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Journal articleScott IC, Zuydam NV, Cann JA, et al., 2025,
IL-33 is associated with alveolar dysfunction in patients with viral lower respiratory tract disease
, Mucosal Immunology, Vol: 18, Pages: 312-325, ISSN: 1933-0219Interleukin (IL)-33 is released following tissue damage, causing airway inflammation and remodelling via reduced IL-33 (IL-33red)/serum stimulation-2 (ST2) and oxidised IL-33 (IL-33ox)/receptor for advanced glycation end products (RAGE)/epidermal growth factor receptor (EGFR) pathways. This study aimed to identify associations of IL-33 with clinical outcomes and pathological mechanisms during viral lower respiratory tract disease (LRTD). Ultra-sensitive immunoassays were developed to measure IL-33red, IL-33ox and IL-33/sST2 complexes in samples from patients hospitalised with COVID-19. Immunohistochemistry and multiomics were used to characterise lung samples. Elevated IL-33 in the airway and IL-33/sST2 complex in the circulation correlated with poor clinical outcomes (death, need for intensive care or mechanical ventilation). IL-33 was localised to airway epithelial and endothelial barriers, whereas IL1RL1 was expressed on aerocytes, alveolar endothelial cells specialised for gaseous exchange. IL-33 increased expression of mediators of neutrophilic inflammation, immune cell infiltration, interferon signalling and coagulation in endothelial cell cultures. Endothelial IL-33 signatures were strongly related with signatures associated with viral LRTD. Increased IL-33 release following respiratory viral infections is associated with poor clinical outcomes and might contribute to alveolar dysfunction. Although this does not show a causal relationship with disease, these results provide a rationale to evaluate pathological roles for IL-33 in viral LRTD.
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Journal articleSagawe JS, Loake V, Openshaw P, et al., 2025,
Aging enhances pro-atrogenic gene expression and skeletal muscle loss following respiratory syncytial virus infection
, GeroScience, Vol: 47, Pages: 1485-1500, ISSN: 2509-2723Aging and many age-related health conditions are associated with skeletal muscle loss. Furthermore, older adults are more susceptible to severe respiratory infections, which can in turn lead to muscle wasting. The mechanisms by which respiratory viral infection can impact skeletal muscle in older adults are not well understood. We determined the effects of acute infection with respiratory syncytial virus (RSV) on the lung and skeletal muscle of aged mice. RSV infection caused more severe disease in aged mice with enhanced weight loss, reduced feeding, higher viral load, and greater airway inflammation. Aged but not young mice showed decreased leg muscle weight at the peak of illness and decreased size of leg muscle fibers. Aged mice increased muscle-specific expression of atrophy-promoting enzymes (Atrogin-1 and MuRF-1) and failed to increase the rate of muscle protein synthesis during RSV infection. In aged mice, the changes in Atrogin-1 and MuRF-1 gene expression in skeletal muscle correlated with IL-6 levels in the lungs. These findings indicate that RSV infection of aged mice provides a model for studying the diverse adverse systemic consequences of respiratory viral infections on health and wellbeing in older adults.
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Journal articleGourlay E, Felton T, Bafadhel M, et al., 2025,
Readability and complexity of written information presented to hospitalised patients for trial consent during the COVID-19 pandemic in the UK: a retrospective document analysis
, BMJ Open, Vol: 15, ISSN: 2044-6055Objectives Patient information sheets (PISs) and informed consent forms (ICFs) are essential tools to communicate and document informed consent for clinical trial participation. These documents need to be easily understandable, especially when used to take informed consent from acutely unwell patients. Health literacy guidance recommends written information should be at a level between reading ages 9–11. We aimed to assess the readability and complexity of PISs/ICFs used for clinical trials of acute therapies during the COVID-19 pandemic.Design Retrospective document analysis.Setting PISs/ICFs used in trials involving pharmaceutical interventions recruiting hospitalised patients with COVID-19 during the first year of the pandemic were sourced from hospitals across the UK.Primary and secondary outcome measures PISs/ICFs were assessed for length, approximate reading time and subsection content. Readability and language complexity were assessed using Flesch-Kincaid Grade Level (FKGL) (range 1–18; higher is more complex), Gunning-Fog (GFOG) (range 1–20; higher is more complex) and Flesch Reading Ease Score (FRES) (range 0–100; below 60 is ‘difficult’ for comprehension).Results 13 documents were analysed with a median length of 5139 words (range 1559–7026), equating to a median reading time of 21.4 min (range 6.5–29.3 min) at 240 words per minute. Median FKGL was 9.8 (9.1–10.8), GFOG 11.8 (10.4–13) and FRES was 54.6 (47.0–58.3). All documents were classified as ‘difficult’ for comprehension and had a reading age of 14 years old or higher.Conclusions All PISs/ICFs analysed contained literary complexity beyond both recommendations and the reading level of many in the UK population. Researchers should seek to improve communications to improve trial volunteer comprehension and recruitment.
