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Journal articleStone RG, Short C, Davies JC, et al., 2024,
Chronic rhinosinusitis in the era of CFTR modulator therapy
, JOURNAL OF CYSTIC FIBROSIS, Vol: 23, Pages: 208-213, ISSN: 1569-1993 -
Journal articleMurphy RA, Pizzato J, Cuthbertson L, et al., 2024,
Antimicrobial peptide glatiramer acetate targets Pseudomonas aeruginosa lipopolysaccharides to breach membranes without altering lipopolysaccharide modification
, npj Antimicrobials and Resistance, Vol: 2, ISSN: 2731-8745Antimicrobial peptides (AMPs) are key components of innate immunity across all domains of life. Natural and synthetic AMPs are receiving renewed attention in efforts to combat the antimicrobial resistance (AMR) crisis and the loss of antibiotic efficacy. The gram-negative pathogen Pseudomonas aeruginosa is one of the most concerning infecting bacteria in AMR, particularly in people with cystic fibrosis (CF) where respiratory infections are difficult to eradicate and associated with increased morbidity and mortality. Cationic AMPs exploit the negatively charged lipopolysaccharides (LPS) on P. aeruginosa to bind and disrupt bacterial membrane(s), causing lethal damage. P. aeruginosa modifies its LPS to evade AMP killing. Free-LPS is also a component of CF sputum and feeds pro-inflammatory cycles. Glatiramer acetate (GA) is a random peptide co-polymer—of glycine, lysine, alanine, tyrosine—used as a drug in treatment of multiple sclerosis (MS); we have previously shown GA to be an AMP which synergises with tobramycin against CF P. aeruginosa, functioning via bacterial membrane disruption. Here, we demonstrate GA’s direct binding and sequestration/neutralisation of P. aeruginosa LPS, in keeping with GA’s ability to disrupt the outer membrane. At CF-relevant LPS concentrations, however, membrane disruption by GA was not strongly inhibited. Furthermore, exposure to GA did not result in increased Lipid A modification of LPS or in increased gene expression of systems involved in AMP sensing and LPS modification. Therefore, despite the electrostatic targeting of LPS by GA as part of its activity, P. aeruginosa does not demonstrate LPS modification in its defence.
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Journal articlePhan M-D, Schirra HJ, Nhu NTK, et al., 2024,
Combined functional genomic and metabolomic approaches identify new genes required for growth in human urine by multidrug-resistant <i>Escherichia coli</i> ST131
, MBIO, ISSN: 2150-7511 -
Journal articleNeedham EJ, Ren AL, Digby RJ, et al., 2024,
Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses (vol 145, pg 4097, 2022)
, BRAIN, Vol: 147, Pages: e22-e22, ISSN: 0006-8950 -
Conference paperGriesenbach U, McLachlan G, Sinadinos A, et al., 2024,
F/HN pseudotyped lentiviral vector-mediated transduction of non-human primates
, 30th Annual Congress of the European-Society-of-Gene-and-Cell-Therapy (ESGCT), Publisher: MARY ANN LIEBERT, INC, Pages: A119-A120, ISSN: 1043-0342 -
Journal articleCostigan D, Fenn J, Yen S, et al., 2024,
A pro-inflammatory gut mucosal cytokine response is associated with mild COVID-19 disease and superior induction of serum antibodies
, Mucosal Immunology, Vol: 17, Pages: 111-123, ISSN: 1933-0219The relationship between gastrointestinal tract infection, the host immune response, and the clinical outcome of disease is not well understood in COVID-19. We sought to understand the effect of intestinal immune responses to SARS-CoV-2 on patient outcomes including the magnitude of systemic antibody induction. Combining two prospective cohort studies, International Severe Acute Respiratory and emerging Infections Consortium Comprehensive Clinical Characterisations Collaboration (ISARIC4C) and Integrated Network for Surveillance, Trials and Investigations into COVID-19 Transmission (INSTINCT), we acquired samples from 88 COVID-19 cases representing the full spectrum of disease severity and analysed viral RNA and host gut cytokine responses in the context of clinical and virological outcome measures. There was no correlation between the upper respiratory tract and faecal viral loads. Using hierarchical clustering, we identified a group of fecal cytokines including Interleukin-17A, Granulocyte macrophage colony-stimulating factor, Tumor necrosis factorα, Interleukin-23, and S100A8, that were transiently elevated in mild cases and also correlated with the magnitude of systemic anti-Spike-receptor-binding domain antibody induction. Receiver operating characteristic curve analysis showed that expression of these gut cytokines at study enrolment in hospitalised COVID-19 cases was associated negatively with overall clinical severity implicating a protective role in COVID-19. This suggests that a productive intestinal immune response may be beneficial in the response to a respiratory pathogen and a biomarker of a successful barrier response.
