Imperial College London

ProfessorClareLloyd

Faculty of MedicineNational Heart & Lung Institute

Vice-Dean (Institutional Affairs); Faculty of Medicine
 
 
 
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Contact

 

+44 (0)20 7594 3102c.lloyd Website

 
 
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Location

 

Office 352Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

270 results found

Pyle C, Patel D, Peiro T, Joulia R, Grabiec A, Hussell T, Tavernier G, Simpson A, Pease J, Harker J, Lloyd C, Snelgrove Ret al., 2022, MMP-12 supports pulmonary B cell follicle formation and local antibody responses during asthma, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

Journal article

Stolting H, Baillon L, Frise R, Bonner K, Hewitt RJ, Molyneaux PL, Gore ML, Barclay WS, Saglani S, Lloyd CMet al., 2022, Distinct airway epithelial immune responses after infection with SARS-CoV-2 compared to H1N1, Mucosal Immunology, Vol: 15, Pages: 952-963, ISSN: 1933-0219

Children are less likely than adults to suffer severe symptoms when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), while influenza A H1N1 severity is comparable across ages except for the very young or elderly. Airway epithelial cells play a vital role in the early defence against viruses via their barrier and immune functions. We investigated viral replication and immune responses in SARS-CoV-2-infected bronchial epithelial cells from healthy paediatric (n = 6; 2.5–5.6 years old) and adult (n = 4; 47–63 years old) subjects and compared cellular responses following infection with SARS-CoV-2 or Influenza A H1N1. While infection with either virus triggered robust transcriptional interferon responses, including induction of type I (IFNB1) and type III (IFNL1) interferons, markedly lower levels of interferons and inflammatory proteins (IL-6, IL-8) were released following SARS-CoV-2 compared to H1N1 infection. Only H1N1 infection caused disruption of the epithelial layer. Interestingly, H1N1 infection resulted in sustained upregulation of SARS-CoV-2 entry factors FURIN and NRP1. We did not find any differences in the epithelial response to SARS-CoV-2 infection between paediatric and adult cells. Overall, SARS-CoV-2 had diminished potential to replicate, affect morphology and evoke immune responses in bronchial epithelial cells compared to H1N1.

Journal article

Rahimi RA, Cho JL, Jakubzick C, Khader SA, Lambrecht BN, Lloyd CM, Molofsky AB, Talbot S, Bonham CA, Drake WP, Sperling A, Singer BDet al., 2022, Advancing Lung Immunology Research An Official American Thoracic Society Workshop Report, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 67, Pages: E1-E18, ISSN: 1044-1549

Journal article

Stolting H, Lloyd CM, 2022, Pseudomonas aeruginosa: a pathogen making itself at home, TRENDS IN IMMUNOLOGY, Vol: 43, Pages: 497-499, ISSN: 1471-4906

Journal article

Salem V, Hirani D, Lloyd C, Regan L, Peters Cet al., 2022, Why are women still leaving academic medicine? A qualitative study within a London Medical School, BMJ Open, Vol: 12, ISSN: 2044-6055

Objectives: To identify factors that influenced women who chose to leave academic medicine.Design and main outcome measures: Independent consultants led a focus group of women in medicine who had left academia after completion of their postgraduate research degree at Imperial College London Faculty of Medicine. Thematic analysis was performed on the transcribed conversations.Participants and setting: Nine women physicians who completed a postgraduate degree (MD or PhD) at a large London Medical School and Academic Health Sciences Centre, Imperial College London, but did not go on to pursue a career in academic medicine.Results: Influences to leave clinical academia were summarised under eight themes—career intentions, supervisor support, institutional human resources support, inclusivity, work–life balance, expectations, mentors and role models, and pregnancy and maternity leave.Conclusion: The women in our focus group reported several factors contributing to their decision to leave clinical academia, which included lack of mentoring tailored to specific needs, low levels of acceptance for flexible working to help meet parental responsibilities and perceived explicit gender biases. We summarise the multiple targeted strategies that Imperial College London has implemented to promote retention of women in academic medicine, although more research needs to be done to ascertain the most effective interventions.

