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Journal articleGahlot DK, Patkowski JB, Fernández de Santaella J, et al., 2024,
Cpx-signalling in Yersinia pseudotuberculosis modulates Lipid-A remodelling and resistance to last-resort antimicrobials
, npj Antimicrobials and Resistance, Vol: 2, ISSN: 2731-8745Antibiotic resistance is a global healthcare crisis. Bacteria are highly adaptable and can rapidly acquire mechanisms of resistance towards conventional antibiotics. The permeability barrier conferred by the Gram-negative bacteria cell envelope constitutes a first line of defence against the action of antibiotics. Exposure to extracytoplasmic stresses can negatively affect cell envelope homoeostasis and this causes localised protein misfolding, compromised envelope integrity and impairs barrier function. The CpxA-CpxR two-component regulatory system has evolved to sense extracytoplasmic stresses and to regulate processes that restore homoeostasis of the cell envelope. Hence, controlled Cpx-signalling assists bacteria in adapting, surviving and proliferating in harsh environments, including exposure to antibiotics. Herein, we determined that an intact Cpx-signalling is key to maintaining the Yersinia pseudotuberculosis resistance to colistin and polymyxin B. The susceptibility displayed by Cpx-signalling defective mutants, correlated with cell-envelope deformity and specific modifications of Lipid-A. In vivo transcriptional analysis and in vitro protein-DNA binding studies demonstrated that these modifications were dependent on the direct regulation of Lipid-A biogenesis and modifications of operons by the active phosphorylated CpxR~P isoform. Altogether, our work defines the regulatory mechanism that enables Cpx-signalling to actively control cell envelope remodelling and the permeability of antibiotics in the clinically relevant enteropathogen Y. pseudotuberculosis.
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Journal articleWaldock J, Cox RJ, Chiu C, et al., 2024,
Inno4Vac Workshop Report Part 1: Controlled Human Influenza Virus Infection Model (CHIVIM) Strain Selection and Immune Assays for CHIVIM Studies, November 2021, MHRA, UK
, INFLUENZA AND OTHER RESPIRATORY VIRUSES, Vol: 18, ISSN: 1750-2640 -
Journal articlePazukhina E, Garcia-Gallo E, Reyes LF, et al., 2024,
Long Covid: a global health issue - a prospective, cohort study set in four continents
, BMJ GLOBAL HEALTH, Vol: 9, ISSN: 2059-7908 -
Journal articleOner D, Vernhes C, Balla-Jhagjhoorsingh S, et al., 2024,
Serum and mucosal antibody-mediated protection and identification of asymptomatic respiratory syncytial virus infection in community-dwelling older adults in Europe
, Frontiers in Immunology, Vol: 15, ISSN: 1664-3224Introduction: Respiratory syncytial virus (RSV) causes acute respiratory tract infection (ARTI) and reinfects adults throughout life, posing a risk for hospitalization in older adults (>60 years) with frailty and comorbidities.Methods: To investigate serum and mucosal antibodies for protection against RSV infections, baseline serum samples were compared for RSV-pre- and -post-fusion (F) binding, and RSV-A2 neutralizing IgG antibodies between symptomatic RSV-ARTI (N = 30), non-RSV (RSV negative) ARTI (N = 386), and no ARTI (N = 338). Mucosal RSV-pre-F IgA and IgG levels, as well as serum RSV-G IgG antibodies, were analyzed to determine their association with protection from symptomatic RSV-ARTI in a subset study.Results: Using a receiver operating characteristic (ROC) analysis, we established thresholds of 1.4- to 1.6-fold change (FC) for RSV-pre-F and -post-F, and RSV-A2 neutralizing IgG antibodies, respectively, enabling the identification of asymptomatic RSV cases with high sensitivity and specificity (>80% and >90%, respectively). As a result, serum RSV-pre-F, RSV-G IgG, and mucosal pre-F binding IgA antibodies showed correlations with protection against symptomatic RSV infection. RSV-pre-F IgG antibodies were correlated with protection from RSV infections irrespective of the symptoms.Discussion: This study provides insights into antibody-mediated protection for symptomatic RSV infection in a community-dwelling older-adult population and establishes a threshold to identify asymptomatic RSV infection using a data-driven approach.
