Publications
157 results found
Ritchie AI, Jackson DJ, Edwards MR, et al., 2016, Airway epithelial orchestration of innate immune function in response to virus infection. A focus on asthma, Annals of the American Thoracic Society, Vol: 13 Suppl 1, Pages: S55-S63, ISSN: 2329-6933
Smits HH, Hiemstra PS, Prazeres da Costa C, et al., 2016, Microbes and asthma: Opportunities for intervention., J Allergy Clin Immunol, Vol: 137, Pages: 690-697
The worldwide incidence and prevalence of asthma continues to increase. Asthma is now understood as an umbrella term for different phenotypes or endotypes, which arise through different pathophysiologic pathways. Understanding the many factors contributing to development of the disease is important for the identification of novel therapeutic targets for the treatment of certain asthma phenotypes. The hygiene hypothesis has been formulated to explain the increasing prevalence of allergic disease, including asthma. This hypothesis postulates that decreased exposure at a young age to certain infectious agents as a result of improved hygiene, increased antibiotic use and vaccination, and changes in lifestyle and dietary habits is associated with changes in the immune system, which predispose subjects to allergy. Many microbes, during their coevolution with human subjects, developed mechanisms to manipulate the human immune system and to increase their chances of survival. Improving models of asthma, as well as choosing adequate end points in clinical trials, will lead to a more complete understanding of the underlying mechanisms, thus providing an opportunity to devise primary and secondary interventions at the same time as identifying new molecular targets for treatment. This article reports the discussion and conclusion of a workshop under the auspices of the Netherlands Lung Foundation to extend our understanding of how modulation of the immune system by bacterial, parasitic, and viral infections might affect the development of asthma and to map out future lines of investigation.
Stokes CA, Kaur R, Edwards MR, et al., 2016, Human rhinovirus-induced inflammatory responses are inhibited by phosphatidylserine containing liposomes, Mucosal Immunology, Vol: 9, Pages: 1303-1316, ISSN: 1935-3456
Human rhinovirus (HRV) infections are major contributors to the healthcare burden associated with acute exacerbations of chronic airway disease, such as chronic obstructive pulmonary disease and asthma. Cellular responses to HRV are mediated through pattern recognition receptors that may in part signal from membrane microdomains. We previously found Toll-like receptor signaling is reduced, by targeting membrane microdomains with a specific liposomal phosphatidylserine species, 1-stearoyl-2-arachidonoyl-sn-glycero-3-phospho-L-serine (SAPS). Here we explored the ability of this approach to target a clinically important pathogen. We determined the biochemical and biophysical properties and stability of SAPS liposomes and studied their ability to modulate rhinovirus-induced inflammation, measured by cytokine production, and rhinovirus replication in both immortalized and normal primary bronchial epithelial cells. SAPS liposomes rapidly partitioned throughout the plasma membrane and internal cellular membranes of epithelial cells. Uptake of liposomes did not cause cell death, but was associated with markedly reduced inflammatory responses to rhinovirus, at the expense of only modest non-significant increases in viral replication, and without impairment of interferon receptor signaling. Thus using liposomes of phosphatidylserine to target membrane microdomains is a feasible mechanism for modulating rhinovirus-induced signaling, and potentially a prototypic new therapy for viral-mediated inflammation.Mucosal Immunology advance online publication, 24 February 2016; doi:10.1038/mi.2015.137.