Journal article

Vijayakumar B, Boustani K, Ogger P, Papadaki A, Tonkin J, Orton C, Ghai P, Suveizdyte K, Hewitt R, Desai S, Devaraj A, Snelgrove R, Molyneaux P, Garner J, Peters J, Shah P, Lloyd C, Harker Jet al., 2022, Immuno-proteomic profiling reveals aberrant immune cell regulation in the airways of individuals with ongoing post-COVD-19 respiratory disease, Immunity, Vol: 55, Pages: 542-556.e5, ISSN: 1074-7613

Some patients hospitalized with acute COVID-19 suffer respiratory symptoms that persist for many months. We delineated the immune-proteomic landscape in the airway and peripheral blood of healthy controls and post-COVID-19 patients 3 to 6 months after hospital discharge. Post-COVID-19 patients showed abnormal airway (but not plasma) proteomes, with elevated concentration of proteins associated with apoptosis, tissue repair and epithelial injury versus healthy individuals. Increased numbers of cytotoxic lymphocytes were observed in individuals with greater airway dysfunction, while increased B cell numbers and altered monocyte subsets were associated with more widespread lung abnormalities. 1 year follow-up of some post-COVID-19 patients indicated that these abnormalities resolved over time. In summary, COVID-19 causes a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to ongoing activation of cytotoxic T cells.

Journal article

Starkey MR, Deshmukh H, Lukacs NW, Lloyd CMet al., 2022, Editorial: Pulmonary Innate Lymphoid Cells - Gatekeepers of Respiratory Health, FRONTIERS IN IMMUNOLOGY, Vol: 13, ISSN: 1664-3224

Journal article

Pattaroni C, Macowan M, Chatzis R, Daunt C, Custovic A, Shields MD, Power UF, Grigg J, Roberts G, Ghazal P, Schwarze J, Gore M, Turner S, Bush A, Saglani S, Lloyd C, Marsland BJet al., 2022, Early life inter-kingdom interactions shape the immunological environment of the airways, Microbiome, Vol: 10, ISSN: 2049-2618

Background: There is increasing evidence that the airway microbiome plays a key role in the establishment of respiratory health by interacting with the developing immune system early in life. While it has become clear that bacteria are involved in this process, there is a knowledge gap concerning the role of fungi. Moreover, the inter-kingdom interactions that influence immune development remain unknown. In this prospective exploratory human study, we aimed to determine early post-natal microbial and immunological features of the upper airways in 121 healthy newborns.Results: We found that the oropharynx and nasal cavity represent distinct ecological niches for bacteria and fungi. Breastfeeding correlated with changes in microbiota composition of oropharyngeal samples with the greatest impact upon the relative abundance of Streptococcus species and Candida. Host transcriptome profiling revealed that genes with the highest expression variation were immunological in nature. Multi-omics factor analysis of host and microbial data revealed unique co-variation patterns. Conclusion: These data provide evidence of a diverse multi-kingdom microbiota linked with local immunological characteristics in the first week of life that could represent distinct trajectories for future respiratory health.

Journal article

Pyle CJ, Labeur-Iurman L, Groves HT, Puttur F, Lloyd CM, Tregoning JS, Harker JAet al., 2021, Enhanced IL-2 in early life limits the development of TFH and protective antiviral immunity, Journal of Experimental Medicine, Vol: 218, ISSN: 0022-1007

T follicular helper cell (TFH)-dependent antibody responses are critical for long-term immunity. Antibody responses are diminished in early life, limiting long-term protective immunity and allowing prolonged or recurrent infection, which may be important for viral lung infections that are highly prevalent in infancy. In a murine model using respiratory syncytial virus (RSV), we show that TFH and the high-affinity antibody production they promote are vital for preventing disease on RSV reinfection. Following a secondary RSV infection, TFH-deficient mice had significantly exacerbated disease characterized by delayed viral clearance, increased weight loss, and immunopathology. TFH generation in early life was compromised by heightened IL-2 and STAT5 signaling in differentiating naive T cells. Neutralization of IL-2 during early-life RSV infection resulted in a TFH-dependent increase in antibody-mediated immunity and was sufficient to limit disease severity upon reinfection. These data demonstrate the importance of TFH in protection against recurrent RSV infection and highlight a mechanism by which this is suppressed in early life.

