Imperial College London

Peter Openshaw - Professor of Experimental Medicine

Faculty of MedicineNational Heart & Lung Institute

Proconsul, Professor of Experimental Medicine
 
 
 
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Contact

 

+44 (0)20 7594 3854p.openshaw Website CV

 
 
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Assistant

 

Ms Gale Lewis +44 (0)20 7594 0944

 
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Location

 

353Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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447 results found

Wiseman DJ, Thwaites RS, Ritchie AI, Finney L, Macleod M, Kamal F, Shahbakhti H, van Smoorenburg LH, Kerstjens HA, Wildenbeest J, Öner D, Aerssens J, Berbers G, Schepp R, Uruchurtu A, Ditz B, Bont L, Allinson JP, van den Berge M, Donaldson GC, Openshaw PJ, Wedzicha J, RESCEU Investigatorset al., 2024, RSV-related Community COPD Exacerbations and Novel Diagnostics: A Binational Prospective Cohort Study., Am J Respir Crit Care Med

RATIONALE: 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.

Journal article

Lin G-L, Drysdale SB, Snape MD, O'Connor D, Brown A, MacIntyre-Cockett G, Mellado-Gomez E, de Cesare M, Ansari MA, Bonsall D, Bray JE, Jolley KA, Bowden R, Aerssens J, Bont L, Openshaw PJM, Martinon-Torres F, Nair H, Golubchik T, Pollard AJ, RESCEU Consortiumet al., 2024, Targeted metagenomics reveals association between severity and pathogen co-detection in infants with respiratory syncytial virus., Nat Commun, Vol: 15

Respiratory syncytial virus (RSV) is the leading cause of hospitalisation for respiratory infection in young children. RSV disease severity is known to be age-dependent and highest in young infants, but other correlates of severity, particularly the presence of additional respiratory pathogens, are less well understood. In this study, nasopharyngeal swabs were collected from two cohorts of RSV-positive infants <12 months in Spain, the UK, and the Netherlands during 2017-20. We show, using targeted metagenomic sequencing of >100 pathogens, including all common respiratory viruses and bacteria, from samples collected from 433 infants, that burden of additional viruses is common (111/433, 26%) but only modestly correlates with RSV disease severity. In contrast, there is strong evidence in both cohorts and across age groups that presence of Haemophilus bacteria (194/433, 45%) is associated with higher severity, including much higher rates of hospitalisation (odds ratio 4.25, 95% CI 2.03-9.31). There is no evidence for association between higher severity and other detected bacteria, and no difference in severity between RSV genotypes. Our findings reveal the genomic diversity of additional pathogens during RSV infection in infants, and provide an evidence base for future causal investigations of the impact of co-infection on RSV disease severity.

Journal article

Johnson M, Chelysheva I, Öner D, McGinley J, Lin G-L, O'Connor D, Robinson H, Drysdale SB, Gammin E, Vernon S, Muller J, Wolfenden H, Westcar S, Anguvaa L, Thwaites RS, Bont L, Wildenbeest J, Martinón-Torres F, Aerssens J, Openshaw PJM, Pollard AJet al., 2024, A genome-wide association study of respiratory syncytial virus infection severity in infants, Journal of Infectious Diseases, Vol: 229, Pages: S112-S119, ISSN: 0022-1899

