 days before administration of the second dose; and 4 weeks after the second dose. Sera were tested for SARS-CoV-2-specific IgG antibodies (to the trimeric spike protein, the receptor-binding domain [RBD] of the spike protein, and the nucleocapsid protein) by automated chemiluminescent ELISA. Two cohorts were used in this study: a discovery cohort, for which blood samples were collected before administration of the first vaccine dose and longitudinally thereafter; and a confirmatory cohort, for which blood samples were only collected from 4 weeks after the prime dose. Analyses were done in the discovery cohort, with validation in the confirmatory cohort, when applicable. FINDINGS: The total study sample consisted of 185 participants. 65 participants received two doses of mRNA-1273 (Spikevax; Moderna), 36 received two doses of BNT162b2 (Comirnaty; Pfizer-BioNTech), and 84 received mRNA-1273 followed by BNT162b2. In the discovery cohort, after a significant increase in anti-RBD and anti-spike IgG concentrations 4 weeks after the prime dose (from 4·86 log binding antibody units [BAU]/mL to 8·53 log BAU/mL for anti-RBD IgG and from 5·21 log BAU/mL to 8·05 log BAU/mL for anti-spike IgG), there was a significant decline in anti-RBD and anti-spike IgG concentrations until the boost dose (7·10 log BAU/mL for anti-RBD IgG and 7·60 log BAU/mL for anti-spike IgG), followed by an increase 4 weeks later for both vaccines (9·58 log BAU/mL for anti-RBD IgG and 9·23 log BAU/mL for anti-spike IgG). SARS-CoV-2-naive individuals showed lower antibody responses than previously infected individuals at all timepoints tested up to 16 weeks after the prime dose, but achieved similar antibody responses to previously infected participants by 4 weeks after the second dose. Individuals primed with the BNT162b2 vaccine showed a larger decrease in mean anti-RBD and anti-spike IgG concentrations with a 16-week interval between doses (from 8·12 log BAU/mL to 4·25 log BAU/mL for anti-RBD IgG responses and from 8·18 log BAU/mL to 6·66 log BAU/mL for anti-spike IgG responses) than did those who received the mRNA-1273 vaccine (two doses of mRNA-1273: from 8·06 log BAU/mL to 7·49 log BAU/mL for anti-RBD IgG responses and from 6·82 log BAU/mL to 7·56 log BAU/mL for anti-spike IgG responses; mRNA-1273 followed by BNT162b2: from 8·83 log BAU/mL to 7·95 log BAU/mL for anti-RBD IgG responses and from 8·50 log BAU/mL to 7·97 log BAU/mL for anti-spike IgG responses). No differences in antibody responses 4 weeks after the second dose were noted between the two vaccines, in either homologous or heterologous combinations. INTERPRETATION: Interim results of this ongoing longitudinal study show that among frail, older people, previous SARS-CoV-2 infection and the type of mRNA vaccine influenced antibody responses when used with a 16-week interval between doses. In these cohorts of frail, older individuals with a similar age and comorbidity distribution, we found that serological responses were similar and clinically equivalent between the discovery and confirmatory cohorts. Homologous and heterologous use of mRNA vaccines was not associated with significant differences in antibody responses 4 weeks following the second dose, supporting their interchangeability. FUNDING: Public Health Agency of Canada, Vaccine Surveillance Reference Group; and the COVID-19 Immunity Task Force. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Vacuna nCoV-2019 mRNA-1273 , Anciano , Vacuna BNT162 , Anciano Frágil , Humanos , Inmunoglobulina G , Estudios Longitudinales , Estudios Prospectivos , ARN Mensajero , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Vacunación , Vacunas Sintéticas , Vacunas de ARNm
15.
Sci Immunol ; : eabp8966, 2022 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-35857576

RESUMEN

Life-threatening 'breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-ß. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.