Journal article

McErlean P, Bell CG, Hewitt RJ, Busharat Z, Ogger PP, Ghai P, Albers GJ, Calamita E, Kingston S, Molyneaux PL, Beck S, Lloyd CM, Maher TM, Byrne AJet al., 2021, DNA methylome alterations are associated with airway macrophage differentiation and phenotype during lung fibrosis., American Journal of Respiratory and Critical Care Medicine, Vol: 204, Pages: 954-966, ISSN: 1073-449X

Rationale: Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, knowledge about the epigenetics of AMs in IPF is limited. Objectives: To assess the role of epigenetic regulation of AMs during lung fibrosis. Methods: We undertook DNA methylation (DNAm) profiling by using Illumina EPIC (850k) arrays in sorted AMs from healthy donors (n = 14) and donors with IPF (n = 30). Cell-type deconvolution was performed by using reference myeloid-cell DNA methylomes. Measurements and Main Results: Our analysis revealed that epigenetic heterogeneity was a key characteristic of IPF AMs. DNAm "clock" analysis indicated that epigenetic alterations in IPF AMs were not associated with accelerated aging. In differential DNAm analysis, we identified numerous differentially methylated positions (n = 11) and differentially methylated regions (n = 49) between healthy and IPF AMs, respectively. Differentially methylated positions and differentially methylated regions encompassed genes involved in lipid (LPCAT1 [lysophosphatidylcholine acyltransferase 1]) and glucose (PFKFB3 [6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3]) metabolism, and importantly, the DNAm status was associated with disease severity in IPF. Conclusions: Collectively, our data identify that changes in the epigenome are associated with the development and function of AMs in the IPF lung.

Journal article

Saglani S, Robinson P, Fontanella S, Ananth S, Martin Alonso A, Cook J, Kaya-de Vries D, Polo Silveira L, Gregory L, Lloyd C, Fleming L, Bush A, Custovic Aet al., 2021, Recurrent severe preschool wheeze: From pre-specified diagnostic labels to underlying endotypes, American Journal of Respiratory and Critical Care Medicine, Vol: 204, Pages: 523-535, ISSN: 1073-449X

Rationale: Preschool wheezing is heterogeneous, but the underlying mechanisms are poorly understood. Objectives: To investigate lower airway inflammation and infection in preschool children with different clinical diagnoses undergoing elective bronchoscopy/bronchoalveolar lavage-BAL. Methods: We recruited 136 children aged 1-5 years (105 recurrent severe wheeze-RSW; 31 non-wheeze respiratory disorders-NWRD). RSW were assigned as episodic viral-EVW or multiple trigger wheeze-MTW. We compared lower airway inflammation/infection in different clinical diagnoses and undertook data-driven analyses to determine clusters of pathophysiological features, and investigated their relationships with pre-specified diagnostic labels. Measurements and Main Results: Blood eosinophils and allergic sensitization were significantly higher in RSW than NWRD. Blood neutrophils, BAL eosinophils and neutrophils, and positive bacterial culture and virus detection rates were similar between groups. However, pathogen distribution differed significantly, with higher detection of rhinovirus in RSW and Moraxella in sensitized RSW. EVW and MTW did not differ in blood/BAL inflammation, or bacterial/virus detection. Partition Around Medoids algorithm revealed 4 clusters of pathophysiological features: (1) Atopic (17.9%); (2) Non-atopic, low infection rate, high inhaled corticosteroids-ICS (31.3%); (3) Non-atopic, high infection rate (23.1%); and (4) Non-atopic, low infection rate, no ICS (27.6%). Cluster allocation differed significantly between RSW and NWRD (RSW evenly distributed across clusters, 60% of NWRD assigned to cluster 4, p<0.001). There was no difference in cluster membership between EVW and MTW. Cluster 1 was dominated by Moraxella detection (p=0.04) and Cluster 3 by Haemophilus/Staphylococcus/ Streptococcus (p=0.02). Conclusions: We identified four clusters of severe preschool wheeze distinguished using sensitization, peripheral eosinophilia, lower airway neutrophilia and bacteriolog