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Journal articleMoureau A, Mikolajczyk R, Gottschick C, et al., 2025,
Serum immunoglobulin A (IgA) as a biomarker for respiratory syncytial virus (RSV) infection in children aged below 2 years
, ERJ Open Research, ISSN: 2312-0541QuestionPast research suggested respiratory syncytial virus (RSV) specific serum immunoglobulin A (IgA) antibodies as a biomarker of previous RSV infections in young infants accounting for maternal immunity. This study aimed to confirm this association, and to establish a serological threshold for discriminating RSV-naïve infants from those who have experienced RSV.Material and MethodsThis study involves 135 infants from the LoewenKIDS Study with nasal swabs collected at each acute respiratory infection, and serum samples collected at ages 1 and 2. RSV presence in swabs was ascertained by RT-PCR; RSV-specific IgG and IgA antibody levels against five different structural proteins and RSV neutralising antibodies were measured in sera. Robust Mixture Discriminant Analysis was used to determine the cut-off values and account for false negatives.ResultsOf 135 included infants, 131 had available data at year 1 (Y1), and 95 at year 2 (Y2). Pre-F IgA concentrations were higher in infants with PCR-confirmed RSV infections. There was a further increase in IgA, IgG and NT concentrations from Y1 to Y2 consistent with reinfections. Based on RMDA, the cut-off values of pre-F IgA level indicative of past RSV infection were 0.23 AU·mL−1 at Y1 and 0.22 AU·mL−1 at Y2.Answer to the questionThis study shows that in children aged <2 years, a previous RSV infection is accompanied by pre-F IgA antibody levels above 0.22 AU·mL−1, a value close to a previously proposed cut-off (0.19 AU·mL−1) based on seroresponse data only. The confirmed threshold can be of use in studies assessing vaccination strategies.
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Journal articleWagstaffe HR, Ascough S, Openshaw PJM, 2025,
Human challenge models for vaccine development—strengths, limitations, and expansion into endemic settings: a HIC-Vac meeting report
, Immunotherapy Advances, Vol: 5, ISSN: 2732-4303The HIC-Vac network is a unique association of researchers focussed on the development and use of human infection challenge (HIC, otherwise known as controlled human infection models or CHIM) studies for vaccine and therapeutic development, particularly for pathogens of high global impact. The fifth annual meeting of the HIC-Vac network was held on 1–3 November 2023. The theme of the meeting was capacity-building in endemic settings particularly in low- and middle-income countries (LMIC), where pathogens cause the greatest morbidity and mortality. In this report we highlight the strengths and limitations of HIC and expansion of such studies into endemic settings, noting that immune responses and vaccine efficacy differ across diverse settings and populations. The consensus was that HIC studies must not be restricted to high income settings if they are to be relevant to LMIC populations. This report summarizes the work presented at the HIC-Vac annual meeting, highlighting current and future challenge models, challenge agent manufacture, public engagement, ethics, and industry perspectives.
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Journal articleBercusson A, Williams TJ, Simmonds NJ, et al., 2025,
Increased NFAT and NFκB signalling contribute to the hyperinflammatory phenotype in response to Aspergillus fumigatus in a mouse model of cystic fibrosis
, PLoS Pathogens, Vol: 21, ISSN: 1553-7366Aspergillus fumigatus (Af) is a major mould pathogen found ubiquitously in the air. It commonly infects the airways of people with cystic fibrosis (CF) leading to Aspergillus bronchitis or allergic bronchopulmonary aspergillosis. Resident alveolar macrophages and recruited neutrophils are important first lines of defence for clearance of Af in the lung. However, their contribution to the inflammatory phenotype in CF during Af infection is not well understood. Here, utilising CFTR deficient mice we describe a hyperinflammatory phenotype in both acute and allergic murine models of pulmonary aspergillosis. We show that during aspergillosis, CFTR deficiency leads to increased alveolar macrophage death and persistent inflammation of the airways in CF, accompanied by impaired fungal control. Utilising CFTR deficient murine cells and primary human CF cells we show that at a cellular level there is increased activation of NFκB and NFAT in response to Af which, as in in vivo models, is associated with increased cell death and reduced fungal control. Taken together, these studies indicate that CFTR deficiency promotes increased activation of inflammatory pathways, the induction of macrophage cell death and reduced fungal control contributing to the hyper-inflammatory of pulmonary aspergillosis phenotypes in CF.
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Conference paperGriesenbach U, McLachlan G, Sinadinos A, et al., 2025,
Administration of lentiviral vector doses achieving high transduction efficiency is well tolerated in mice
, Publisher: MARY ANN LIEBERT, INC, Pages: E354-E355, ISSN: 1043-0342 -
Conference paperDavies JC, Mall MA, Polineni D, et al., 2025,
Lenticlair™ 1: A Phase 1/2 trial evaluating the safety, tolerability and efficacy of an inhaled F/HN-pseudotyped lentiviral vector for CF gene therapy in people with CF ineligible for CFTRmodulators
, Publisher: MARY ANN LIEBERT, INC, Pages: E349-E350, ISSN: 1043-0342 -
Conference paperDavies JC, Mall MA, Polineni D, et al., 2025,
™LenticlairT-ON: An extension trial examining long-term safety and efficacy outcomes associated with an inhaled F/HN-pseudotyped lentiviral vector for CF gene therapy in people with CF
, Publisher: MARY ANN LIEBERT, INC, Pages: E352-E353, ISSN: 1043-0342 -
Journal articleHabich A, Chaves Vargas V, Robinson LA, et al., 2025,
Distribution of the four type VI secretion systems in Pseudomonas aeruginosa and classification of their core and accessory effectors
, Nature Communications, Vol: 16, ISSN: 2041-1723Bacterial type VI secretion systems (T6SSs) are puncturing molecular machines that transport effector proteins to kill microbes, manipulate eukaryotic cells, or facilitate nutrient uptake. How and why T6SS machines and effectors differ within a species is not fully understood. Here, we applied molecular population genetics to the T6SSs in a global population of the opportunistic pathogen Pseudomonas aeruginosa. We reveal varying occurrence of up to four distinct T6SS machines. Moreover, we define conserved core T6SS effectors, likely critical for the biology of P. aeruginosa, and accessory effectors that can exhibit mutual exclusivity between strains. By ancestral reconstruction, we observed dynamic changes in the gain and loss of effector genes in the species’ evolutionary history. Our work highlights the potential importance of T6SS intraspecific diversity in bacterial ecology and evolution.
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