BACKGROUND: Respiratory syncytial virus (RSV) is a significant cause of infant morbidity and mortality worldwide; however, understanding the genetic risk factors of severe RSV is incomplete. Neutrophils and monocytes have been previously identified as major cell subsets involved in airway inflammation, however the pathophysiology of these events is also not fully characterised. Given that the majority of children experience at least one RSV infection by the age of two years, but not all develop severe disease, we used genomic and transcriptomic data to explore potential mechanistic biomarkers of disease severity. METHODS: We conducted a genome-wide association study (GWAS) to investigate the genetic factors underlying RSV severity, assessed by the ReSVinet scale, in a cohort of 251 infants aged from 1 week old to 1 year of age. Genotyping data was collected from multiple European study sites as part of the RESCEU Consortium. Data and were analysed following quality control and genotype imputation using the TOPMed server. Generalised linear regression models were employed to assess the impact of genotype on RSV severity. Matrix eQTL in R was used to model the impact of candidate SNPs genotype on gene expression as measured by microarray. RESULTS: While no SNPs reached the genome-wide statistical significance threshold (p < 5 × 10-8), we identified 816 candidate SNPs with a p-value of < 1 × 10-4 and 75 SNPs with a p-value of < 1 × 10-5. Subsequent functional annotation of candidate SNPs highlighted variants previously identified in GWAS studies of inflammatory diseases, and genes relevant to neutrophil trafficking and cytoskeletal functions, including LSP1 and RAB27A. Furthermore, the eQTL analysis revealed that SNPs within the RAB27A locus significantly altered gene expression (FDR p < 0.05). CONCLUSIONS: These findings may provide insights

Journal article

Shankar-Hari M, Calandra T, Soares MP, Bauer M, Wiersinga WJ, Prescott HC, Knight JC, Baillie KJ, Bos LDJ, Derde LPG, Finfer S, Hotchkiss RS, Marshall J, Openshaw PJM, Seymour CW, Venet F, Vincent J-L, Le Tourneau C, Maitland-van der Zee AH, McInnes IB, van der Poll Tet al., 2024, Reframing sepsis immunobiology for translation: towards informative subtyping and targeted immunomodulatory therapies., Lancet Respir Med

Sepsis is a common and deadly condition. Within the current model of sepsis immunobiology, the framing of dysregulated host immune responses into proinflammatory and immunosuppressive responses for the testing of novel treatments has not resulted in successful immunomodulatory therapies. Thus, the recent focus has been to parse observable heterogeneity into subtypes of sepsis to enable personalised immunomodulation. In this Personal View, we highlight that many fundamental immunological concepts such as resistance, disease tolerance, resilience, resolution, and repair are not incorporated into the current sepsis immunobiology model. The focus for addressing heterogeneity in sepsis should be broadened beyond subtyping to encompass the identification of deterministic molecular networks or dominant mechanisms. We explicitly reframe the dysregulated host immune responses in sepsis as altered homoeostasis with pathological disruption of immune-driven resistance, disease tolerance, resilience, and resolution mechanisms. Our proposal highlights opportunities to identify novel treatment targets and could enable successful immunomodulation in the future.

Journal article

Costigan D, Fenn J, Yen S, Ilott N, Bullers S, Hale J, Greenhalf W, Conibear E, Koycheva A, Madon K, Jahan I, Huang M, Badhan A, Parker E, Rosadas C, Jones K, McClure M, Tedder R, Taylor G, Baillie KJ, Semple MG, Openshaw PJM, Pearson C, Johnson J, INSTINCT Study Group, ISARIC4C investigators, Lalvani A, Thornton EEet 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: 1933-0219

The 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.

Journal article

Elneima O, McAuley HJC, Leavy OC, Chalmers JD, Horsley A, Ho LP, Marks M, Poinasamy K, Raman B, Shikotra A, Singapuri A, Sereno M, Harris VC, Houchen-Wolloff L, Saunders RM, Greening NJ, Richardson M, Quint JK, Briggs A, Docherty AB, Kerr S, Harrison EM, Lone NI, Thorpe M, Heaney LG, Lewis KE, Aul R, Beirne P, Bolton CE, Brown JS, Choudhury G, Bakerly ND, Easom N, Echevarria C, Fuld J, Hart N, Hurst JR, Jones MG, Parekh D, Pfeffer P, Rahman NM, Rowland-Jones SL, Thompson AR, Jolley C, Shah AM, Wootton DG, Chalder T, Davies MJ, De Soyza A, Geddes JR, Greenhalf W, Heller S, Howard LS, Jacob J, Jenkins RG, Lord JM, Man WDC, McCann GP, Neubauer S, Openshaw PJ, Porter JC, Rowland MJ, Scott JT, Semple MG, Singh SJ, Thomas DC, Toshner M, Smith N, Sheikh A, Brightling CE, Wain LV, Evans RAet al., 2024, Cohort Profile: Post-Hospitalisation COVID-19 (PHOSP-COVID) study, International Journal of Epidemiology, Vol: 53, ISSN: 0300-5771