Journal article

Branchett WJ, Cook J, Oliver RA, Bruno N, Walker SA, StÓ§lting H, Mack M, OGarra A, Saglani S, Lloyd CMet al., 2021, Airway macrophage-intrinsic TGF-β1 regulates pulmonary immunity during early life allergen exposure, Journal of Allergy and Clinical Immunology, Vol: 147, Pages: 1892-1906, ISSN: 0091-6749

BackgroundEarly life represents a major risk window for asthma development. However, the mechanisms controlling the threshold for establishment of allergic airway inflammation in early life are incompletely understood. Airway macrophages (AMs) regulate pulmonary allergic responses and undergo TGF-β–dependent postnatal development, but the role of AM maturation factors such as TGF-β in controlling the threshold for pathogenic immune responses to inhaled allergens remains unclear.ObjectiveOur aim was to test the hypothesis that AM-derived TGF-β1 regulates pathogenic immunity to inhaled allergen in early life.MethodsConditional knockout (Tgfb1ΔCD11c) mice, with TGF-β1 deficiency in AMs and other CD11c+ cells, were analyzed throughout early life and following neonatal house dust mite (HDM) inhalation. The roles of specific chemokine receptors were determined by using in vivo blocking antibodies.ResultsAM-intrinsic TGF-β1 was redundant for initial population of the neonatal lung with AMs, but AMs from Tgfb1ΔCD11c mice failed to adopt a mature homeostatic AM phenotype in the first weeks of life. Evidence of constitutive TGF-β1 signaling was also observed in pediatric human AMs. TGF-β1–deficient AMs expressed enhanced levels of monocyte-attractant chemokines, and accordingly, Tgfb1ΔCD11c mice exposed to HDM throughout early life accumulated CCR2-dependent inflammatory CD11c+ mononuclear phagocytes into the airway niche that expressed the proallergic chemokine CCL8. Tgfb1ΔCD11c mice displayed augmented TH2, group 2 innate lymphoid cell, and airway remodeling responses to HDM, which were ameliorated by blockade of the CCL8 receptor CCR8.ConclusionOur results highlight a causal relationship between AM maturity, chemokines, and pathogenic immunity to environmental stimuli in early life and identify TGF-β1 as a key regulator of this.

Journal article

Harker JA, Lloyd CM, 2021, Overlapping and distinct features of viral and allergen immunity in the human lung, IMMUNITY, Vol: 54, Pages: 617-631, ISSN: 1074-7613

Journal article

Invernizzi R, Wu BG, Barnett J, Ghai P, Kingston S, Hewitt RJ, Feary J, Li Y, Chua F, Wu Z, Wells AU, Renzoni EA, Nicholson AG, Rice A, Devaraj A, Segal LN, Byrne AJ, Maher TM, Lloyd CM, Molyneaux PLet al., 2021, The respiratory microbiome in chronic hypersensitivity pneumonitis is distinct from that of idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 339-347, ISSN: 1073-449X

RATIONALE: Chronic hypersensitivity pneumonitis (CHP) is a condition that arises following repeated exposure and sensitisation to inhaled antigens. The lung microbiome is increasingly implicated in respiratory disease but to date, no study has investigated the composition of microbial communities in the lower airways in CHP. OBJECTIVE: To characterise and compare the airway microbiome in subjects with CHP, idiopathic pulmonary fibrosis (IPF) and controls. METHODS: We prospectively recruited individuals diagnosed with CHP (n=110), IPF (n=45) and controls (n=28). Subjects underwent bronchoalveolar lavage and bacterial DNA was isolated, quantified by qPCR and the 16S rRNA gene was sequenced to characterise the bacterial communities in the lower airways. MAIN MEASUREMENTS AND RESULTS: Distinct differences in the microbial profiles were evident in the lower airways of subjects with CHP and IPF. At the phylum level, the prevailing microbiota of both IPF and CHP subjects included Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria. However, in IPF, Firmicutes dominated while the percentage of reads assigned to Proteobacteria in the same group was significantly lower compared to CHP subjects. At the genus level, Staphylococcus was increased in CHP and Actinomyces and Veillonella in IPF. The lower airway bacterial burden in CHP subjects was higher than controls but lower than those with IPF. In contrast to IPF, there was no association between bacterial burden and survival in CHP. CONCLUSIONS: The microbial profile of the lower airways in subjects with CHP is distinct from that of IPF and, notably, bacterial burden in individuals with CHP fails to predict survival.