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Journal articleWiseman DJ, Thwaites RS, Ritchie AI, et al., 2024,
Respiratory syncytial virus-related community COPD exacerbations and novel diagnostics: a binational prospective cohort study
, American Journal of Respiratory and Critical Care Medicine, Vol: 210, Pages: 994-1001, ISSN: 1073-449XRATIONALE: Respiratory syncytial virus (RSV) is a common global respiratory virus increasingly recognized as a major pathogen in frail older adults and as a cause of chronic obstructive pulmonary disease (COPD) exacerbations. There is no single test for RSV in adults with acceptable diagnostic accuracy. Trials of RSV vaccines have recently shown excellent safety and efficacy against RSV in older adults; defining the frequency of RSV-related community infections and COPD exacerbations is important for vaccine deployment decisions. OBJECTIVES: This prospective study aimed to establish the frequency of outpatient-managed RSV-related exacerbations of COPD in two well-characterized patient cohorts using a combination of diagnostic methods. METHODS: Participants were recruited at specialist clinics in London, UK and Groningen, NL from 2017 and observed for three consecutive RSV seasons, during exacerbations and at least twice yearly. RSV infections were detected by reverse transcription-polymerase chain reaction (RT-PCR) and serologic testing. MEASUREMENTS AND MAIN RESULTS: 377 patients with COPD attended 1,999 clinic visits and reported 310 exacerbations. There were 27 RSV-related exacerbations (8·7% of total); of these, seven were detected only on PCR, 16 only on serology and 4 by both methods. Increases in RSV specific N-protein antibody were as sensitive as antibody to pre-F or post-F for serodiagnosis of RSV related exacerbations. CONCLUSIONS: RSV is associated with 8.7% of outpatient managed COPD exacerbations in this study. Antibodies to RSV-N protein may have diagnostic value, potentially important in a vaccinated population. The introduction of vaccines that prevent RSV is expected to benefit patients with COPD. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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Journal articleBoos J, van der Made CI, Ramakrishnan G, et al., 2024,
Stratified analyses refine association between TLR7 rare variants and severe COVID-19
, Human Genetics and Genomics Advances, Vol: 5, ISSN: 2666-2477Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway.
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Journal articleShort C, Semple T, Abkir M, et al., 2024,
Silence of the lungs: comparing measures of slow and noncommunicating lung units from pulmonary function tests with computed tomography
, Journal of Applied Physiology, Vol: 137, Pages: 883-891, ISSN: 8750-7587Multiple breath washout (MBW) has successfully assessed the silent lung zone particularly in cystic fibrosis lung disease, however, it is limited to the communicating lung only. There are a number of different pulmonary function methods that can assess what is commonly referred to as trapped air, with varying approaches and sensitivity. Twenty-five people with cystic fibrosis (pwCF) underwent MBW, spirometry, body plethysmography, and spirometry-controlled computed tomography (spiro-CT) on the same day. PwCF also performed extensions to MBW that evaluate air trapping, including our novel extension (MBWShX), which reveals the extent of underventilated lung units (UVLU). In addition, we used two previously established 5-breath methods that provide a volume of trapped gas (VTG). We used trapped air % from spiro-CT as the gold standard for comparison. UVLU derived from MBWShX showed the best agreement with trapped air %, both in terms of correlation (RS 0.89, P < 0.0001) and sensitivity (79%). Bland–Altman analysis demonstrated a significant underestimation of the VTG by both 5-breath methods (−249 mL [95% CI −10,796; 580 mL] and −203 mL [95% CI −997; 591 mL], respectively). Parameters from both spirometry and body plethysmography were suboptimal at assessing this pathophysiology. The parameters from MBWShX demonstrated the best relationship with spiro-CT and had the best sensitivity compared with the other pulmonary function methods assessed in this study. MBWShX shows promise to assess and monitor this critical pathophysiological feature, which has been shown to be a driver of lung disease progression in pwCF.NEW & NOTEWORTHY We consider the term “trapped air” either in the use of imaging or pulmonary function testing, something of a misnomer that can lead to an inaccurate assessment of an important physiological feature. Instead, we propose the term underventilated lung units (UVLU). Of the many pulmonary function meth
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Journal articleCoindy EL, Efstathiou C, Talwar S, et al., 2024,
Antibody-mediated protection against respiratory syncytial virus in children.