16.
Am J Respir Cell Mol Biol ; 45(5): 984-90, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21493783

RESUMEN

Severe or refractory asthma affects 5 to 15% of all patients with asthma, but is responsible for more than half of the health burden associated with the disease. Severe asthma is characterized by a dramatic increase in smooth muscle and airway inflammation. Although glucocorticoids are the mainstay of treatment in asthma, they are unable to fully control the disease in individuals with severe asthma. We found that airway smooth muscle cells (ASMCs) from individuals with severe asthma showed elevated activities of the ERK1/ERK2 and p38 MAPK pathways despite treatment with oral and inhaled glucocorticoids, which increased the expression of DUSP1, a phosphatase shown to limit p38 MAPK activity. In ex vivo ASMCs, TNF-α but not IL-17A induced expression of the neutrophil chemoattractant CXCL8. Moreover, TNF-α led to up-regulation of the ERK1/ERK2 and p38 MAPKs pathways, with only the latter being sensitive to pretreatment with the glucocorticoid dexamethasone. In contrast to epithelial and endothelial cells, TNF-α-stimulated CXCL8 synthesis was dependent on ERK1/ERK2 but not on p38 MAPK. Moreover, suppressing ERK1/ERK2 activation prevented neutrophil recruitment by ASMCs, whereas suppressing p38 MAPK activity had no impact. Taken together, these results highlight the ERK1/ERK2 MAPK cascade as a novel and attractive target in severe asthma because the activation of this pathway is insensitive to the action of glucocorticoids and is involved in neutrophil recruitment, contributing the to inflammation seen in the disease.


Asunto(s)
Asma/metabolismo , Interleucina-8/biosíntesis , Sistema de Señalización de MAP Quinasas , Neutrófilos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Asma/patología , Células Cultivadas , Fosfatasa 1 de Especificidad Dual/biosíntesis , Femenino , Glucocorticoides/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/farmacología , Regulación hacia Arriba , Adulto Joven
17.
J Biol Chem ; 285(29): 22299-307, 2010 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-20460375

RESUMEN

In cystic fibrosis (CF), the absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) translates into chronic bacterial infection, excessive inflammation, tissue damage, impaired lung function and eventual death. Understanding the mechanisms underlying this vicious circle of inflammation is important to design better therapies for CF. We found in CF lung biopsies increased immunoreactivity for p38 MAPK activity markers. Moreover, when compared with their non-CF counterpart, airway epithelial cells expressing the most common mutation in CF (CFTRDeltaF508) were more potent at inducing neutrophil chemotaxis through increased interleukin (IL)-6 synthesis when challenged with Pseudomonas aeruginosa diffusible material. We then discovered that in CFTRDeltaF508 cells, the p38 and ERK MAPKs are hyperactivated in response to P. aeruginosa diffusible material, leading to increased IL-6 mRNA expression and stability. Moreover, although TLR5 contributes to p38 MAPK activation upon P. aeruginosa challenge, it only played a weak role in IL-6 synthesis. Instead, we found that the production of reactive oxygen species is essential for IL-6 synthesis in response to P. aeruginosa diffusible material. Finally, we uncovered that in CFTRDeltaF508 cells, the extracellular glutathione levels are decreased, leading to a greater sensitivity to reactive oxygen species, providing an explanation for the hyperactivation of the p38 and ERK MAPKs and increased IL-6 synthesis. Taken together, our study has characterized a mechanism whereby the CFTRDeltaF508 mutation in airway epithelial cells contributes to increase inflammation of the airways.


Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Células Epiteliales/enzimología , Células Epiteliales/microbiología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Interleucina-6/biosíntesis , Pseudomonas aeruginosa/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Adolescente , Adulto , Línea Celular , Quimiotaxis de Leucocito , Fibrosis Quística/enzimología , Fibrosis Quística/microbiología , Fibrosis Quística/patología , Activación Enzimática , Células Epiteliales/patología , Femenino , Regulación de la Expresión Génica , Glutatión/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Interleucina-6/genética , Pulmón/enzimología , Pulmón/microbiología , Pulmón/patología , Masculino , Neutrófilos/citología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores de Citocinas/metabolismo , Receptores de Reconocimiento de Patrones/metabolismo
18.
Curr Opin Immunol ; 72: 21-26, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33756276

RESUMEN

Autosomal recessive mutations in Inducible T Cell Costimulator Ligand (ICOSLG) result in a combined immunodeficiency syndrome of humans, saliently marked by recurrent respiratory tract infections and significant disease with DNA-based viruses at epithelial barriers, including human papillomavirus (HPV). These features are also seen in persons with loss of function of the complementary gene, ICOS. The infection phenotypes associated with these natural experiments disclose a critical role of the corresponding proteins, ICOSL and ICOS, in human immunity at mucocutaneous barriers. Here, we review the syndromes of ICOSL and ICOS deficiency and explore the mechanisms by which the ICOSL:ICOS axis mediates epithelial host defenses.