Journal article

Invernizzi R, Giallourou N, Swann JR, Hewitt RJ, Ghai P, Wu BG, Li Y, Segal LN, Byrne AJ, Maher TM, Lloyd CM, Molyneaux PLet al., 2021, THE RESPIRATORY MICROBIOME AND METABOLOME IN IDIOPATHIC PULMONARY FIBROSIS, Publisher: BMJ PUBLISHING GROUP, Pages: A2-A3, ISSN: 0040-6376

Conference paper

Albers GJ, Iwasaki J, McErlean P, Ogger PP, Ghai P, Khoyratty TE, Udalova IA, Lloyd CM, Byrne AJet al., 2021, IRF5 regulates airway macrophage metabolic responses, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 204, Pages: 134-143, ISSN: 0009-9104

Journal article

Hewitt RJ, Lloyd CM, 2021, Regulation of immune responses by the airway epithelial cell landscape, NATURE REVIEWS IMMUNOLOGY, Vol: 21, Pages: 347-362, ISSN: 1474-1733

Journal article

Jones SA, Bryant C, Lloyd CM, McInnes I, O'Neill Let al., 2021, A Vision for Cytokine Biology with 20/20 Clarity, FUNCTION, Vol: 2

Journal article

Branchett WJ, Walker SA, Lloyd CM, 2021, Experimental Mouse Models of Asthma and Analysis of CD4 T Cells., Methods Mol Biol, Vol: 2285, Pages: 329-348

Asthma is a highly prevalent lung disease, characterized by airway dysfunction and chronic inflammation. Asthma occurs in both children and adults, but frequently originates in early life. Heterogeneous asthma phenotypes exist, but Th2 cells are key players in a large proportion of cases, while other CD4+ T cell subsets are also implicated in driving and limiting pathology. In this chapter, we describe methods for establishing allergic airway disease to model asthma in adult and neonatal mice, along with protocols for measuring key disease parameters and quantifying and phenotyping CD4+ T cell subtypes.

Journal article

Durrington HJ, Krakowiak K, Meijer P, Begley N, Maidstone R, Goosey L, Gibbs JE, Blaikley JF, Gregory LG, Lloyd CM, Loudon AS, Ray DWet al., 2020, Circadian asthma airway responses are gated by REV-ERB alpha, EUROPEAN RESPIRATORY JOURNAL, Vol: 56, ISSN: 0903-1936

Journal article

Porsbjerg CM, Sverrild A, Lloyd CM, Menzies-Gow AN, Bel EHet al., 2020, Anti-alarmins in asthma: targeting the airway epithelium with next-generation biologics, EUROPEAN RESPIRATORY JOURNAL, Vol: 56, ISSN: 0903-1936

Journal article

Ogger PP, Albers GJ, Hewitt RJ, O'Sullivan BJ, Powell JE, Calamita E, Ghai P, Walker SA, McErlean P, Saunders P, Kingston S, Molyneaux PL, Halket JM, Gray R, Chambers DC, Maher TM, Lloyd CM, Byrne AJet al., 2020, Itaconate controls the severity of pulmonary fibrosis, Science Immunology, Vol: 5, Pages: 1-13, ISSN: 2470-9468

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression (ACOD1) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, Acod1-/- mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in Acod1-/- tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.

