188 results on '"Staples, Karl J."'
Search Results
2. Patient perceived barriers to exercise and their clinical associations in difficult asthma
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Freeman, Anna T., Hill, David, Newell, Colin, Moyses, Helen, Azim, Adnan, Knight, Deborah, Presland, Laura, Harvey, Matthew, Haitchi, Hans Michael, Watson, Alastair, Staples, Karl J., Kurukulaaratchy, Ramesh J., and Wilkinson, Tom M. A.
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- 2020
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3. Innate and adaptive T cells in asthmatic patients: Relationship to severity and disease mechanisms
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Hinks, Timothy S.C., Zhou, Xiaoying, Staples, Karl J., Dimitrov, Borislav D., Manta, Alexander, Petrossian, Tanya, Lum, Pek Y., Smith, Caroline G., Ward, Jon A., Howarth, Peter H., Walls, Andrew F., Gadola, Stephan D., and Djukanović, Ratko
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- 2015
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4. Multitissue Transcriptomics Delineates the Diversity of Airway T Cell Functions in Asthma
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Singhania, Akul, Wallington, Joshua C., Smith, Caroline G., Horowitz, Daniel, Staples, Karl J., Howarth, Peter H., Gadola, Stephan D., Djukanović, Ratko, Woelk, Christopher H., and Hinks, Timothy S. C.
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- 2018
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5. Making a bad relationship good
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Staples, Karl J.
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- 2019
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6. Development of flow cytometric opsonophagocytosis and antibody-mediated complement deposition assays for non-typeable Haemophilus influenzae
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Thomas, Stephen R., Leung, Stephanie, Knox, Katy, Wilkinson, Tom M. A., Staples, Karl J., Lestrate, Pascal, Wauters, Dominique, Gorringe, Andrew, and Taylor, Stephen C.
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- 2018
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7. Impact of radiologically stratified exacerbations: insights into pneumonia aetiology in COPD
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Williams, Nicholas P., Ostridge, Kristoffer, Devaster, Jeanne-Marie, Kim, Viktoriya, Coombs, Ngaire A., Bourne, Simon, Clarke, Stuart C., Harden, Stephen, Abbas, Ausami, Aris, Emmanuel, Lambert, Christophe, Tuck, Andrew, Williams, Anthony, Wootton, Stephen, Staples, Karl J., Wilkinson, Tom M. A., and on behalf of the AERIS Study Group
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- 2018
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8. Relationship of CT-quantified emphysema, small airways disease and bronchial wall dimensions with physiological, inflammatory and infective measures in COPD
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Ostridge, Kristoffer, Williams, Nicholas P., Kim, Viktoriya, Harden, Stephen, Bourne, Simon, Clarke, Stuart C., Aris, Emmanuel, Mesia-Vela, Sonia, Devaster, Jeanne-Marie, Tuck, Andrew, Williams, Anthony, Wootton, Stephen, Staples, Karl J., Wilkinson, Tom M. A., and on behalf of the AERIS Study Group
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- 2018
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9. A prospective, observational cohort study of the seasonal dynamics of airway pathogens in the aetiology of exacerbations in COPD
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Wilkinson, Tom M A, Aris, Emmanuel, Bourne, Simon, Clarke, Stuart C, Peeters, Mathieu, Pascal, Thierry G, Schoonbroodt, Sonia, Tuck, Andrew C, Kim, Viktoriya, Ostridge, Kristoffer, Staples, Karl J, Williams, Nicholas, Williams, Anthony, Wootton, Stephen, and Devaster, Jeanne-Marie
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- 2017
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10. IFN-γ Influences Epithelial Antiviral Responses via Histone Methylation of the RIG-I Promoter
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Spalluto, Mirella C., Singhania, Akul, Cellura, Doriana, Woelk, Christopher H., Sanchez-Elsner, Tilman, Staples, Karl J., and Wilkinson, Tom M. A.
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- 2017
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11. Antiviral Responses of Tissue-resident CD49a1 Lung Natural Killer Cells Are Dysregulated in Chronic Obstructive Pulmonary Disease.
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Cooper, Grace E., Mayall, Jemma, Donovan, Chantal, Haw, Tatt J., Budden, Kurtis F., Hansbro, Nicole G., Blomme, Evy E., Maes, Tania, Chia Wei Kong, Horvat, Jay C., Khakoo, Salim I., Wilkinson, Tom M. A., Hansbro, Philip M., and Staples, Karl J.
- Abstract
Rationale: Tissue-resident natural killer (trNK) cells have been identified in numerous organs, but little is known about their functional contribution to respiratory immunity, in particular during chronic lung diseases such as chronic obstructive pulmonary disease (COPD). Objectives: To investigate the phenotype and antiviral responses of trNK cells in murine cigarette smoke–induced experimental COPD and in human lung parenchyma from COPD donors. Methods: Mice were exposed to cigarette smoke for 12 weeks to induce COPD-like lung disease. Lung trNK cell phenotypes and function were analyzed by flow cytometry in both murine and human disease with and without challenge with influenza A virus. Measurements and Main Results: In the mouse lung, CD49a
+ CD49b+ EOMES+ and CD49a+ CD49b- EOMESlo NK cell populations had a distinct phenotype compared with CD49a- circulating NK cells. CD49a+ NK cells were more extensively altered earlier in disease onset than circulating NK cells, and increased proportions of CD49a+ NK cells correlated with worsening disease in both murine and human COPD. Furthermore, the presence of lung disease delayed both circulating and trNK cell functional responses to influenza infection. CD49a+ NK cells markedly increased their NKG2D, CD103, and CD69 expression in experimental COPD after influenza infection, and human CD49a+ NK cells were hyperactive to ex vivo influenza infection in COPD donors. Conclusions: Collectively, these results demonstrate that trNK cell function is altered in cigarette smoke–induced disease and suggests that smoke exposure may aberrantly prime trNK cell responsiveness to viral infection. This may contribute to excess inflammation during viral exacerbations of COPD. [ABSTRACT FROM AUTHOR]- Published
- 2023
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12. Monocyte-derived macrophages matured under prolonged hypoxia transcriptionally up-regulate HIF-1α mRNA
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Staples, Karl J., Sotoodehnejadnematalahi, Fattah, Pearson, Helen, Frankenberger, Marion, Francescut, Lorenza, Ziegler-Heitbrock, Loems, and Burke, Bernard
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- 2011
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13. A Deletion Defining a Common Asian Lineage of Mycobacterium tuberculosis Associates with Immune Subversion
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Newton, Sandra M., Smith, Rebecca J., Wilkinson, Katalin A., Nicol, Mark P., Garton, Natalie J., Staples, Karl J., Stewar, Graham R., Wain, John R., Martineau, Adrian R., Fandrich, Sarah, Smallie, Timothy, Foxwell, Brian, Al-Obaidi, Ahmed, Shafi, Jamila, Rajakumar, Kumar, Kampmann, Beate, Andrew, Peter W., Ziegler-Heitbrock, Loems, Barer, Michael R., and Wilkinson, Robert J.
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- 2006
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14. Dysregulation of Antiviral Function of CD8+ T Cells in the Chronic Obstructive Pulmonary Disease Lung. Role of the PD-1-PD-L1 Axis
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McKendry, Richard T., Spalluto, Mirella C., Burke, Hannah, Nicholas, Ben, Cellura, Doriana, Al-Shamkhani, Aymen, Staples, Karl J., and Wilkinson, Tom M. A.
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- 2016
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15. Relationship between pulmonary matrix metalloproteinases and quantitative CT markers of small airways disease and emphysema in COPD
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Ostridge, Kristoffer, Williams, Nicholas, Kim, Viktoriya, Bennett, Michael, Harden, Stephen, Welch, Lindsay, Bourne, Simon, Coombs, Ngaire A, Elkington, Paul T, Staples, Karl J, and Wilkinson, Tom MA
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- 2016
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16. Mechanism of Interferon-gamma mediated down-regulation of Interleukin-10 gene expression
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Schaefer, Annette, Unterberger, Claudia, Frankenberger, Marion, Lohrum, Marion, Staples, Karl J., Werner, Thomas, Stunnenberg, Henk, and Ziegler-Heitbrock, Loems
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- 2009
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17. Nontypeable Haemophilus influenzae infection of pulmonary macrophages drives neutrophilic inflammation in severe asthma.