Journal article

Wagstaffe HR, Thwaites RS, Reynaldi A, Sidhu JK, McKendry R, Ascough S, Papargyris L, Collins AM, Xu J, Lemm N-M, Siggins MK, Chain BM, Killingley B, Kalinova M, Mann A, Catchpole A, Davenport MP, Openshaw PJM, Chiu Cet al., 2024, Mucosal and systemic immune correlates of viral control after SARS-CoV-2 infection challenge in seronegative adults, Science Immunology, Vol: 9, ISSN: 2470-9468

Human 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.

Journal article

Lord JM, Veenith T, Sullivan J, Sharma-Oates A, Richter AG, Greening NJ, McAuley HJC, Evans RA, Moss P, Moore SC, Turtle L, Gautam N, Gilani A, Bajaj M, Wain LV, Brightling C, Raman B, Marks M, Singapuri A, Elneima O, Openshaw PJM, Duggal NA, PHOSP-COVID Study collaborative group, ISARIC4C investigatorset al., 2024, Accelarated immune ageing is associated with COVID-19 disease severity, Immunity and Ageing, Vol: 21, ISSN: 1742-4933

BACKGROUND: 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

Journal article

Swieboda D, Thwaites R, Rice T, Guo Y, Nadel S, Openshaw P, Holder E, Culley Fet 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: 0009-9104

Early 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.

Journal article

Michael BD, Dunai C, Needham EJ, Tharmaratnam K, Williams R, Huang Y, Boardman SA, Clark JJ, Sharma P, Subramaniam K, Wood GK, Collie C, Digby R, Ren A, Norton E, Leibowitz M, Ebrahimi S, Fower A, Fox H, Tato E, Ellul MA, Sunderland G, Held M, Hetherington C, Egbe FN, Palmos A, Stirrups K, Grundmann A, Chiollaz A-C, Sanchez J-C, Stewart JP, Griffiths M, Solomon T, Breen G, Coles AJ, Kingston N, Bradley JR, Chinnery PF, Cavanagh J, Irani SR, Vincent A, Baillie JK, Openshaw PJ, Semple MG, ISARIC4C Investigators, COVID-CNS Consortium, Taams LS, Menon DKet al., 2023, Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses, Nature Communications, Vol: 14, ISSN: 2041-1723

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1-11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.

Journal article

Thwaites R, Sidhu J, Siggins M, Liew F, Russel C, Uruchurtu A, Davis C, Turtle L, Moore S, Hardwick H, Oosthuyzen W, Thomson E, Semple M, Baillie JK, Openshaw Pet al., 2023, Delayed mucosal anti-viral responses despite robust peripheral inflammation in fatal COVID-19, Journal of Infectious Diseases, ISSN: 0022-1899

Background:While inflammatory and immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished coronavirus disease 2019 (COVID-19) severity categories, and relate these to disease progression and peripheral inflammation.Methods:We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalized with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0–5 days after symptom onset) or late (6–20 days after symptom onset) phase.Results:Patients that survived severe COVID-19 showed interferon (IFN)-dominated mucosal immune responses (IFN-γ, CXCL10, and CXCL13) early in infection. These early mucosal responses were absent in patients who would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by interleukin 2 (IL-2), IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease.Conclusions:Defective early mucosal antiviral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19.