Journal article

Ubags NDJ, Alcazar MAA, Kallapur SG, Knapp S, Lanone S, Lloyd CM, Morty RE, Pattaroni C, Reynaert NL, Rottier RJ, Smits HH, Piters WAADS, Strickland DH, Collins JJPet al., 2020, Early origins of lung disease: towards an interdisciplinary approach, EUROPEAN RESPIRATORY REVIEW, Vol: 29, ISSN: 0905-9180

Journal article

Albers GJ, Iwasaki J, Mcerlean P, Ogger PP, Ghai P, Khoyratty TE, Udalova IA, Lloyd CM, Byrne AJet al., 2020, IRF5 regulates airway macrophage metabolic responses to viral challenge, European-Academy-of-Allergology-and-Clinical-Immunology Digital Congress (EAACI), Publisher: WILEY, Pages: 42-43, ISSN: 0105-4538

Conference paper

Andersson CK, Iwasaki J, Cook J, Robinson P, Nagakumar P, Mogren S, Fleming L, Bush A, Saglani S, Lloyd CMet al., 2020, Impaired airway epithelial cell wound-healing capacity is associated with airway remodelling following RSV infection in severe preschool wheeze, ALLERGY, Vol: 75, Pages: 3195-3207, ISSN: 0105-4538

Journal article

Invernizzi R, Lloyd CM, Molyneaux PL, 2020, Respiratory microbiome and epithelial interactions shape immunity in the lungs, Immunology, Vol: 160, Pages: 171-182, ISSN: 0019-2805

The airway epithelium represents a physical barrier to the external environment acting as the first line of defence against potentially harmful environmental stimuli including microbes and allergens. However, lung epithelial cells are increasingly recognised as active effectors of microbial defence, contributing to both innate and adaptive immune function in the lower respiratory tract. These cells express an ample repertoire of pattern-recognition receptors with specificity for conserved microbial and host motifs. Modern molecular techniques have uncovered the complexity of the lower respiratory tract microbiome. The interaction between the microbiota and the airway epithelium is key to understanding how stable immune homeostasis is maintained. Loss of epithelial integrity following exposure to infection can result in the onset of inflammation in susceptible individuals and may culminate in lung disease. Here we discuss the current knowledge regarding the molecular and cellular mechanisms by which the pulmonary epithelium interacts with the lung microbiome in shaping immunity in the lung. Specifically, we focus on the interactions between the lung microbiome and the cells of the conducting airways in modulating immune cell regulation and how defects in barrier structure and function may culminate in lung disease. Understanding these interactions is fundamental in the search for more effective therapies for respiratory diseases.

Journal article

Foster W, Grime C, Tan H-L, Robinson M, Williams G, Carlesso G, Saglani S, Lloyd C, Harker Jet al., 2020, Enhanced frequency and function of follicular T cells in the tonsils of house dust mite sensitized children, Allergy, Vol: 75, Pages: 1240-1243, ISSN: 0105-4538

Journal article

Invernizzi R, Barnett J, Rawal B, Nair A, Ghai P, Kingston S, Chua F, Wu Z, Wells A, Renzoni E, Nicholson A, Rice A, Lloyd C, Byrne A, Maher T, Devaraj A, Molyneaux Pet al., 2020, Bacterial burden in the lower airways predicts disease progression in idiopathic pulmonary fibrosis and is independent of radiological disease extent, European Respiratory Journal, Vol: 55, Pages: 1-9, ISSN: 0903-1936

Increasing bacterial burden in the lower airways of patients with idiopathic pulmonary fibrosis confers an increased risk of disease progression and mortality. However, it remains unclear whether this increased bacterial burden directly influences progression of fibrosis or simply reflects the magnitude of the underlying disease extent or severity.We prospectively recruited 193 patients who underwent bronchoscopy and received a multidisciplinary diagnosis of idiopathic pulmonary fibrosis. Quantification of the total bacterial burden in bronchoalveolar lavage fluid was performed by 16S rRNA gene qPCR. Imaging was independently evaluated by two readers assigning quantitative scores for extent, severity and topography of radiographic changes and relationship of these features with bacterial burden was assessed.Increased bacterial burden significantly associated with disease progression (hazard ratio 2.1; 95% confidence interval 1.287–3.474; p=0.0028). Multivariate stepwise regression demonstrated no relationship between bacterial burden and radiological features or extent of disease. When specifically considering patients with definite or probable usual interstitial pneumonia there was no difference in bacterial burden between these two groups. Despite a postulated association between pleuroparenchymal fibroelastosis and clinical infection, there was no relationship between either the presence or extent of pleuroparenchymal fibroelastosis and bacterial burden.We demonstrate that bacterial burden in the lower airways is not simply secondary to the extent of the underlying architectural destruction of the lung parenchyma seen in idiopathic pulmonary fibrosis. The independent nature of this association supports a relationship with the underlying pathogenic mechanisms and highlights the urgent need for functional studies.