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Ackland, Jodie, Barber, Clair, Heinson, Ashley, Azim, Adnan, Cleary, David W., Christodoulides, Myron, Kurukulaaratchy, Ramesh J., Howarth, Peter, Wilkinson, Tom M. A., and Staples, Karl J.
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HAEMOPHILUS diseases ,HAEMOPHILUS influenzae ,LUNG infections ,ASTHMATICS ,MACROPHAGES - Abstract
Background: Nontypeable Haemophilus influenzae (NTHi) is a respiratory tract pathobiont that chronically colonizes the airways of asthma patients and is associated with severe, neutrophilic disease phenotypes. The mechanism of NTHi airway persistence is not well understood, but accumulating evidence suggests NTHi can persist within host airway immune cells such as macrophages. We hypothesized that NTHi infection of pulmonary macrophages drives neutrophilic inflammation in severe asthma. Methods: Bronchoalveolar lavage (BAL) samples from 25 severe asthma patients were assessed by fluorescence in situ hybridisation to quantify NTHi presence. Weighted gene correlation network analysis (WGCNA) was performed on RNASeq data from NTHi‐infected monocyte‐derived macrophages to identify transcriptomic networks associated with NTHi infection. Results: NTHi was detected in 56% of BAL samples (NTHi+) and was associated with longer asthma duration (34 vs 22.5 years, p =.0436) and higher sputum neutrophil proportion (67% vs 25%, p =.0462). WGCNA identified a transcriptomic network of immune‐related macrophage genes significantly associated with NTHi infection, including upregulation of T17 inflammatory mediators and neutrophil chemoattractants IL1B, IL8, IL23 and CCL20 (all p <.05). Macrophage network genes SGPP2 (p =.0221), IL1B (p =.0014) and GBP1 (p =.0477) were more highly expressed in NTHi+ BAL and moderately correlated with asthma duration (IL1B; rho = 0.41, p =.041) and lower prebronchodilator FEV1/FVC% (GBP1; rho = −0.43, p =.046 and IL1B; rho = −0.42, p =.055). Conclusions: NTHi persistence with pulmonary macrophages may contribute to chronic airway inflammation and T17 responses in severe asthma, which can lead to decreased lung function and reduced steroid responsiveness. Identifying therapeutic strategies to reduce the burden of NTHi in asthma could improve patient outcomes. [ABSTRACT FROM AUTHOR]
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- 2022
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18. Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans
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Wilkinson, Tom M, Li, Chris K F, Chui, Cecilia S C, Huang, Arthur K Y, Perkins, Molly, Liebner, Julia C, Lambkin-Williams, Rob, Gilbert, Anthony, Oxford, John, Nicholas, Ben, Staples, Karl J, Dong, Tao, Douek, Daniel C, McMichael, Andrew J, and Xu, Xiao-Ning
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- 2012
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19. Role of STAT3 in glucocorticoid-induced expression of the human IL-10 gene
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Unterberger, Claudia, Staples, Karl J., Smallie, Timothy, Williams, Lynn, Foxwell, Brian, Schaefer, Annette, Kempkes, Bettina, Hofer, T.P.J., Koeppel, Max, Lohrum, Marion, Stunnenberg, Henk, Frankenberger, Marion, and Ziegler-Heitbrock, Loems
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- 2008
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20. Expression of p57-Kip2 in monocytes and macrophages
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Hofer, Thomas P.J., Frankenberger, Marion, Staples, Karl J., and Ziegler-Heitbrock, Löms
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- 2006
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21. Coadministration of the cyanobacterial lipopolysaccharide antagonist CyP with antibiotic inhibits cytokine production by an in vitro meningitis model infected with Neisseria meningitidis
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Oliver, Rebecca, Staples, Karl J., Heckels, John, Rossetti, Carlo, Molteni, Monica, and Christodoulides, Myron
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- 2012
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22. Immunopeptidomic analysis of influenza A virus infected human tissues identifies internal proteins as a rich source of HLA ligands.
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Nicholas, Ben, Bailey, Alistair, Staples, Karl J., Wilkinson, Tom, Elliott, Tim, and Skipp, Paul
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INFLUENZA ,T cells ,VIRAL proteins ,INFLUENZA A virus ,EXTRACELLULAR matrix proteins ,IMMUNOGLOBULIN producing cells ,INFLUENZA viruses - Abstract
CD8+ and CD4+ T cells provide cell-mediated cross-protection against multiple influenza strains by recognising epitopes bound as peptides to human leukocyte antigen (HLA) class I and -II molecules respectively. Two challenges in identifying the immunodominant epitopes needed to generate a universal T cell influenza vaccine are: A lack of cell models susceptible to influenza infection which present population-prevalent HLA allotypes, and an absence of a reliable in-vitro method of identifying class II HLA peptides. Here we present a mass spectrometry-based proteomics strategy for identifying viral peptides derived from the A/H3N2/X31 and A/H3N2/Wisconsin/67/2005 strains of influenza. We compared the HLA-I and -II immunopeptidomes presented by ex-vivo influenza challenged human lung tissues. We then compared these with directly infected immortalised macrophage-like cell line (THP1) and primary dendritic cells fed apoptotic influenza-infected respiratory epithelial cells. In each of the three experimental conditions we identified novel influenza class I and II HLA peptides with motifs specific for the host allotype. Ex-vivo infected lung tissues yielded few class-II HLA peptides despite significant numbers of alveolar macrophages, including directly infected ones, present within the tissues. THP1 cells presented HLA-I viral peptides derived predominantly from internal proteins. Primary dendritic cells presented predominantly viral envelope-derived HLA class II peptides following phagocytosis of apoptotic infected cells. The most frequent viral source protein for HLA-I and -II was matrix 1 protein (M1). This work confirms that internal influenza proteins, particularly M1, are a rich source of CD4+ and CD8+ T cell epitopes. Moreover, we demonstrate the utility of two ex-vivo fully human infection models which enable direct HLA-I and -II immunopeptide identification without significant viral tropism limitations. Application of this epitope discovery strategy in a clinical setting will provide more certainty in rational vaccine design against influenza and other emergent viruses. Author summary: Influenza infections present a significant global health challenge. High rates of mutation require reformulation of vaccines annually. Vaccines are designed to induce antibody responses to the surface proteins of the influenza virus, but the contribution of T cells to overall immunity is unclear. Here, we used several totally human laboratory models to show how the viral proteins are presented to the T cells to induce immunity. We found that CD8 T cells, which kill infected cells, and CD4 T cells which support the CD8 T cells as well as the antibody-producing B cells, mainly see proteins from inside the viral particle, not the surface ones which are targeted by antibodies. These internal viral proteins are more similar between different viral strains than the surface proteins, and therefore suggest that vaccines designed to induce T cell responses could be better protective if they target internal viral proteins. [ABSTRACT FROM AUTHOR]
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- 2022
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23. The Role of Extracellular Vesicles as a Shared Disease Mechanism Contributing to Multimorbidity in Patients With COPD.
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Reid, Laura V., Spalluto, C. Mirella, Watson, Alastair, Staples, Karl J., and Wilkinson, Tom M. A.