Asunto(s)
Resistencia a la Enfermedad/genética , Epitelio/inmunología , Epitelio/metabolismo , Interacciones Huésped-Patógeno/genética , Ligando Coestimulador de Linfocitos T Inducibles/genética , Ligando Coestimulador de Linfocitos T Inducibles/metabolismo , Animales , Resistencia a la Enfermedad/inmunología , Susceptibilidad a Enfermedades/inmunología , Predisposición Genética a la Enfermedad , Genotipo , Centro Germinal/inmunología , Centro Germinal/metabolismo , Interacciones Huésped-Patógeno/inmunología , Humanos , Infecciones/etiología , Infecciones/metabolismo , Mutación , Especificidad de Órganos
19.
JCI Insight ; 6(1)2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33232301

RESUMEN

Clostridioides difficile is a major cause of health care-associated diarrhea. Severity ranges from mild to life-threatening, but this variability remains poorly understood. Microbiologic diagnosis of C. difficile infection (CDI) is straightforward but offers little insight into the patient's prognosis or into pathophysiologic determinants of clinical trajectory. The aim of this study was to discover host-derived, CDI-specific fecal biomarkers involved in disease severity. Subjects without and with CDI diarrhea were recruited. CDI severity was based on Infectious Diseases Society of America/Society for Healthcare Epidemiology of America criteria. We developed a liquid chromatography tandem mass spectrometry approach to identify host-derived protein biomarkers from stool and applied it to diagnostic samples for cohort-wise comparison (CDI-negative vs. nonsevere CDI vs. severe CDI). Selected biomarkers were orthogonally confirmed and subsequently verified in a CDI mouse model. We identified a protein signature from stool, consisting of alpha-2-macroglobulin (A2MG), matrix metalloproteinase-7 (MMP-7), and alpha-1-antitrypsin (A1AT), that not only discriminates CDI-positive samples from non-CDI ones but also is potentially associated with disease severity. In the mouse model, this signature with the murine homologs of the corresponding proteins was also identified. A2MG, MMP-7, and A1AT serve as biomarkers in patients with CDI and define novel components of the host response that may determine disease severity.


Asunto(s)
Biomarcadores/análisis , Infecciones por Clostridium/diagnóstico , Infecciones por Clostridium/metabolismo , Heces/química , Anciano , Animales , Estudios de Casos y Controles , Clostridioides difficile/aislamiento & purificación , Estudios de Cohortes , Modelos Animales de Enfermedad , Heces/microbiología , Femenino , Humanos , Masculino , Metaloproteinasa 7 de la Matriz/análisis , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , alfa 2-Macroglobulinas Asociadas al Embarazo/análisis , Índice de Severidad de la Enfermedad , alfa 1-Antitripsina/análisis
20.
Biochem Biophys Res Commun ; 391(1): 505-9, 2010 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-19931506

RESUMEN

In Cystic Fibrosis (CF), the absence of functional Cystic Fibrosis Transmembrane conductance Regulator (CFTR) translates into chronic bacterial infection, excessive inflammation, tissue damage, impaired lung function and eventual death. Understanding the mechanisms underlying this vicious circle of inflammation is key to better therapies for CF. In this manuscript, we have found that the presence of IL-17 in the airways of CF patients not only exacerbates inflammation through the recruitment of neutrophils via secretion of CXCL8, but also by priming airway epithelial cells lacking functional CFTR to increase response to the bacterial sensor NOD1. IL-17 stimulation of airway epithelial cells (AECs) lacking functional CFTR increased the expression of NOD1, NOD2, TLR4 and its own receptors IL-17RA and IL-17RC. Moreover, prior stimulation of AECs expressing the CFTRDeltaF508 mutant with IL-17 showed much greater CXCL8 secretion in response to a NOD1 agonist and Pseudomonas aeruginosa diffusible material. Taken together our results show that IL-17 primes AECs expressing CFTRDeltaF508 to increase host defence response to bacteria through the up-regulation of PRRs, and in particular of NOD1, and identifies another mechanism of action through which the CFTRDeltaF508 mutation leads to increase inflammation in response to bacterial ligands. Therefore preventing IL-17 function in CF may prove an important strategy in decreasing lung inflammation due to both direct and indirect effects.


Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Fibrosis Quística/complicaciones , Interleucina-17/metabolismo , Proteína Adaptadora de Señalización NOD1/biosíntesis , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa , Mucosa Respiratoria/inmunología , Adolescente , Células Cultivadas , Fibrosis Quística/genética , Fibrosis Quística/inmunología , Fibrosis Quística/patología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Células Epiteliales/inmunología , Células Epiteliales/microbiología , Células Epiteliales/patología , Humanos , Interleucina-8/metabolismo , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Neutrófilos/inmunología , Infecciones por Pseudomonas/patología , Receptores de Interleucina-17/biosíntesis , Mucosa Respiratoria/microbiología , Mucosa Respiratoria/patología , Receptor Toll-Like 4/biosíntesis
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