Journal article

Broadbent L, Manzoor S, Zarcone MC, Barabas J, Shields MD, Saglani S, Lloyd CM, Bush A, Custovic A, Ghazal P, Gore M, Marsland B, Roberts G, Schwarze J, Turner S, Power UFet al., 2020, Comparative primary paediatric nasal epithelial cell culture differentiation and RSV-induced cytopathogenesis following culture in two commercial media, PLoS One, Vol: 15, Pages: 1-12, ISSN: 1932-6203

The culture of differentiated human airway epithelial cells allows the study of pathogen-host interactions and innate immune responses in a physiologically relevant in vitro model. As the use of primary cell culture has gained popularity the availability of the reagents needed to generate these cultures has increased. In this study we assessed two different media, Promocell and PneumaCult, during the differentiation and maintenance of well-differentiated primary nasal epithelial cell cultures (WD-PNECs). We compared and contrasted the consequences of these media on WD-PNEC morphological and physiological characteristics and their responses to respiratory syncytial virus (RSV) infection. We found that cultures generated using PneumaCult resulted in greater total numbers of smaller, tightly packed, pseudostratified cells. However, cultures from both media resulted in similar proportions of ciliated and goblet cells. There were no differences in RSV growth kinetics, although more ciliated cells were infected in the PneumaCult cultures. There was also significantly more IL-29/IFNλ1 secreted from PneumaCult compared to Promocell cultures following infection. In conclusion, the type of medium used for the differentiation of primary human airway epithelial cells may impact experimental results.

Journal article

Branchett W, Stoelting H, Oliver R, Walker S, Puttur F, Gregory L, Gabrysova L, Wilson M, O'Garra A, Lloyd Cet al., 2020, A T cell-myeloid IL-10 axis regulates pathogenic IFN-γ-dependent immunity in a mouse model of type 2-low asthma, Journal of Allergy and Clinical Immunology, Vol: 145, Pages: 666-678.e9, ISSN: 0091-6749

BackgroundAlthough originally defined as a type 2 (T2) immune-mediated condition, non-T2 cytokines, such as IFN-γ and IL-17A, have been implicated in asthma pathogenesis, particularly severe disease. IL-10 regulates T helper (Th) cell phenotypes and can dampen T2 immunity to allergens, but its functions in controlling non-T2 cytokine responses in asthma are unclear. Objective: Determine how IL-10 regulates the balance of Th cell responses to inhaled allergen.MethodsAllergic airway disease (AAD) was induced in wild-type, IL-10 reporter and conditional IL-10 or IL-10 receptor α (IL-10Rα) knockout mice, by repeated intranasal administration of house dust mite (HDM). IL-10 and IFN-γ signalling were disrupted using blocking antibodies.ResultsRepeated HDM inhalation induced a mixed IL-13/IL-17A response and accumulation of IL-10-producing FoxP3- effector CD4+ T cells in the lungs. Ablation of T cell-derived IL-10 increased the IFN-γ and IL-17A response to HDM, reducing IL-13 levels and airway eosinophilia without affecting IgE or airway hyperresponsiveness. The increased IFN-γ response could be recapitulated by IL-10Rα deletion in CD11c+ myeloid cells or local IL-10Rα blockade. Disruption of the T cell-myeloid IL-10 axis resulted in elevated pulmonary monocyte-derived dendritic cell numbers and increased IFN-γ-dependent expression of CXCR3 ligands by airway macrophages, suggestive of a feedforward loop of Th1 cell recruitment. Augmented IFN-γ responses in the HDM AAD model were accompanied by increased disruption of airway epithelium, which was reversed by therapeutic blockade of IFN-γ.ConclusionsIL-10 from effector T cells signals to CD11c+ myeloid cells to suppress an atypical and pathogenic IFN-γ response to inhaled HDM.

Journal article

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