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EXTRACELLULAR vesicles ,CHRONIC obstructive pulmonary disease ,COMORBIDITY ,DISEASE risk factors ,NON-coding RNA ,CHRONIC bronchitis ,IDIOPATHIC pulmonary fibrosis - Abstract
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide. Individuals with COPD typically experience a progressive, debilitating decline in lung function as well as systemic manifestations of the disease. Multimorbidity, is common in COPD patients and increases the risk of hospitalisation and mortality. Central to the genesis of multimorbidity in COPD patients is a self-perpetuating, abnormal immune and inflammatory response driven by factors including ageing, pollutant inhalation (including smoking) and infection. As many patients with COPD have multiple concurrent chronic conditions, which require an integrative management approach, there is a need to greater understand the shared disease mechanisms contributing to multimorbidity. The intercellular transfer of extracellular vesicles (EVs) has recently been proposed as an important method of local and distal cell-to-cell communication mediating both homeostatic and pathological conditions. EVs have been identified in many biological fluids and provide a stable capsule for the transfer of cargo including proteins, lipids and nucleic acids. Of these cargo, microRNAs (miRNAs), which are short 17-24 nucleotide non-coding RNA molecules, have been amongst the most extensively studied. There is evidence to support that miRNA are selectively packaged into EVs and can regulate recipient cell gene expression including major pathways involved in inflammation, apoptosis and fibrosis. Furthermore changes in EV cargo including miRNA have been reported in many chronic diseases and in response to risk factors including respiratory infections, noxious stimuli and ageing. In this review, we discuss the potential of EVs and EV-associated miRNA to modulate shared pathological processes in chronic diseases. Further delineating these may lead to the identification of novel biomarkers and therapeutic targets for patients with COPD and multimorbidities. [ABSTRACT FROM AUTHOR]
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- 2021
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24. Dual RNASeq Reveals NTHi-Macrophage Transcriptomic Changes During Intracellular Persistence.
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Ackland, Jodie, Heinson, Ashley I., Cleary, David W., Christodoulides, Myron, Wilkinson, Tom M. A., and Staples, Karl J.
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TRANSCRIPTOMES ,RNA sequencing ,TREATMENT effectiveness ,HAEMOPHILUS influenzae ,AIRWAY (Anatomy) ,RIBOSOMES - Abstract
Nontypeable Haemophilus influenzae (NTHi) is a pathobiont which chronically colonises the airway of individuals with chronic respiratory disease and is associated with poor clinical outcomes. It is unclear how NTHi persists in the airway, however accumulating evidence suggests that NTHi can invade and persist within macrophages. To better understand the mechanisms of NTHi persistence within macrophages, we developed an in vitro model of NTHi intracellular persistence using human monocyte-derived macrophages (MDM). Dual RNA Sequencing was used to assess MDM and NTHi transcriptomic regulation occurring simultaneously during NTHi persistence. Analysis of the macrophage response to NTHi identified temporally regulated transcriptomic profiles, with a specific 'core' profile displaying conserved expression of genes across time points. Gene list enrichment analysis identified enrichment of immune responses in the core gene set, with KEGG pathway analysis revealing specific enrichment of intracellular immune response pathways. NTHi persistence was facilitated by modulation of bacterial metabolic, stress response and ribosome pathways. Levels of NTHi genes bioC , mepM and dps were differentially expressed by intracellular NTHi compared to planktonic NTHi, indicating that the transcriptomic adaption was distinct between the two different NTHi lifestyles. Overall, this study provides crucial insights into the transcriptomic adaptations facilitating NTHi persistence within macrophages. Targeting these reported pathways with novel therapeutics to reduce NTHi burden in the airway could be an effective treatment strategy given the current antimicrobial resistance crisis and lack of NTHi vaccines. [ABSTRACT FROM AUTHOR]
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- 2021
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25. The Role of Non-Typeable Haemophilus influenzae Biofilms in Chronic Obstructive Pulmonary Disease.
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Weeks, Jake R., Staples, Karl J., Spalluto, C. Mirella, Watson, Alastair, and Wilkinson, Tom M. A.
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OBSTRUCTIVE lung diseases ,STREPTOCOCCUS pneumoniae ,HAEMOPHILUS influenzae ,MUCOCILIARY system ,QUORUM sensing ,RESPIRATORY mucosa ,MORAXELLA catarrhalis ,BIOFILMS - Abstract
Non-typeable Haemophilus influenzae (NTHi) is an ubiquitous commensal-turned-pathogen that colonises the respiratory mucosa in airways diseases including Chronic Obstructive Pulmonary Disease (COPD). COPD is a progressive inflammatory syndrome of the lungs, encompassing chronic bronchitis that is characterised by mucus hypersecretion and impaired mucociliary clearance and creates a static, protective, humid, and nutrient-rich environment, with dysregulated mucosal immunity; a favourable environment for NTHi colonisation. Several recent large COPD cohort studies have reported NTHi as a significant and recurrent aetiological pathogen in acute exacerbations of COPD. NTHi proliferation has been associated with increased hospitalisation, disease severity, morbidity and significant lung microbiome shifts. However, some cohorts with patients at different severities of COPD do not report that NTHi is a significant aetiological pathogen in their COPD patients, indicating other obligate pathogens including Moraxella catarrhalis, Streptococcus pneumoniae and Pseudomonas aeruginosa as the cause. NTHi is an ubiquitous organism across healthy non-smokers, healthy smokers and COPD patients from childhood to adulthood, but it currently remains unclear why NTHi becomes pathogenic in only some cohorts of COPD patients, and what behaviours, interactions and adaptations are driving this susceptibility. There is emerging evidence that biofilm-phase NTHi may play a significant role in COPD. NTHi displays many hallmarks of the biofilm lifestyle and expresses key biofilm formation-promoting genes. These include the autoinducer-mediated quorum sensing system, epithelial- and mucus-binding adhesins and expression of a protective, self-produced polymeric substance matrix. These NTHi biofilms exhibit extreme tolerance to antimicrobial treatments and the immune system as well as expressing synergistic interspecific interactions with other lung pathogens including S. pneumoniae and M. catarrhalis. Whilst the majority of our understanding surrounding NTHi as a biofilm arises from otitis media or in-vitro bacterial monoculture models, the role of NTHi biofilms in the COPD lung is now being studied. This review explores the evidence for the existence of NTHi biofilms and their impact in the COPD lung. Understanding the nature of chronic and recurrent NTHi infections in acute exacerbations of COPD could have important implications for clinical treatment and identification of novel bactericidal targets. [ABSTRACT FROM AUTHOR]
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- 2021
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26. Glucocorticoid Inhibition of Granulocyte Macrophage-Colony-Stimulating Factor from T cells Is Independent of Control by Nuclear Factor-κB and Conserved Lymphokine Element 0
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Bergmann, Martin W., Staples, Karl J., Smith, Susan J., Barnes, Peter J., and Newton, Robert
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- 2004
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27. Nuclear factor-κB does not mediate the inhibitory effects of dexamethasone on granulocyte–macrophage colony-stimulating factor expression
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BERGMANN, MARTIN W., STAPLES, KARL J., BARNES, PETER J., and NEWTON, ROBERT
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- 2004
28. Phenotypic characterization of lung macrophages in asthmatic patients: Overexpression of CCL17
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Staples, Karl J., Hinks, Timothy S.C., Ward, Jon A., Gunn, Victoria, Smith, Caroline, and Djukanović, Ratko
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- 2012
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29. Evidence for post-transcriptional regulation of interleukin-5 by dexamethasone
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STAPLES, KARL J., BERGMANN, MARTIN W., BARNES, PETER J., and NEWTON, ROBERT
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- 2003
30. Sputum processing by mechanical dissociation: A rapid alternative to traditional sputum assessment approaches.
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Barber, Clair, Lau, Laurie, Ward, Jonathan A., Daniels, Thomas, Watson, Alastair, Staples, Karl J., Wilkinson, Tom M. A., and Howarth, Peter H.