Edwards MR, Facchinetti F, Civelli M, et al., 2016, Anti-inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus-inducible cytokines, Pharmacology Research and Perspectives, Vol: 4, ISSN: 2052-1707
Respiratory virus infections precipitate asthma and chronic obstructive pulmonary disease (COPD) exacerbations, with most exacerbations due to rhinovirus infection. Both asthma and COPD exacerbations are not well controlled by steroid therapies, and there is a much research interest in finding improved therapies or combinations of therapies for controlling exacerbations. CHF6001 is a new, inhaled highly potent and selective phosphodiesterase type 4 (PDE4) inhibitor. Using in vitro human bronchial epithelial cells (BEAS-2B), we investigated the potential anti-inflammatory effects of CHF6001 on rhinovirus (RV1B)-induced cytokines. Cytokine mRNA was measured by real-time PCR, while protein release was measured by ELISA. CHF6001 was used in a 7-point dose–response curve (1000–0.001 nmol/L) as a 1.5-h pretreatment prior to infection in comparison with roflumilast. Both roflumilast and CHF6001 reduced RV1B-induced IL-8, IL-29, IP-10, and RANTES mRNA and protein in a concentration-dependent manner. Generally, CHF6001 was 13- to 16-fold more potent (subnanomolar EC50 values) than roflumilast at reducing IL-8, IL-29, IP-10, and RANTES mRNA and protein release, but had similar efficacies. In combination with the steroid fluticasone propionate (1 nmol/L), CHF6001 had additive effects, significantly reducing RV-induced cytokines when compared with steroid or CHF6001 alone. Combined low-dose steroid and low-dose CHF6001 had a similar efficacy as high-dose steroid or CHF6001 alone, indicating the combination had steroid and PDE4 inhibitor sparing effects. Overall results indicate that PDE4 inhibitors have anti-inflammatory activity against virus-induced inflammatory mediators and that CHF6001 is more potent than roflumilast.
Edwards MR, Porter JD, Khaitov M, et al., 2016, Azithromycin Augments Rv-Induced Type I And Type Iii Interferon Production Via Interaction With Mavs, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Johnston S, Edwards MR, Schwarze J, et al., 2016, Where Next In Asthma Research? A Review Of Current Understanding And Future Focus To Prevent And Cure Asthma, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
- Author Web Link
- Cite
- Citations: 1
Hilzendeger C, Da Silva J, Schleich FN, et al., 2016, Reduction Of Interferon-Stimulated Genes In COPD Prone To Exacerbation, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Finney LJ, Belchamber KBR, Edwards MR, et al., 2016, Rhinovirus Impairs Phagocytosis Of Bacteria By Monocyte Derived Macrophages In Chronic Obstructive Pulmonary Disease, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Dhariwal J, Cameron A, Trujillo-Torralbo B, et al., 2016, Novel Nasal Sampling Techniques Identify Ilc2s As Important Responders In Asthma During Nasal Allergen Challenge, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
- Author Web Link
- Cite
- Citations: 2
Almond MH, Bakhsoliani E, Edwards MR, et al., 2016, Airway C-Reactive Protein Levels Correlate Positively With Body Mass Index, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Schögler A, Stokes AB, Casaulta C, et al., 2015, Interferon response of the cystic fibrosis bronchial epithelium to major and minor group rhinovirus infection, Journal of Cystic Fibrosis, Vol: 15, Pages: 332-339, ISSN: 1873-5010
Rhinoviruses (RVs) are associated with exacerbations of cystic fibrosis (CF), asthma and COPD. There is growing evidence suggesting the involvement of the interferon (IFN) pathway in RV-associated morbidity in asthma and COPD. The mechanisms of RV-triggered exacerbations in CF are poorly understood. In a pilot study, we assessed the antiviral response of CF and healthy bronchial epithelial cells (BECs) to RV infection, we measured the levels of IFNs, pattern recognition receptors (PRRs) and IFN-stimulated genes (ISGs) upon infection with major and minor group RVs and poly(IC) stimulation. Major group RV infection of CF BECs resulted in a trend towards a diminished IFN response at the level of IFNs, PRRs and ISGs in comparison to healthy BECs. Contrary to major group RV, the IFN pathway induction upon minor group RV infection was significantly increased at the level of IFNs and PRRs in CF BECs compared to healthy BECs.