Journal article

Thwaites R, Uruchurtu ASS, Negri VA, Cole M, Singh N, Poshai N, Jackson D, Hoschler K, Baker T, Scott I, Romero Ros X, Cohen ES, Zambon M, Pollock K, Hansel T, Openshaw Pet al., 2023, Early mucosal events drive distinct mucosal and systemic antibody responses to live attenuated influenza vaccine, Nature Communications, Vol: 14, ISSN: 2041-1723

Compared to intramuscular vaccines, nasally administered vaccines have the advantage of inducing local mucosal immune responses that may block infection and interrupt transmission of respiratory pathogens. Live attenuated influenza vaccine (LAIV) is effective in preventing influenza in children, but a correlate of protection for LAIV remains unclear. Studying young adult volunteers, we observe that LAIV induces distinct, compartmentalized, antibody responses in the mucosa and blood. Seeking immunologic correlates of these distinct antibody responses we find associations with mucosal IL-33 release in the first 8 hours post-inoculation and divergent CD8+ and circulating T follicular helper (cTfh) T cell responses 7 days post-inoculation. Mucosal antibodies are induced separately from blood antibodies, are associated with distinct immune responses early post-inoculation, and may provide a correlate of protection for mucosal vaccination. This study was registered as NCT04110366 and reports primary (mucosal antibody) and secondary (blood antibody, and nasal viral load and cytokine) endpoint data.

Journal article

Zivanovic N, Öner D, Abraham Y, McGinley J, Drysdale SB, Wildenbeest JG, Crabbe M, Vanhoof G, Thys K, Thwaites RS, Robinson H, Bont L, Openshaw PJM, Martinón-Torres F, RESCEU Investigators, Pollard AJ, Aerssens Jet al., 2023, Single-cell immune profiling reveals markers of emergency myelopoiesis that distinguish severe from mild respiratory syncytial virus disease in infants, Clinical and Translational Medicine, Vol: 13, ISSN: 2001-1326

Whereas most infants infected with respiratory syncytial virus (RSV) show no or only mild symptoms, an estimated 3 million children under five are hospitalized annually due to RSV disease. This study aimed to investigate biological mechanisms and associated biomarkers underlying RSV disease heterogeneity in young infants, enabling the potential to objectively categorize RSV-infected infants according to their medical needs. Immunophenotypic and functional profiling demonstrated the emergence of immature and progenitor-like neutrophils, proliferative monocytes (HLA-DRLow , Ki67+), impaired antigen-presenting function, downregulation of T cell response and low abundance of HLA-DRLow B cells in severe RSV disease. HLA-DRLow monocytes were found as a hallmark of RSV-infected infants requiring hospitalization. Complementary transcriptomics identified genes associated with disease severity and pointed to the emergency myelopoiesis response. These results shed new light on mechanisms underlying the pathogenesis and development of severe RSV disease and identified potential new candidate biomarkers for patient stratification.

Journal article

Alrezaihi A, Penrice-Randal R, Dong X, Prince T, Randle N, Semple MG, Openshaw PJM, MacGill T, Myers T, Orr R, Zakotnik S, Suljič A, Avšič-Županc T, Petrovec M, Korva M, AlJabr W, Hiscox JA, ISARIC4C Investigatorset al., 2023, Enrichment of SARS-CoV-2 sequence from nasopharyngeal swabs whilst identifying the nasal microbiome, Journal of Clinical Virology, Vol: 171, ISSN: 1386-6532

Simultaneously characterising the genomic information of coronaviruses and the underlying nasal microbiome from a single clinical sample would help characterise infection and disease. Metatranscriptomic approaches can be used to sequence SARS-CoV-2 (and other coronaviruses) and identify mRNAs associated with active transcription in the nasal microbiome. However, given the large sequence background, unenriched metatranscriptomic approaches often do not sequence SARS-CoV-2 to sufficient read and coverage depth to obtain a consensus genome, especially with moderate and low viral loads from clinical samples. In this study, various enrichment methods were assessed to detect SARS-CoV-2, identify lineages and define the nasal microbiome. The methods were underpinned by Oxford Nanopore long-read sequencing and variations of sequence independent single primer amplification (SISPA). The utility of the method(s) was also validated on samples from patients infected seasonal coronaviruses. The feasibility of profiling the nasal microbiome using these enrichment methods was explored. The findings shed light on the performance of different enrichment strategies and their applicability in characterising the composition of the nasal microbiome.