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SPUTUM ,CELL suspensions ,EOSINOPHILS - Abstract
Background: Sputum cytology is currently the gold standard to evaluate cellular inflammation in the airways and phenotyping patients with airways diseases. Sputum eosinophil proportions have been used to guide treatment for moderate to severe asthma. Furthermore, raised sputum neutrophils are associated with poor disease control and impaired lung function in both asthma and COPD and small airways disease in cystic fibrosis. However, induced‐sputum analysis is subjective and resource heavy, requiring dedicated specialist processing and assessment; this limits its utility in most clinical settings. Indirect blood eosinophil measures have been adopted in clinical care. However, there are currently no good peripheral blood biomarkers of airway neutrophils. A resource‐light sputum processing approach could thus help integrate induced sputum more readily into routine clinical care. New mechanical disruption (MD) methods can rapidly obtain viable single cell suspensions from sputum samples. Aims: The aim of this study was to compare MD sputum processing to traditional methods for cell viability, granulocyte proportions and sputum cytokine analysis. Methods: Sputum plugs were split and processed using traditional methods and the MD method, and samples were then compared. Results: The MD method produced a homogeneous cell suspension in 62 s; 70 min faster than the standard method used. No significant difference was seen between the cell viability (p = 0.09), or the concentration of eosinophils (p = 0.83), neutrophils (p = 0.99) or interleukin‐8 (p = 0.86) using MD. Conclusion: This cost‐effective method of sputum processing could provide a more pragmatic, sustainable means of directly monitoring the airway milieu. Therefore, we recommend this method be taken forward for further investigation. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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31. Dysregulation of COVID-19 related gene expression in the COPD lung.
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Watson, Alastair, Öberg, Lisa, Angermann, Bastian, Spalluto, C. Mirella, Hühn, Michael, Burke, Hannah, Cellura, Doriana, Freeman, Anna, Muthas, Daniel, Etal, Damla, Belfield, Graham, Karlsson, Fredrik, Nordström, Karl, Ostridge, Kris, Staples, Karl J., Wilkinson, Tom, the MICA II Studygroup, Angerman, Bastian, Ashenden, Stephanie, and Bawden, Sarah
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ANGIOTENSIN converting enzyme ,COVID-19 ,OBSTRUCTIVE lung diseases ,GENE expression ,CARDIOVASCULAR diseases - Abstract
Background: Chronic obstructive pulmonary disease (COPD) patients are at increased risk of poor outcome from Coronavirus disease (COVID-19). Early data suggest elevated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) receptor angiotensin converting enzyme 2 (ACE2) expression, but relationships to disease phenotype and downstream regulators of inflammation in the Renin-Angiotensin system (RAS) are unknown. We aimed to determine the relationship between RAS gene expression relevant to SARS-CoV-2 infection in the lung with disease characteristics in COPD, and the regulation of newly identified SARS-CoV-2 receptors and spike-cleaving proteases, important for SARS-CoV-2 infection.Methods: We quantified gene expression using RNA sequencing of epithelial brushings and bronchial biopsies from 31 COPD and 37 control subjects.Results: ACE2 gene expression (log2-fold change (FC)) was increased in COPD compared to ex-smoking (HV-ES) controls in epithelial brushings (0.25, p = 0.042) and bronchial biopsies (0.23, p = 0.050), and correlated with worse lung function (r = - 0.28, p = 0.0090). ACE2 was further increased in frequent exacerbators compared to infrequent exacerbators (0.51, p = 0.00045) and associated with use of ACE inhibitors (ACEi) (0.50, p = 0.0034), having cardiovascular disease (0.23, p = 0.048) or hypertension (0.34, p = 0.0089), and inhaled corticosteroid use in COPD subjects in bronchial biopsies (0.33, p = 0.049). Angiotensin II receptor type (AGTR)1 and 2 expression was decreased in COPD bronchial biopsies compared to HV-ES controls with log2FC of -0.26 (p = 0.033) and - 0.40, (p = 0.0010), respectively. However, the AGTR1:2 ratio was increased in COPD subjects compared with HV-ES controls, log2FC of 0.57 (p = 0.0051). Basigin, a newly identified potential SARS-CoV-2 receptor was also upregulated in both brushes, log2FC of 0.17 (p = 0.0040), and bronchial biopsies, (log2FC of 0.18 (p = 0.017), in COPD vs HV-ES. Transmembrane protease, serine (TMPRSS)2 was not differentially regulated between control and COPD. However, various other spike-cleaving proteases were, including TMPRSS4 and Cathepsin B, in both epithelial brushes (log2FC of 0.25 (p = 0.0012) and log2FC of 0.56 (p = 5.49E-06), respectively) and bronchial biopsies (log2FC of 0.49 (p = 0.00021) and log2FC of 0.246 (p = 0.028), respectively).Conclusion: This study identifies key differences in expression of genes related to susceptibility and aetiology of COVID-19 within the COPD lung. Further studies to understand the impact on clinical course of disease are now required. [ABSTRACT FROM AUTHOR]- Published
- 2021
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32. Interrelationships Among Small Airways Dysfunction, Neutrophilic Inflammation, and Exacerbation Frequency in COPD.
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Day, Kerry, Ostridge, Kristoffer, Conway, Joy, Cellura, Doriana, Watson, Alastair, Spalluto, Cosma Mirella, Staples, Karl J., Thompson, Bruce, and Wilkinson, Tom
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COMPUTED tomography ,OBSTRUCTIVE lung diseases ,AIRWAY (Anatomy) ,LUNG volume measurements ,LUNG volume - Abstract
Background: Small airways disease (SAD) is a key component of COPD and is a main contributing factor to lung function decline.Research Question: Is SAD a key feature of frequent COPD exacerbators and is this related to airway inflammation?Study Design and Methods: Thirty-nine COPD patients defined as either frequent exacerbator (FE) group (≥ 2 exacerbations/y; n = 17) and infrequent exacerbator (IFE) group (≤ 1 exacerbation/y; n = 22) underwent the forced oscillation technique (resistance at 5 Hz minus 19 Hz [R5-R19], area of reactance [AX]), multiple breath nitrogen washout (conducting airways ventilation heterogeneity, acinar ventilation heterogeneity [Sacin]), plethysmography (ratio of residual volume to total lung capacity), single-breath transfer factor of the lung for carbon monoxide, spirometry (FEV1, FEV1/FVC), and paired inspiratory-expiratory CT scans to ascertain SAD. A subpopulation underwent bronchoscopy to enable enumeration of BAL cell proportions.Results: Sacin was significantly higher in the COPD FE group compared with the IFE group (P = .027). In the FE group, markers of SAD were associated strongly with BAL neutrophil proportions, R5-R19 (P = .001, r = 0.795), AX (P = .049, ρ = 0.560), residual volume to total lung capacity ratio (P = .004, r = 0.730), and the mean lung density of the paired CT scans (P = .018, r = 0.639).Interpretation: Increased Sacin may be a consequence of previous exacerbations or may highlight a group of patients prone to exacerbations. Measures of SAD were associated strongly with neutrophilic inflammation in the small airways of FE patients, supporting the hypothesis that frequent exacerbations are associated with SAD related to increased cellular inflammation. [ABSTRACT FROM AUTHOR]- Published
- 2021
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33. Influence of Hypoxia on the Epithelial-Pathogen Interactions in the Lung: Implications for Respiratory Disease.
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Page, Lee K., Staples, Karl J., Spalluto, C. Mirella, Watson, Alastair, and Wilkinson, Tom M. A.
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RESPIRATORY diseases ,OBSTRUCTIVE lung diseases ,HYPOXEMIA ,LUNGS ,LUNG diseases - Abstract
Under normal physiological conditions, the lung remains an oxygen rich environment. However, prominent regions of hypoxia are a common feature of infected and inflamed tissues and many chronic inflammatory respiratory diseases are associated with mucosal and systemic hypoxia. The airway epithelium represents a key interface with the external environment and is the first line of defense against potentially harmful agents including respiratory pathogens. The protective arsenal of the airway epithelium is provided in the form of physical barriers, and the production of an array of antimicrobial host defense molecules, proinflammatory cytokines and chemokines, in response to activation by receptors. Dysregulation of the airway epithelial innate immune response is associated with a compromised immunity and chronic inflammation of the lung. An increasing body of evidence indicates a distinct role for hypoxia in the dysfunction of the airway epithelium and in the responses of both innate immunity and of respiratory pathogens. Here we review the current evidence around the role of tissue hypoxia in modulating the host-pathogen interaction at the airway epithelium. Furthermore, we highlight the work needed to delineate the role of tissue hypoxia in the pathophysiology of chronic inflammatory lung diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease in addition to novel respiratory diseases such as COVID-19. Elucidating the molecular mechanisms underlying the epithelial-pathogen interactions in the setting of hypoxia will enable better understanding of persistent infections and complex disease processes in chronic inflammatory lung diseases and may aid the identification of novel therapeutic targets and strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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34. Unfractionated heparin inhibits live wild type SARS-CoV-2 cell infectivity at therapeutically relevant concentrations.