Schoegler A, Stokes AB, Casaulta C, et al., 2015, Differential interferon response of the cystic fibrosis bronchial epithelium to major and minor group rhinovirus infection, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Toussaint M, Jackson DJ, Edwards MR, et al., 2015, Role of dsDNA in rhinovirus-induced allergic asthma exacerbations, Congress of the European-Academy-of-Allergy-and-Clinical-Immunology, Publisher: WILEY-BLACKWELL, Pages: 219-219, ISSN: 0105-4538
Moskwa S, Piotrowski W, Marczak J, et al., 2015, Expression of interferon λ1 and interferon regulatory factor 7 (IRF7) in response to parainfluenza virus 3 (PIV-3) infection in primary bronchial epithelial cells (BECs) from patients with various asthma phenotypes, Congress of the European-Academy-of-Allergy-and-Clinical-Immunology, Publisher: WILEY-BLACKWELL, Pages: 23-24, ISSN: 0105-4538
Jackson DJ, Trujillo-Torralbo M-B, del-Rosario J, et al., 2015, The influence of asthma control on the severity of virus-induced asthma exacerbations, Journal of Allergy and Clinical Immunology, Vol: 136, Pages: 497-500.e3, ISSN: 1097-6825
Gielen V, Sykes A, Zhu J, et al., 2015, Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons, Journal of Allergy and Clinical Immunology, Vol: 136, Pages: 177-188e.11, ISSN: 1097-6825
BackgroundRhinovirus infections are the dominant cause of asthma exacerbations, and deficient virus induction of IFN-α/β/λ in asthmatic patients is important in asthma exacerbation pathogenesis. Mechanisms causing this interferon deficiency in asthmatic patients are unknown.ObjectiveWe sought to investigate the expression of suppressor of cytokine signaling (SOCS) 1 in tissues from asthmatic patients and its possible role in impaired virus-induced interferon induction in these patients.MethodsWe assessed SOCS1 mRNA and protein levels in vitro, bronchial biopsy specimens, and mice. The role of SOCS1 was inferred by proof-of-concept studies using overexpression with reporter genes and SOCS1-deficient mice. A nuclear role of SOCS1 was shown by using bronchial biopsy staining, overexpression of mutant SOCS1 constructs, and confocal microscopy. SOCS1 levels were also correlated with asthma-related clinical outcomes.ResultsWe report induction of SOCS1 in bronchial epithelial cells (BECs) by asthma exacerbation–related cytokines and by rhinovirus infection in vitro. We found that SOCS1 was increased in vivo in bronchial epithelium and related to asthma severity. SOCS1 expression was also increased in primary BECs from asthmatic patients ex vivo and was related to interferon deficiency and increased viral replication. In primary human epithelium, mouse lung macrophages, and SOCS1-deficient mice, SOCS1 suppressed rhinovirus induction of interferons. Suppression of virus-induced interferon levels was dependent on SOCS1 nuclear translocation but independent of proteasomal degradation of transcription factors. Nuclear SOCS1 levels were also increased in BECs from asthmatic patients.ConclusionWe describe a novel mechanism explaining interferon deficiency in asthmatic patients through a novel nuclear function of SOCS1 and identify SOCS1 as an important therapeutic target for asthma exacerbations.
Edwards MR, Brouwer W, Choi CH, et al., 2015, Analysis of IgE antibodies from a patient with atopic dermatitis: biased V gene usage and evidence for polyreactive IgE heavy chain complementarity-determining region 3., Jounal of Immunology, Vol: 168, Pages: 6305-6313
Jackson DJ, Glanville N, Trujillo-Torralbo M-B, et al., 2015, Interleukin-18 Is Associated With Protection Against Rhinovirus-Induced Colds and Asthma Exacerbations, Clinical Infectious Diseases, Vol: 60, Pages: 1528-1531, ISSN: 1537-6591
Rhinoviruses cause the common cold and exacerbations of asthma. Animal models of infection have identified a protective role for interleukin-18 (IL-18). Following experimental rhinovirus infection, we observed increased respiratory symptoms in healthy and asthmatic subjects with low nasal and bronchial IL-18 levels.