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Journal articleWagstaffe HR, Thwaites RS, Reynaldi A, et al., 2024,
Mucosal and systemic immune correlates of viral control after SARS-CoV-2 infection challenge in seronegative adults
, Science Immunology, Vol: 9, ISSN: 2470-9468Human infection challenge permits in-depth, early, and pre-symptomatic characterization of the immune response, enabling the identification of factors that are important for viral clearance. Here, we performed intranasal inoculation of 34 young adult, seronegative volunteers with a pre-Alpha severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain. Of these participants, 18 (53%) became infected and showed an interferon-dominated mediator response with divergent kinetics between nasal and systemic sites. Peripheral CD4+ and CD8+ T cell activation and proliferation were early and robust but showed distinct kinetic and phenotypic profiles; antigen-specific T cells were largely CD38+Ki67+ and displayed central and effector memory phenotypes. Both mucosal and systemic antibodies became detectable around day 10, but nasal antibodies plateaued after day 14 while circulating antibodies continued to rise. Intensively granular measurements in nasal mucosa and blood allowed modeling of immune responses to primary SARS-CoV-2 infection that revealed CD8+ T cell responses and early mucosal IgA responses strongly associated with viral control, indicating that these mechanisms should be targeted for transmission-reducing intervention.
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Journal articleElneima O, McAuley HJC, Leavy OC, et al., 2024,
Cohort profile: Post-Hospitalisation COVID-19 (PHOSP-COVID) study
, International Journal of Epidemiology, Vol: 53, ISSN: 0300-5771 -
Journal articleLord JM, Veenith T, Sullivan J, et al., 2024,
Accelarated immune ageing is associated with COVID-19 disease severity
, Immunity and Ageing, Vol: 21, ISSN: 1742-4933BACKGROUND: The striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls. RESULTS: We performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3-5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28-ve CD57+ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57+ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 sur
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Journal articleSwieboda D, Thwaites R, Rice T, et al., 2024,
Natural killer cells and innate lymphoid cells but not NKT cells are mature in their cytokine production at birth
, Clinical and Experimental Immunology, Vol: 215, Pages: 1-14, ISSN: 0009-9104Early life is a time of increased susceptibility to infectious diseases and development of allergy. Innate lymphocytes are crucial components of the initiation and regulation of immune responses at mucosal surfaces, but functional differences in innate lymphocytes early in life are not fully described. We aimed to characterise the abundance and function of different innate lymphocyte cell populations in cord blood in comparison to that of adults. Blood was collected from adult donors and umbilical vessels at birth. Multicolour flow cytometry panels were used to identify and characterise lymphocyte populations and their capacity to produce hallmark cytokines. Lymphocytes were more abundant in cord blood compared to adults, however, mucosal-associated invariant T (MAIT) cells and Natural Killer T (NKT)-like cells, were far less abundant. The capacity of NKT-like cells to produce cytokines and their expression of the cytotoxic granule protein granzyme B and the marker of terminal differentiation CD57 were much lower in cord blood than in adults. In contrast, Natural Killer (NK) cells were as abundant in cord blood as in adults, they could produce IFNγ, and their expression of granzyme B was not significantly different to that of adult NK cells, although CD57 expression was lower. All innate lymphoid cell (ILC) subsets were more abundant in cord blood, and ILC1 and ILC2 were capable of production of IFNγ and IL-13, respectively. In conclusion, different innate lymphoid cells differ in both abundance and function in peripheral blood at birth and with important implications for immunity in early life.
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