- Author
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Tree, Julia A., Turnbull, Jeremy E., Buttigieg, Karen R., Elmore, Michael J., Coombes, Naomi, Hogwood, John, Mycroft‐West, Courtney J., Lima, Marcelo A., Skidmore, Mark A., Karlsson, Richard, Chen, Yen‐Hsi, Yang, Zhang, Spalluto, Cosma Mirella, Staples, Karl J., Yates, Edwin A., Gray, Elaine, Singh, Dave, Wilkinson, Tom, Page, Clive P., and Carroll, Miles W.
- Subjects
SARS-CoV-2 ,COVID-19 treatment ,COVID-19 ,PROTEIN receptors ,CARRIER proteins ,HEPARIN - Abstract
Background and Purpose: Currently, there are no licensed vaccines and limited antivirals for the treatment of COVID-19. Heparin (delivered systemically) is currently used to treat anticoagulant anomalies in COVID-19 patients. Additionally, in the United Kingdom, Brazil and Australia, nebulised unfractionated heparin (UFH) is being trialled in COVID-19 patients as a potential treatment. A systematic comparison of the potential antiviral effect of various heparin preparations on live wild type SARS-CoV-2, in vitro, is needed.Experimental Approach: Seven different heparin preparations including UFH and low MW heparins (LMWH) of porcine or bovine origin were screened for antiviral activity against live SARS-CoV-2 (Australia/VIC01/2020) using a plaque inhibition assay with Vero E6 cells. Interaction of heparin with spike protein RBD was studied using differential scanning fluorimetry and the inhibition of RBD binding to human ACE2 protein using elisa assays was examined.Key Results: All the UFH preparations had potent antiviral effects, with IC50 values ranging between 25 and 41 μg·ml-1 , whereas LMWHs were less inhibitory by ~150-fold (IC50 range 3.4-7.8 mg·ml-1 ). Mechanistically, we observed that heparin binds and destabilizes the RBD protein and furthermore, we show heparin directly inhibits the binding of RBD to the human ACE2 protein receptor.Conclusion and Implications: This comparison of clinically relevant heparins shows that UFH has significantly stronger SARS-CoV-2 antiviral activity compared to LMWHs. UFH acts to directly inhibit binding of spike protein to the human ACE2 protein receptor. Overall, the data strongly support further clinical investigation of UFH as a potential treatment for patients with COVID-19. [ABSTRACT FROM AUTHOR]- Published
- 2021
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35. Human Lung Conventional Dendritic Cells Orchestrate Lymphoid Neogenesis during Chronic Obstructive Pulmonary Disease.
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Naessens, Thomas, Morias, Yannick, Hamrud, Eva, Gehrmann, Ulf, Budida, Ramachandramouli, Mattsson, Johan, Baker, Tina, Skogberg, Gabriel, Israelsson, Elisabeth, Thörn, Kristofer, Schuijs, Martijn J., Angermann, Bastian, Melville, Faye, Staples, Karl J., Cunoosamy, Danen M., and Lambrecht, Bart N.
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OBSTRUCTIVE lung diseases ,LUNG diseases ,DENDRITIC cells ,HETEROGENEITY ,PHENOTYPES ,RESEARCH ,CELL culture ,LUNGS ,RESEARCH methodology ,EVALUATION research ,MEDICAL cooperation ,COMPARATIVE studies ,T cells ,DISEASE complications - Abstract
Rationale: Emerging evidence supports a crucial role for tertiary lymphoid organs (TLOs) in chronic obstructive pulmonary disease (COPD) progression. However, mechanisms of immune cell activation leading to TLOs in COPD remain to be defined.Objectives: To examine the role of lung dendritic cells (DCs) in T follicular helper (Tfh)-cell induction, a T-cell subset critically implicated in lymphoid organ formation, in COPD.Methods: Myeloid cell heterogeneity and phenotype were studied in an unbiased manner via single-cell RNA sequencing on HLA-DR+ cells sorted from human lungs. We measured the in vitro capability of control and COPD lung DC subsets, sorted using a fluorescence-activated cell sorter, to polarize IL-21+CXCL13+ (IL-21-positive and C-X-C chemokine ligand type 13-positive) Tfh-like cells. In situ imaging analysis was performed on Global Initiative for Chronic Obstructive Lung Disease stage IV COPD lungs with TLOs.Measurements and Main Results: Single-cell RNA-sequencing analysis revealed a high degree of heterogeneity among human lung myeloid cells. Among these, conventional dendritic type 2 cells (cDC2s) showed increased induction of IL-21+CXCL13+ Tfh-like cells. Importantly, the capacity to induce IL-21+ Tfh-like cells was higher in cDC2s from patients with COPD than in those from control patients. Increased Tfh-cell induction by COPD cDC2s correlated with increased presence of Tfh-like cells in COPD lungs as compared with those in control lungs, and cDC2s colocalized with Tfh-like cells in TLOs of COPD lungs. Mechanistically, cDC2s exhibited a unique migratory signature and (transcriptional) expression of several pathways and genes related to DC-induced Tfh-cell priming. Importantly, blocking the costimulatory OX40L (OX40 ligand)-OX40 axis reduced Tfh-cell induction by control lung cDC2s.Conclusions: In COPD lungs, we found lung EBI2+ (Epstein-Barr virus-induced gene 2-positive) OX-40L-expressing cDC2s that induced IL-21+ Tfh-like cells, suggesting an involvement of these cells in TLO formation. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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36. Defining a role for exercise training in the management of asthma.
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Freeman, Anna T., Staples, Karl J., and Wilkinson, Tom M. A.
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EXERCISE ,MORTALITY ,ASTHMA treatment ,DISEASE management ,QUALITY of life ,TARGETED drug delivery - Abstract
The prevalence of asthma remains high worldwide, with increasing awareness of the morbidity and mortality from asthma in low-income countries. In the UK, despite the development of biological treatments, many patients remain suboptimally controlled, and mortality rates have been static for decades. Therefore, new approaches are needed to treat asthma that are scalable at minimal cost. Exercise immunology is an expanding field, and there is growing evidence that exercise can modulate inflammatory and immune processes in asthma. Whilst exercise is encouraged in current treatment guidelines, there are no specific recommendations as to the intensity, frequency or duration of exercise exposure. Despite national and international guidance to increase exercise, patients with asthma are less likely to engage in physical activity. This review explores the disease modifying benefit of exercise in asthma. We also review the domains in which exercise exerts positive clinical effects in asthma, including the effects of exercise on symptom scores, quality of life, psychosocial health, and in the obese asthma phenotype. Finally, we review the barriers to exercise in asthma, given the benefits it confers. A better understanding of the mechanisms through which exercise exerts its positive effects in asthma may provide more accurate prescription of exercise training programmes as part of broader asthma management, with the potential of identification of new drug targets. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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37. Dynamics of IFN-β responses during respiratory viral infection: insights for therapeutic strategies.
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Watson, Alastair, Spalluto, C. Mirella, McCrae, Christopher, Cellura, Doriana, Burke, Hannah, Cunoosamy, Danen, Freeman, Anna, Hicks, Alex, Hühn, Michael, Ostridge, Kristoffer, Staples, Karl J., Vaarala, Outi, and Wilkinson, Tom
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INTERFERON beta 1b ,RESPIRATORY infections ,THERAPEUTICS ,EPITHELIAL cell culture ,MACROPHAGES ,BRONCHI - Abstract
The article present a study on dynamics of Interferon beta (IFN-β) responses during respiratory viral infection and insights for therapeutic strategies. Topics discussed include culturing macrophages and epithelial cells; expression of interferons (IFNs) and interferon-stimulated genes (ISGs) upon treatment with IFN-β and infection; and duration of interferon-stimulated gene (ISG) induction of macrophages and primary bronchial epithelial cells (PBECs) after interferon (IFN)-β administration.