Journal article

Swets MC, Kerr S, Scott-Brown J, Brown AB, Gupta R, Millar JE, Spata E, McCurrach F, Bretherick AD, Docherty A, Harrison D, Rowan K, Young N, ISARIC4C Investigators, Groeneveld GH, Dunning J, Nguyen-Van-Tam JS, Openshaw P, Horby PW, Harrison E, Staplin N, Semple MG, Lone N, Baillie JKet al., 2023, Evaluation of pragmatic oxygenation measurement as a proxy for Covid-19 severity., Nat Commun, Vol: 14

Choosing optimal outcome measures maximizes statistical power, accelerates discovery and improves reliability in early-phase trials. We devised and evaluated a modification to a pragmatic measure of oxygenation function, the [Formula: see text] ratio. Because of the ceiling effect in oxyhaemoglobin saturation, [Formula: see text] ratio ceases to reflect pulmonary oxygenation function at high [Formula: see text] values. We found that the correlation of [Formula: see text] with the reference standard ([Formula: see text]/[Formula: see text] ratio) improves substantially when excluding [Formula: see text] and refer to this measure as [Formula: see text]. Using observational data from 39,765 hospitalised COVID-19 patients, we demonstrate that [Formula: see text] is predictive of mortality, and compare the sample sizes required for trials using four different outcome measures. We show that a significant difference in outcome could be detected with the smallest sample size using [Formula: see text]. We demonstrate that [Formula: see text] is an effective intermediate outcome measure in COVID-19. It is a non-invasive measurement, representative of disease severity and provides greater statistical power.

Journal article

Postma MJ, Cheng C-Y, Buyukkaramikli NC, Hernandez Pastor L, Vandersmissen I, Van Effelterre T, Openshaw P, Simoens Set al., 2023, Reply to Standaert, B. Comment on "Postma et al. Predicted Public Health and Economic Impact of Respiratory Syncytial Virus Vaccination with Variable Duration of Protection for Adults ≥60 Years in Belgium"., Vaccines (Basel), Vol: 11, ISSN: 2076-393X

We have read the commentary from Baudouin Standaert [...].

Journal article

C-MOREPHOSP-COVID Collaborative Group, 2023, Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study, The Lancet Respiratory Medicine, Vol: 11, Pages: 1003-1019, ISSN: 2213-2600

INTRODUCTION: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. METHODS: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. FINDINGS: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2-6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MR

Journal article

Almond M, Jackson M, Jha A, Katosulis O, Pitts O, Tunstall T, Regis E, Dunning J, Byrne A, Mallia P, Kon OM, Saunders K, Karen S, Snelgrove R, Openshaw P, Edwards M, Barclay W, Heaney L, Johnston S, Singanayagam Aet al., 2023, Obesity dysregulates the pulmonary antiviral immune response, Nature Communications, Vol: 14, ISSN: 2041-1723

Obesity is a well-recognized risk factor for severe influenza infections but the mechanisms underlying susceptibility are poorly understood. Here, we identify that obese individuals have deficient pulmonary antiviral immune responses in bronchoalveolar lavage cells but not in bronchial epithelial cells or peripheral blood dendritic cells. We show that the obese human airway metabolome is perturbed with associated increases in the airway concentrations of the adipokine leptin which correlated negatively with the magnitude of ex vivo antiviral responses. Exogenous pulmonary leptin administration in mice directly impaired antiviral type I interferon responses in vivo and ex vivo in cultured airway macrophages. Obese individuals hospitalised with influenza showed dysregulated upper airway immune responses. These studies provide insight into mechanisms driving propensity to severe influenza infections in obesity and raise the potential for development of leptin manipulation or interferon administration as novel strategies for conferring protection from severe infections in obese higher risk individuals.