Contoli M, Ito K, Padovani A, et al., 2015, Th2 cytokines impair innate immune responses to rhinovirus in respiratory epithelial cells, Allergy, Vol: 70, Pages: 910-920, ISSN: 0105-4538
BackgroundAsthma and other Th2 inflammatory conditions have been associated with increased susceptibility to viral infections. The mechanisms by which Th2 cytokines can influence immune responses to infections are largely unknown.MethodsWe measured the effects of Th2 cytokines (IL-4 and IL-13) on bronchial epithelial cell innate immune antiviral responses by assessing interferon (IFN-β and IFN-λ1) induction following rhinovirus (RV)-16 infection. We also investigated the modulatory effects of Th2 cytokines on Toll-like receptor 3 (TLR3), interferon-responsive factor 3 (IRF3) and nuclear factor (NF)-kB, that is key molecules and transcription factors involved in the rhinovirus-induced interferon production and inflammatory cascade. Pharmacological and redox modulation of these pathways was also assessed.ResultsTh2 cytokines impaired RV-16-induced interferon production, increased rhinovirus replication and impaired TLR3 expression in bronchial epithelial cells. These results were replicated in vivo: we found increased IL-4 mRNA levels in nasal epithelial cells from nasal brushing of atopic rhinitis patients and a parallel reduction in TLR3 expression and increased RV-16 replication compared to nonatopic subjects. Mechanistically, Th2 cytokines impaired RV-16-induced activation of IRF3, but had no effects on RV-16-induced NF-kB activation in bronchial epithelial cell cultures. N-acetylcysteine and phosphoinositide 3-kinase (PI3K) inhibitor restored the inhibitory effects of Th2 cytokines over RV-16-induced activation of IRF3.ConclusionsIL-4 and IL-13, through inhibition of TLR3 expression and signalling (IRF3), impair immune response to RV-16 infection. These data suggest that Th2 conditions increase susceptibility to infections and identify pharmacological approaches with potential to restore impaired immune response in these conditions.
Schogler A, Kopf BS, Edwards MR, et al., 2015, Novel antiviral properties of azithromycin in cystic fibrosis airway epithelial cells, EUROPEAN RESPIRATORY JOURNAL, Vol: 45, Pages: 428-439, ISSN: 0903-1936
- Author Web Link
- Cite
- Citations: 105
Almond MH, Bakhsoliani E, Edwards MR, et al., 2015, Obesity Is Associated With Decreased Expression Of Suppressor Of Cytokine Signalling 3 In Human Alveolar Macrophages, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Edwards MR, 2014, Effects of Th2 inflammation on the anti-viral response in rhinovirus infection, IMMUNOLOGY, Vol: 143, Pages: 3-3, ISSN: 0019-2805
Jackson DJ, Makrinioti H, Rana BMJ, et al., 2014, IL-33-dependent Type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo, American Journal of Respiratory and Critical Care Medicine, Vol: 190, Pages: 1373-1382, ISSN: 1535-4970
Rationale: Rhinoviruses are the major cause of asthmaexacerbations; however, its underlying mechanisms are poorlyunderstood. We hypothesized that the epithelial cell–derivedcytokine IL-33 plays a central role in exacerbation pathogenesisthrough augmentation of type 2 inflammation.Objectives: To assess whether rhinovirus induces a type 2inflammatory response in asthma in vivo and to define a role for IL-33in this pathway.Methods: We used a human experimental model of rhinovirusinfection and novel airway sampling techniques to measure IL-4, IL-5,IL-13, and IL-33 levels in the asthmatic and healthy airways duringa rhinovirus infection. Additionally, we cultured human T cells and type2 innate lymphoid cells (ILC2s) with the supernatants of rhinovirusinfectedbronchial epithelial cells (BECs) to assess type 2 cytokineproduction in the presence or absence of IL-33 receptor blockade.Measurements and Main Results: IL-4, IL-5, IL-13, and IL-33 areall induced by rhinovirus in the asthmatic airway in vivo and relate toexacerbation severity. Further, induction of IL-33 correlates withviral load and IL-5 and IL-13 levels. Rhinovirus infection of humanprimary BECs induced IL-33, and culture of human T cells and ILC2swith supernatants of rhinovirus-infected BECs strongly inducedtype 2 cytokines. This induction was entirely dependent on IL-33.Conclusions: IL-33 and type 2 cytokines are induced duringa rhinovirus-induced asthma exacerbation in vivo. Virus-inducedIL-33 and IL-33–responsive T cells and ILC2s are key mechanisticlinks between viral infection and exacerbation of asthma. IL-33inhibition is a novel therapeutic approach for asthma exacerbations
Beale J, Jayaraman A, Jackson DJ, et al., 2014, Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation, Science Translational Medicine, Vol: 6, ISSN: 1946-6234
Rhinoviruses (RVs), which are the most common cause of virally induced asthma exacerbations, account for much of the burden of asthma in terms of morbidity, mortality, and associated cost. Interleukin-25 (IL-25) activates type 2–driven inflammation and is therefore potentially important in virally induced asthma exacerbations. To investigate this, we examined whether RV-induced IL-25 could contribute to asthma exacerbations. RV-infected cultured asthmatic bronchial epithelial cells exhibited a heightened intrinsic capacity for IL-25 expression, which correlated with donor atopic status. In vivo human IL-25 expression was greater in asthmatics at baseline and during experimental RV infection. In addition, in mice, RV infection induced IL-25 expression and augmented allergen-induced IL-25. Blockade of the IL-25 receptor reduced many RV-induced exacerbation-specific responses including type 2 cytokine expression, mucus production, and recruitment of eosinophils, neutrophils, basophils, and T and non-T type 2 cells. Therefore, asthmatic epithelial cells have an increased intrinsic capacity for expression of a pro–type 2 cytokine in response to a viral infection, and IL-25 is a key mediator of RV-induced exacerbations of pulmonary inflammation.