- Published
- 2020
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38. Using Novel Computed Tomography Analysis to Describe the Contribution and Distribution of Emphysema and Small Airways Disease in Chronic Obstructive Pulmonary Disease.
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Ostridge, Kristoffer, Gove, Kerry, Paas, Karlien H. W., Burke, Hannah, Freeman, Anna, Harden, Stephen, Kirby, Miranda, Peterson, Sam, Sieren, Jered, McCrae, Chris, Vaarala, Outi, Staples, Karl J., Wilkinson, Tom M. A., and Paas, Karlien Hw
- Abstract
Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, caused by emphysema and small airways disease (SAD). Computed tomography (CT) coupled with image analysis enables the quantification of these abnormalities; however, the optimum method for doing so has not been determined.Objectives: This study aims to compare two CT quantitative analysis techniques, disease probability measure (DPM) and parametric response mapping (PRM), and assess their relationship with specific physiological measures of SAD.Methods: Subjects with mild to moderate COPD, never smokers, and healthy ex-smokers were recruited. Each had airway oscillometry and multiple-breath nitrogen washout, measuring peripheral airway resistance, peripheral airway reactance, and acinar airway inhomogeneity. Subjects also had an inspiratory and expiratory chest CT, with DPM and PRM analysis performed by coregistering images and classifying each voxel as normal, emphysema, or nonemphysematous gas trapping related to SAD.Results: Thirty-eight subjects with COPD, 18 never smokers, and 23 healthy ex-smokers were recruited. There were strong associations between DPM and PRM analysis when measuring gas trapping (ρ = 0.87; P < 0.001) and emphysema (ρ = 0.99; P < 0.001). DPM assigned significantly more voxels as emphysema and gas trapped than PRM (P < 0.001). Both techniques showed significantly greater emphysema and gas trapping in subjects with COPD than in never smokers and ex-smokers (P < 0.001). All CT measures had significant associations with peripheral airway resistance and reactance, with disease probability measure of nonemphysematous gas trapping related to SAD having the strongest independent association with peripheral airway resistance (β = 0.42; P = 0.001) and peripheral airway reactance (β = 0.41; P = 0.001). Emphysema measures had the strongest associations with acinar airway inhomogeneity (β = 0.35-0.38).Conclusions: These results provide further validation for the use of DPM/PRM analysis in COPD by demonstrating significant relationships with specific physiological measures of SAD. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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39. Breaching the Defenses? Mucosal-associated Invariant T Cells, Smoking, and Chronic Obstructive Pulmonary Disease.
- Author
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Staples, Karl J.
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CHRONIC obstructive pulmonary disease - Abstract
An editorial is presented on cigarette smoking being one of the primary causes of chronic obstructive pulmonary disease (COPD). Topics include precise mechanisms by which cigarette smoke (CS) exposure leading to COPD are yet to be elucidated; and activating MAIT cells or a consequence of the high baseline activation being closer to a maximal stimulation being unclear.
- Published
- 2023
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40. Human CD49a+ Lung Natural Killer Cell Cytotoxicity in Response to Influenza A Virus.
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Cooper, Grace E., Ostridge, Kristoffer, Khakoo, Salim I., Wilkinson, Tom M. A., and Staples, Karl J.
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INFLUENZA A virus ,KILLER cells ,CELL-mediated cytotoxicity - Abstract
Influenza A virus (IAV) is a major global public health burden due to its routine evasion of immunization strategies. Natural killer (NK) cells are innate cytotoxic cells with important antiviral activity in the human body, yet the function of these cells in the control of IAV infection is unclear. The aim of this study was to determine the role of lung NK cell cytotoxic responses to IAV. Human lung explants were infected ex vivo with IAV, and lung NK cell activation was analyzed by flow cytometry. Cytotoxic responses of NK cell subsets against IAV-infected macrophages were measured by flow cytometry and ELISA. Despite reports of hypofunctionality in the pulmonary environment, human lung-associated NK cells responded rapidly to ex vivo IAV infection, with upregulation of surface CD107a 24 h post-infection. The lung NK cell phenotype is similar in maturity and differentiation to NK cells of the peripheral blood but a unique CD56
bright CD49a+ CD103+ CD69+ NK cell population was identified in the lung, indicating NK cell residency within this organ. In response to ex vivo IAV infection a greater proportion of resident CD56bright CD49a+ NK cells expressed surface CD107a compared with CD56brightCD49a- NK cells, suggesting a hyperfunctional NK cell population may be present within human lung tissue and could be the result of innate immunological training. Furthermore, NK cells provided significant antiviral, cytotoxic activity following contact with influenza-infected cells, including the production and release of IFN-γ and granzyme-B resulting in macrophage cell death. These results suggest that a resident, trained NK cell population are present in the human lung and may provide early and important control of viral infection. A greater understanding of this resident mucosal population may provide further insight into the role of these cells in controlling viral infection and generating appropriate adaptive immunity to IAV. [ABSTRACT FROM AUTHOR]- Published
- 2018
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41. Longitudinal profiling of the lung microbiome in the AERIS study demonstrates repeatability of bacterial and eosinophilic COPD exacerbations.
- Author
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Mayhew, David, Devos, Nathalie, Lambert, Christophe, Brown, James R., Clarke, Stuart C., Kim, Viktoriya L., Magid-Slav, Michal, Miller, Bruce E., Ostridge, Kristoffer K., Patel, Ruchi, Sathe, Ganesh, Simola, Daniel F., Staples, Karl J., Sung, Ruby, Tal-Singer, Ruth, Tuck, Andrew C., Van Horn, Stephanie, Weynants, Vincent, Williams, Nicholas P., and Devaster, Jeanne-Marie
- Subjects
OBSTRUCTIVE lung diseases ,DISEASE exacerbation ,LUNG microbiology ,PREVENTION ,DISEASE risk factors ,SPUTUM microbiology ,RNA analysis ,COMPARATIVE studies ,HAEMOPHILUS ,LONGITUDINAL method ,RESEARCH methodology ,MEDICAL cooperation ,RESEARCH ,SPUTUM ,STREPTOCOCCUS ,PHENOTYPES ,DISEASE relapse ,EVALUATION research ,SEVERITY of illness index ,DISEASE progression ,GRAM-negative aerobic bacteria ,GRAM-negative anaerobic bacteria ,PULMONARY eosinophilia ,DISEASE complications - Abstract
Background: Alterations in the composition of the lung microbiome associated with adverse clinical outcomes, known as dysbiosis, have been implicated with disease severity and exacerbations in COPD.Objective: To characterise longitudinal changes in the lung microbiome in the AERIS study (Acute Exacerbation and Respiratory InfectionS in COPD) and their relationship with associated COPD outcomes.Methods: We surveyed 584 sputum samples from 101 patients with COPD to analyse the lung microbiome at both stable and exacerbation time points over 1 year using high-throughput sequencing of the 16S ribosomal RNA gene. We incorporated additional lung microbiology, blood markers and in-depth clinical assessments to classify COPD phenotypes.Results: The stability of the lung microbiome over time was more likely to be decreased in exacerbations and within individuals with higher exacerbation frequencies. Analysis of exacerbation phenotypes using a Markov chain model revealed that bacterial and eosinophilic exacerbations were more likely to be repeated in subsequent exacerbations within a subject, whereas viral exacerbations were not more likely to be repeated. We also confirmed the association of bacterial genera, including Haemophilus and Moraxella, with disease severity, exacerbation events and bronchiectasis.Conclusions: Subtypes of COPD have distinct bacterial compositions and stabilities over time. Some exacerbation subtypes have non-random probabilities of repeating those subtypes in the future. This study provides insights pertaining to the identification of bacterial targets in the lung and biomarkers to classify COPD subtypes and to determine appropriate treatments for the patient.Trial Registration Number: Results, NCT01360398. [ABSTRACT FROM AUTHOR]- Published
- 2018
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42. Seasonality, risk factors and burden of community-acquired pneumonia in COPD patients: a population database study using linked health care records.