Journal article

Salaun B, De Smedt J, Vernhes C, Moureau A, Öner D, Bastian AR, Janssens M, Balla-Jhagjhoorsingh S, Aerssens J, Lambert C, Coenen S, Butler CC, Drysdale SB, Wildenbeest JG, Pollard AJ, Openshaw PJM, Bont Let al., 2023, T cells, more than antibodies, may prevent symptoms developing from respiratory syncytial virus infections in older adults, Frontiers in Immunology, Vol: 14, ISSN: 1664-3224

INTRODUCTION: The immune mechanisms supporting partial protection from reinfection and disease by the respiratory syncytial virus (RSV) have not been fully characterized. In older adults, symptoms are typically mild but can be serious in patients with comorbidities when the infection extends to the lower respiratory tract. METHODS: This study formed part of the RESCEU older-adults prospective-cohort study in Northern Europe (2017-2019; NCT03621930) in which a thousand participants were followed over an RSV season. Peripheral-blood samples (taken pre-season, post-season, during illness and convalescence) were analyzed from participants who (i) had a symptomatic acute respiratory tract infection by RSV (RSV-ARTI; N=35) or (ii) asymptomatic RSV infection (RSV-Asymptomatic; N=16). These analyses included evaluations of antibody (Fc-mediated-) functional features and cell-mediated immunity, in which univariate and machine-learning (ML) models were used to explore differences between groups. RESULTS: Pre-RSV-season peripheral-blood biomarkers were predictive of symptomatic RSV infection. T-cell data were more predictive than functional antibody data (area under receiver operating characteristic curve [AUROC] for the models were 99% and 76%, respectively). The pre-RSV season T-cell phenotypes which were selected by the ML modelling and which were more frequent in RSV-Asymptomatic group than in the RSV-ARTI group, coincided with prominent phenotypes identified during convalescence from RSV-ARTI (e.g., IFN-γ+, TNF-α+ and CD40L+ for CD4+, and IFN-γ+ and 4-1BB+ for CD8+). CONCLUSION: The evaluation and statistical modelling of numerous immunological parameters over the RSV season suggests a primary role of cellular immunity in preventing symptomatic RSV infections in older adults.

Journal article

Roper KJ, Thomas J, Albalawi W, Maddocks E, Dobson S, Alshehri A, Barone FG, Baltazar M, Semple MG, Ho A, Turtle L, ISARIC4C Consortium, Paxton WA, Pollakis Get al., 2023, Quantifying neutralising antibody responses against SARS-CoV-2 in dried blood spots (DBS) and paired sera, Scientific Reports, Vol: 13, ISSN: 2045-2322

The ongoing SARS-CoV-2 pandemic was initially managed by non-pharmaceutical interventions such as diagnostic testing, isolation of positive cases, physical distancing and lockdowns. The advent of vaccines has provided crucial protection against SARS-CoV-2. Neutralising antibody (nAb) responses are a key correlate of protection, and therefore measuring nAb responses is essential for monitoring vaccine efficacy. Fingerstick dried blood spots (DBS) are ideal for use in large-scale sero-surveillance because they are inexpensive, offer the option of self-collection and can be transported and stored at ambient temperatures. Such advantages also make DBS appealing to use in resource-limited settings and in potential future pandemics. In this study, nAb responses in sera, venous blood and fingerstick blood stored on filter paper were measured. Samples were collected from SARS-CoV-2 acutely infected individuals, SARS-CoV-2 convalescent individuals and SARS-CoV-2 vaccinated individuals. Good agreement was observed between the nAb responses measured in eluted DBS and paired sera. Stability of nAb responses was also observed in sera stored on filter paper at room temperature for 28 days. Overall, this study provides support for the use of filter paper as a viable sample collection method to study nAb responses.