, Eur Respir Rev, Vol: 33Respiratory syncytial virus (RSV) is a major global pathogen, causing lower respiratory tract disease in at-risk populations including young children. Antibodies form a crucial layer of protection from RSV disease, particularly in immunologically naïve infants. Such antibodies are derived from the mother via transplacental transfer and breast milk, but may be particularly low in high-risk infants such as those born preterm. Maternally derived antibodies can now be supplemented by the administration of anti-RSV monoclonal antibodies, while a rising wave of maternal and paediatric vaccine strategies are approaching. The implementation of these prophylactics may profoundly decrease the healthcare burden of RSV. In this article, we review the role of antibody-mediated immunity in protecting children from RSV. We focus on maternally derived antibodies as the main source of protection against RSV and study factors that influence the scale of this transfer. The role of passive and active prophylactic approaches in protecting infants against RSV are discussed and knowledge gaps in our understanding of antibody-mediated protection against RSV are identified.
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Journal articleCoindy E, Efstathiou C, Talwar S, et al., 2024,
Antibody-mediated protection against respiratory syncytial virus in children
, European Respiratory Review, Vol: 33, ISSN: 0905-9180Respiratory syncytial virus (RSV) is a major global pathogen, causing lower respiratory tract disease in at-risk populations including young children. Antibodies form a crucial layer of protection from RSV disease, particularly in immunologically naïve infants. Such antibodies are derived from the mother via transplacental transfer and breast milk, but may be particularly low in high-risk infants such as those born preterm. Maternally derived antibodies can now be supplemented by the administration of anti-RSV monoclonal antibodies, while a rising wave of maternal and paediatric vaccine strategies are approaching. The implementation of these prophylactics may profoundly decrease the healthcare burden of RSV. In this article, we review the role of antibody-mediated immunity in protecting children from RSV. We focus on maternally derived antibodies as the main source of protection against RSV and study factors that influence the scale of this transfer. The role of passive and active prophylactic approaches in protecting infants against RSV are discussed and knowledge gaps in our understanding of antibody-mediated protection against RSV are identified.
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Journal articleTrender W, Hellyer P, Killingley B, et al., 2024,
Changes in memory and cognition during the SARS-CoV-2 Human Challenge Study
, EClinicalMedicine, Vol: 76, ISSN: 2589-5370BackgroundPatient-reported outcomes and cross-sectional evidence show an association between COVID-19 and persistent cognitive problems. The causal basis, longevity and domain specificity of this association is unclear due to population variability in baseline cognitive abilities, vulnerabilities, virus variants, vaccination status and treatment.MethodsThirty-four young, healthy, seronegative volunteers were inoculated with Wildtype SARS-CoV-2 under prospectively controlled conditions. Volunteers completed daily physiological measurements and computerised cognitive tasks during quarantine and follow-up at 30, 90, 180, 270, and 360 days. Linear modelling examined differences between ‘infected’ and ‘inoculated but uninfected’ individuals. The main cognitive endpoint was the baseline corrected global cognitive composite score across the battery of tasks administered to the volunteers. Exploratory cognitive endpoints included baseline corrected scores from individual tasks. The study was registered on ClinicalTrials.gov with the identifier NCT04865237 and took place between March 2021 and July 2022.FindingsEighteen volunteers developed infection by qPCR criteria of sustained viral load, one without symptoms and the remainder with mild illness. Infected volunteers showed statistically lower baseline-corrected global composite cognitive scores than uninfected volunteers, both acutely and during follow up (mean difference over all time points = −0.8631, 95% CI = −1.3613, −0.3766) with significant main effect of group in repeated measures ANOVA (F (1,34) = 7.58, p = 0.009). Sensitivity analysis replicated this cross-group difference after controlling for community upper respiratory tract infection, task-learning, remdesivir treatment, baseline reference and model structure. Memory and executive function tasks showed the largest between-group differences. No volunteers reported persistent subjective cognitive symptoms.InterpretationT
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