- Author
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Williams, Nicholas P., Coombs, Ngaire A., Johnson, Matthew J., Josephs, Lynn K., Rigge, Lucy A., Staples, Karl J., Thomas, Mike, and Wilkinson, Tom M. A.
- Published
- 2017
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43. Relationships between Mucosal Antibodies, Non-Typeable Haemophilus influenzae (NTHi) Infection and Airway Inflammation in COPD.
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Staples, Karl J., Taylor, Stephen, Thomas, Steve, Leung, Stephanie, Cox, Karen, Pascal, Thierry G., Ostridge, Kristoffer, Welch, Lindsay, Tuck, Andrew C., Clarke, Stuart C., Gorringe, Andrew, and Wilkinson, Tom M. A.
- Subjects
- *
HAEMOPHILUS influenzae , *ANTI-inflammatory agents , *ANTIPYRETICS , *SPONDYLODISCITIS , *MEDICAL microbiology - Abstract
Non-typeable Haemophilus influenzae (NTHi) is a key pathogen in COPD, being associated with airway inflammation and risk of exacerbation. Why some patients are susceptible to colonisation is not understood. We hypothesised that this susceptibility may be due to a deficiency in mucosal humoral immunity. The aim of our study (NCT01701869) was to quantify the amount and specificity of antibodies against NTHi in the lungs and the associated risk of infection and inflammation in health and COPD. Phlebotomy, sputum induction and bronchoscopy were performed on 24 mild-to-moderate COPD patients and 8 age and smoking-matched controls. BAL (Bronchoalveolar lavage) total IgG1, IgG2, IgG3, IgM and IgA concentrations were significantly increased in COPD patients compared to controls. NTHi was detected in the lungs of 7 of the COPD patients (NTHi+ve—29%) and these patients had a higher median number of previous exacerbations than NTHi-ve patients as well as evidence of increased systemic inflammation. When comparing NTHi+ve versus NTHi-ve patients we observed a decrease in the amount of both total IgG1 (p = 0.0068) and NTHi-specific IgG1 (p = 0.0433) in the BAL of NTHi+ve patients, but no differences in total IgA or IgM. We observed no evidence of decreased IgG1 in the serum of NTHi+ve patients, suggesting this phenomenon is restricted to the airway. Furthermore, the NTHi+ve patients had significantly greater levels of IL-1β (p = 0.0003), in BAL than NTHi-ve COPD patients.This study indicates that the presence of NTHi is associated with reduced levels and function of IgG1 in the airway of NTHi-colonised COPD patients. This decrease in total and NTHI-specific IgG1 was associated with greater systemic and airway inflammation and a history of more frequent exacerbations and may explain the susceptibility of some COPD patients to the impacts of NTHi. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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44. Steroid-induced Deficiency of Mucosal-associated Invariant T Cells in the Chronic Obstructive Pulmonary Disease Lung. Implications for Nontypeable Haemophilus influenzae Infection.
- Author
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Hinks, Timothy S. C., Wallington, Joshua C., Williams, Anthony P., Djukanović, Ratko, Staples, Karl J., and Wilkinson, Tom M. A.
- Subjects
ADRENOCORTICAL hormones ,FLOW cytometry ,HAEMOPHILUS diseases ,HAEMOPHILUS influenzae ,OBSTRUCTIVE lung diseases ,RESEARCH funding ,DISEASE complications - Abstract
Rationale: Mucosal-associated invariant T (MAIT) cells are a recently described abundant, proinflammatory T-cell subset with unknown roles in pulmonary immunity. Nontypeable Haemophilus influenzae (NTHi) is the leading bacterial pathogen during chronic obstructive pulmonary disease (COPD) exacerbations and is a plausible target for MAIT cells.Objectives: To investigate whether MAIT cells respond to NTHi and the effects of inhaled corticosteroids (ICS) on their frequency and function in COPD.Methods: Eleven subjects with COPD receiving ICS, 8 steroid-naive subjects with COPD, and 21 healthy control subjects underwent phlebotomy, sputum induction, bronchoalveolar lavage, and endobronchial biopsy. Pulmonary and monocyte-derived macrophages were cultured in vitro with NTHi.Measurements and Main Results: Frequencies of Vα7.2+CD161+ MAIT cells, surface expression of the major histocompatibility complex-related protein 1 (MR1), and intracellular IFN-γ expression were measured by flow cytometry. MAIT-cell frequencies were reduced in peripheral blood of ICS-treated subjects with COPD (median 0.38%; interquartile range [IQR], 0.25-0.96) compared with healthy control subjects (1.8%; IQR, 1.4-2.5; P = 0.001) or steroid-naive patients with COPD (1.8%; IQR, 1.2-2.3; P = 0.04). MAIT cells were reduced in bronchial biopsies from subjects with COPD treated with steroids (0.73%; IQR, 0.46-1.3) compared with healthy control subjects (4.0%; IQR, 1.6-5.0; P = 0.02). Coculture of live NTHi increased macrophage surface expression of MR1 and induced IFN-γ from CD4 cells and CD8 cells, but most potently from MAIT cells (median IFN-γ-positive frequencies, 2.9, 8.6, and 27.6%, respectively). In vitro fluticasone and budesonide reduced MR1 surface expression twofold and decreased NTHi-induced IFN-γ secretion eightfold.Conclusions: MAIT cells are deficient in blood and bronchial tissue in steroid-treated, but not steroid-naive, COPD. NTHi constitutes a target for pulmonary MAIT-cell immune responses, which are significantly impaired by corticosteroids. [ABSTRACT FROM AUTHOR]- Published
- 2016
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45. Viral Inhibition of Bacterial Phagocytosis by Human Macrophages: Redundant Role of CD36.
- Author
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Cooper, Grace E., Pounce, Zoe C., Wallington, Joshua C., Bastidas-Legarda, Leidy Y., Nicholas, Ben, Chidomere, Chiamaka, Robinson, Emily C., Martin, Kirstin, Tocheva, Anna S., Christodoulides, Myron, Djukanovic, Ratko, Wilkinson, Tom M. A., and Staples, Karl J.
- Subjects
PHAGOCYTOSIS ,CD36 antigen ,INFLUENZA ,MACROPHAGES ,STREPTOCOCCUS pneumoniae ,HOMEOSTASIS ,SCAVENGER receptors (Biochemistry) - Abstract
Macrophages are essential to maintaining lung homoeostasis and recent work has demonstrated that influenza-infected lung macrophages downregulate their expression of the scavenger receptor CD36. This receptor has also been shown to be involved in phagocytosis of Streptococcus pneumoniae, a primary agent associated with pneumonia secondary to viral infection. The aim of this study was to investigate the role of CD36 in the effects of viral infection on macrophage phagocytic function. Human monocyte-derived macrophages (MDM) were exposed to H3N2 X31 influenza virus, M37 respiratory syncytial virus (RSV) or UV-irradiated virus. No infection of MDM was seen upon exposure to UV-irradiated virus but incubation with live X31 or M37 resulted in significant levels of viral detection by flow cytometry or RT-PCR respectively. Infection resulted in significantly diminished uptake of S. pneumoniae by MDM and significantly decreased expression of CD36 at both the cell surface and mRNA level. Concurrently, there was a significant increase in IFNβ gene expression in response to infection and we observed a significant decrease in bacterial phagocytosis (p = 0.031) and CD36 gene expression (p = 0.031) by MDM cultured for 24 h in 50IU/ml IFNβ. Knockdown of CD36 by siRNA resulted in decreased phagocytosis, but this was mimicked by transfection reagent alone. When MDM were incubated with CD36 blocking antibodies no effect on phagocytic ability was observed. These data indicate that autologous IFNβ production by virally-infected cells can inhibit bacterial phagocytosis, but that decreased CD36 expression by these cells does not play a major role in this functional deficiency. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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46. Distinct emphysema subtypes defined by quantitative CT analysis are associated with specific pulmonary matrix metalloproteinases.