Jayaraman A, Jackson DJ, Message SD, et al., 2014, IL-15 complexes induce NK- and T-cell responses independent of type I IFN signaling during rhinovirus infection, MUCOSAL IMMUNOLOGY, Vol: 7, Pages: 1151-1164, ISSN: 1933-0219
Rhinoviruses are among the most common viruses to infect man, causing a range of serious respiratory diseases including exacerbations of asthma and COPD. Type I IFN and IL-15 are thought to be required for antiviral immunity; however, their function during rhinovirus infection in vivo is undefined. In RV-infected human volunteers, IL-15 protein expression in fluid from the nasal mucosa and in bronchial biopsies was increased. In mice, RV induced type I IFN-dependent expressions of IL-15 and IL-15Rα, which in turn were required for NK- and CD8+ T-cell responses. Treatment with IL-15–IL-15Rα complexes (IL-15c) boosted RV-induced expression of IL-15, IL-15Rα, IFN-γ, CXCL9, and CXCL10 followed by recruitment of activated, IFN-γ-expressing NK, CD8+, and CD4+ T cells. Treating infected IFNAR1−/− mice with IL-15c similarly increased IL-15, IL-15Rα, IFN-γ, and CXCL9 (but not CXCL10) expression also followed by NK-, CD8+-, and CD4+-T-cell recruitment and activation. We have demonstrated that type I IFN-induced IFN-γ and cellular immunity to RV was mediated by IL-15 and IL-15Rα. Importantly, we also show that IL-15 could be induced via a type I IFN-independent mechanism by IL-15 complex treatment, which in turn was sufficient to drive IFN-γ expression and lymphocyte responses.
Wong EHC, Porter JD, Edwards MR, et al., 2014, The role of macrolides in asthma: current evidence and future directions, LANCET RESPIRATORY MEDICINE, Vol: 2, Pages: 657-670, ISSN: 2213-2600
- Author Web Link
- Cite
- Citations: 76
Rohde G, Message SD, Haas JJ, et al., 2014, CXC chemokines and antimicrobial peptides in rhinovirus-induced experimental asthma exacerbations, CLINICAL AND EXPERIMENTAL ALLERGY, Vol: 44, Pages: 930-939, ISSN: 0954-7894
- Author Web Link
- Open Access Link
- Cite
- Citations: 42
Reed DM, Foldes G, Gatheral T, et al., 2014, Pathogen Sensing Pathways in Human Embryonic Stem Cell Derived-Endothelial Cells: Role of NOD1 Receptors, PLOS One, Vol: 9, ISSN: 1932-6203
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.
Sykes A, Macintyre J, Edwards MR, et al., 2014, Rhinovirus-induced interferon production is not deficient in well controlled asthma, THORAX, Vol: 69, Pages: 240-246, ISSN: 0040-6376
- Author Web Link
- Cite
- Citations: 109
Jackson DJ, Shamji B, Trujillo-Torralbo M-B, et al., 2014, Prostaglandin D2 Is Induced During Rhinovirus-Induced Asthma Exacerbations And Related To Exacerbation Severity In Vivo, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 189, ISSN: 1073-449X
- Author Web Link
- Cite
- Citations: 1
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.