Journal article

Jacobsen H, Walendy-Gnirss K, Tekin-Bubenheim N, Kouassi NM, Ben-Batalla I, Berenbrok N, Wolff M, dos Reis VP, Zickler M, Scholl L, Gries A, Jania H, Duesedau A, Pilnitz-Stolze G, Jeridi A, Yildirim AO, Fuchs H, Gailus-Durner V, Stoeger C, de Angelis MH, Manuylova T, Klingel K, Culley FJ, Behrends J, Loges S, Schneider B, Krauss-Etschmann S, Openshaw P, Gabriel Get al., 2023, Offspring born to influenza A virus infected pregnant mice show increased vulnerability to viral and bacterial infections in early life, 12th International Workshop Reunion Island Reproductive Immunology, Immunological tolerance and Immunology of preeclampsia, Publisher: ELSEVIER IRELAND LTD, Pages: 7-8, ISSN: 0165-0378

Conference paper

Zhu Y, Almeida FJ, Baillie JK, Bowen AC, Britton PN, Brizuela ME, Buonsenso D, Burgner D, Chew KY, Chokephaibulkit K, Cohen C, Cormier SA, Crawford N, Curtis N, Farias CGA, Gilks CF, von Gottberg A, Hamer D, Jarovsky D, Jassat W, Jesus AR, Kemp LS, Khumcha B, McCallum G, Miller JE, Morello R, Munro APS, Openshaw PJM, Padmanabhan S, Phongsamart W, Reubenson G, Ritz N, Rodrigues F, Rungmaitree S, Russell F, Safadi MAP, Saner C, Semple MG, da Silva DGBP, de Sousa LMM, Souza MDM, Spann K, Walaza S, Wolter N, Xia Y, Yeoh DK, Zar HJ, Zimmermann P, Short KRet al., 2023, International Pediatric COVID-19 Severity Over the Course of the Pandemic, JAMA PEDIATRICS, ISSN: 2168-6203

Journal article

Ward KE, Steadman L, Karim AR, Reynolds GM, Pugh M, Chua W, Faustini SE, Veenith T, Thwaites RS, Openshaw PJM, Drayson MT, Shields AM, Cunningham AF, Wraith DC, Richter AGet al., 2023, SARS-CoV-2 infection is associated with anti-desmoglein 2 autoantibody detection, Clinical and Experimental Immunology, Vol: 213, Pages: 243-251, ISSN: 0009-9104

Post-acute cardiac sequelae, following SARS-CoV-2 infection, are well recognized as complications of COVID-19. We have previously shown the persistence of autoantibodies against antigens in skin, muscle, and heart in individuals following severe COVID-19; the most common staining on skin tissue displayed an inter-cellular cement pattern consistent with antibodies against desmosomal proteins. Desmosomes play a critical role in maintaining the structural integrity of tissues. For this reason, we analyzed desmosomal protein levels and the presence of anti-desmoglein (DSG) 1, 2, and 3 antibodies in acute and convalescent sera from patients with COVID-19 of differing clinical severity. We find increased levels of DSG2 protein in sera from acute COVID-19 patients. Furthermore, we find that DSG2 autoantibody levels are increased significantly in convalescent sera following severe COVID-19 but not in hospitalized patients recovering from influenza infection or healthy controls. Levels of autoantibody in sera from patients with severe COVID-19 were comparable to levels in patients with non-COVID-19-associated cardiac disease, potentially identifying DSG2 autoantibodies as a novel biomarker for cardiac damage. To determine if there was any association between severe COVID-19 and DSG2, we stained post-mortem cardiac tissue from patients who died from COVID-19 infection. This confirmed DSG2 protein within the intercalated discs and disruption of the intercalated disc between cardiomyocytes in patients who died from COVID-19. Our results reveal the potential for DSG2 protein and autoimmunity to DSG2 to contribute to unexpected pathologies associated with COVID-19 infection.