- Author
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Ostridge, Kristoffer, Williams, Nicholas, Kim, Viktoriya, Harden, Stephen, Bourne, Simon, Coombs, Ngaire A., Elkington, Paul T., San Jose Estepar, Raul, Washko, George, Staples, Karl J., Wilkinson, Tom M. A., and Estepar, Raul San Jose
- Subjects
PULMONARY emphysema ,MATRIX metalloproteinases ,PROTEOLYTIC enzymes ,COMPUTED tomography ,CIGARETTE smokers ,PROTEIN metabolism ,BODY fluids ,BRONCHOSCOPY ,LUNGS ,OBSTRUCTIVE lung diseases ,PULMONARY function tests ,RESPIRATORY obstructions ,SMOKING ,PROTEASE inhibitors ,PHARMACODYNAMICS - Abstract
Background: Emphysema is characterised by distinct pathological sub-types, but little is known about the divergent underlying aetiology. Matrix-metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix and have been identified as potentially important in the development of emphysema. However, the relationship between MMPs and emphysema sub-type is unknown. We investigated the role of MMPs and their inhibitors in the development of emphysema sub-types by quantifying levels and determining relationships with these sub-types in mild-moderate COPD patients and ex/current smokers with preserved lung function.Methods: Twenty-four mild-moderate COPD and 8 ex/current smokers with preserved lung function underwent high resolution CT and distinct emphysema sub-types were quantified using novel local histogram-based assessment of lung density. We analysed levels of MMPs and tissue inhibitors of MMPs (TIMPs) in bronchoalveolar lavage (BAL) and assessed their relationship with these emphysema sub-types.Results: The most prevalent emphysema subtypes in COPD subjects were mild and moderate centrilobular (CLE) emphysema, while only small amounts of severe centrilobular emphysema, paraseptal emphysema (PSE) and panlobular emphysema (PLE) were present. MMP-3, and -10 associated with all emphysema sub-types other than mild CLE, while MMP-7 and -8 had associations with moderate and severe CLE and PSE. MMP-9 also had associations with moderate CLE and paraseptal emphysema. Mild CLE occurred in substantial quantities irrespective of whether airflow obstruction was present and did not show any associations with MMPs.Conclusion: Multiple MMPs are directly associated with emphysema sub-types identified by CT imaging, apart from mild CLE. This suggests that MMPs play a significant role in the tissue destruction seen in the more severe sub-types of emphysema, whereas early emphysematous change may be driven by a different mechanism.Trial Registration: Trial registration number NCT01701869 . [ABSTRACT FROM AUTHOR]- Published
- 2016
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47. Influenza A Virus Challenge Models in Cynomolgus Macaques Using the Authentic Inhaled Aerosol and Intra-Nasal Routes of Infection.
- Author
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Marriott, Anthony C., Dennis, Mike, Kane, Jennifer A., Gooch, Karen E., Hatch, Graham, Sharpe, Sally, Prevosto, Claudia, Leeming, Gail, Zekeng, Elsa-Gayle, Staples, Karl J., Hall, Graham, Ryan, Kathryn A., Bate, Simon, Moyo, Nathifa, Whittaker, Catherine J., Hallis, Bassam, Silman, Nigel J., Lalvani, Ajit, Wilkinson, Tom M., and Hiscox, Julian A.
- Subjects
INFLUENZA A virus ,MACAQUES ,AEROSOLS ,PHYLOGENY ,MACROPHAGES - Abstract
Non-human primates are the animals closest to humans for use in influenza A virus challenge studies, in terms of their phylogenetic relatedness, physiology and immune systems. Previous studies have shown that cynomolgus macaques (Macaca fascicularis) are permissive for infection with H1N1pdm influenza virus. These studies have typically used combined challenge routes, with the majority being intra-tracheal delivery, and high doses of virus (> 10
7 infectious units). This paper describes the outcome of novel challenge routes (inhaled aerosol, intra-nasal instillation) and low to moderate doses (103 to 106 plaque forming units) of H1N1pdm virus in cynomolgus macaques. Evidence of virus replication and sero-conversion were detected in all four challenge groups, although the disease was sub-clinical. Intra-nasal challenge led to an infection confined to the nasal cavity. A low dose (103 plaque forming units) did not lead to detectable infectious virus shedding, but a 1000-fold higher dose led to virus shedding in all intra-nasal challenged animals. In contrast, aerosol and intra-tracheal challenge routes led to infections throughout the respiratory tract, although shedding from the nasal cavity was less reproducible between animals compared to the high-dose intra-nasal challenge group. Intra-tracheal and aerosol challenges induced a transient lymphopaenia, similar to that observed in influenza-infected humans, and greater virus-specific cellular immune responses in the blood were observed in these groups in comparison to the intra-nasal challenge groups. Activation of lung macrophages and innate immune response genes was detected at days 5 to 7 post-challenge. The kinetics of infection, both virological and immunological, were broadly in line with human influenza A virus infections. These more authentic infection models will be valuable in the determination of anti-influenza efficacy of novel entities against less severe (and thus more common) influenza infections. [ABSTRACT FROM AUTHOR]- Published
- 2016
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48. Dysregulation of anti-viral function of CD8+T cells in the COPD lung: role of the PD1/PDL1 axis.
- Author
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McKendry, Richard T., Spalluto, C. Mirella, Burke, Hannah, Nicholas, Ben, Cellura, Doriana, Al-Shamkhani, Aymen, Staples, Karl J., and Wilkinson, Tom M. A.
- Published
- 2016
49. Macrophages and neutrophils: dynamic duo or partners in crime?
- Author
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Staples, Karl J.
- Subjects
MACROPHAGES ,NEUTROPHILS ,ANTIGEN presenting cells ,CONNECTIVE tissue cells ,KILLER cells ,CRIME ,INTERLEUKIN-1 - Published
- 2018
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50. A Novel Lung Explant Model for the Ex Vivo Study of Efficacy and Mechanisms of Anti-Influenza Drugs.
- Author
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Nicholas, Ben, Staples, Karl J., Moese, Stefan, Meldrum, Eric, Ward, Jon, Dennison, Patrick, Havelock, Tom, Hinks, Timothy S. C., Amer, Khalid, Woo, Edwin, Chamberlain, Martin, Singh, Neeta, North, Malcolm, Pink, Sandy, Wilkinson, Tom M. A., and Djukanović, Ratko
- Subjects
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INFLUENZA treatment , *VIRAL disease treatment , *FLOW cytometry , *DRUG development , *VIRAL replication - Abstract
Influenza A virus causes considerable morbidity and mortality largely because of a lack of effective antiviral drugs. Viral neuraminidase inhibitors, which inhibit viral release from the infected cell, are currently the only approved drugs for influenza, but have recently been shown to be less effective than previously thought. Growing resistance to therapies that target viral proteins has led to increased urgency in the search for novel anti-influenza compounds. However, discovery and development of new drugs have been restricted because of differences in susceptibility to influenza between animal models and humans and a lack of translation between cell culture and in vivo measures of efficacy. To circumvent these limitations, we developed an experimental approach based on ex vivo infection of human bronchial tissue explants and optimized a method of flow cytometric analysis to directly quantify infection rates in bronchial epithelial tissues. This allowed testing of the effectiveness of TVB024, a vATPase inhibitor that inhibits viral replication rather than virus release, and to compare efficacy with the current frontline neuraminidase inhibitor, oseltamivir. The study showed that the vATPase inhibitor completely abrogated epithelial cell infection, virus shedding, and the associated induction of proinflammatory mediators, whereas oseltamivir was only partially effective at reducing these mediators and ineffective against innate responses. We propose, therefore, that this explant model could be used to predict the efficacy of novel anti-influenza compounds targeting diverse stages of the viral replication cycle, thereby complementing animal models and facilitating progression of new drugs into clinical trials. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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