Journal article

Pairo-Castineira E, Rawlik K, Bretherick AD, Qi T, Wu Y, Nassiri I, McConkey GA, Zechner M, Klaric L, Griffiths F, Oosthuyzen W, Kousathanas A, Richmond A, Millar J, Russell CD, Malinauskas T, Thwaites R, Morrice K, Keating S, Maslove D, Nichol A, Semple MG, Knight J, Shankar-Hari M, Summers C, Hinds C, Horby P, Ling L, McAuley D, Montgomery H, Openshaw PJM, Begg C, Walsh T, Tenesa A, Flores C, Riancho JA, Rojas-Martinez A, Lapunzina P, Clohisey S, Abellan J, Alex B, Shelton JF, Yang J, Ponting CP, Wilson JF, Vitart V, Abedalthagafi M, Luchessi AD, Parra EJ, Cruz R, Carracedo A, Fawkes A, Murphy L, Rowan K, Pereira AC, Law A, Fairfax B, Hendry SC, Baillie JKet al., 2023, Author Correction: GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19, Nature, Vol: 619, Pages: E61-E61, ISSN: 0028-0836

Journal article

Yang H, Sun H, Brackenridge S, Zhuang X, Wing PAC, Quastel M, Walters L, Garner L, Wang B, Yao X, Felce SL, Peng Y, Moore S, Peeters BWA, Rei M, Gomes JC, Tomas AG, Davidson A, Semple MG, Turtle LCW, Openshaw PJMJ, Baillie JK, Mentzer AJ, Klenerman P, Borrow P, Dong T, McKeating JA, Gillespie GM, McMichael AJet al., 2023, HLA-E-restricted SARS-CoV-2-specific T cells from convalescent COVID-19 patients suppress virus replication despite HLA class Ia down-regulation, SCIENCE IMMUNOLOGY, Vol: 8, ISSN: 2470-9468

Journal article

Pairo-Castineira E, Rawlik K, Bretherick AD, Qi T, Wu Y, Nassiri I, McConkey GA, Zechner M, Klaric L, Griffiths F, Oosthuyzen W, Kousathanas A, Richmond A, Millar J, Russell CD, Malinauskas T, Thwaites R, Morrice K, Keating S, Maslove D, Nichol A, Semple MG, Knight J, Shankar-Hari M, Summers C, Hinds C, Horby P, Ling L, McAuley D, Montgomery H, Openshaw PJM, Begg C, Walsh T, Tenesa A, Flores C, Riancho JA, Rojas-Martinez A, Lapunzina P, GenOMICC Investigators, SCOURGE Consortium, ISARICC Investigators, 23andMe COVID-19 Team, Yang J, Ponting CP, Wilson JF, Vitart V, Abedalthagafi M, Luchessi AD, Parra EJ, Cruz R, Carracedo A, Fawkes A, Murphy L, Rowan K, Pereira AC, Law A, Fairfax B, Hendry SC, Baillie JKet al., 2023, GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19, Nature, Vol: 617, Pages: 764-768, ISSN: 0028-0836

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Journal article

Morfopoulou S, Buddle S, Torres Montaguth OE, Atkinson L, Guerra-Assunção JA, Moradi Marjaneh M, Zennezini Chiozzi R, Storey N, Campos L, Hutchinson JC, Counsell JR, Pollara G, Roy S, Venturini C, Antinao Diaz JF, Siam A, Tappouni LJ, Asgarian Z, Ng J, Hanlon KS, Lennon A, McArdle A, Czap A, Rosenheim J, Andrade C, Anderson G, Lee JCD, Williams R, Williams CA, Tutill H, Bayzid N, Martin Bernal LM, Macpherson H, Montgomery K-A, Moore C, Templeton K, Neill C, Holden M, Gunson R, Shepherd SJ, Shah P, Cooray S, Voice M, Steele M, Fink C, Whittaker TE, Santilli G, Gissen P, Kaufer BB, Reich J, Andreani J, Simmonds P, Alrabiah DK, Castellano S, Chikowore P, Odam M, Rampling T, Houlihan C, Hoschler K, Talts T, Celma C, Gonzalez S, Gallagher E, Simmons R, Watson C, Mandal S, Zambon M, Chand M, Hatcher J, De S, Baillie K, Semple MG, DIAMONDS Consortium, PERFORM Consortium, ISARIC4C Investigators, Martin J, Ushiro-Lumb I, Noursadeghi M, Deheragoda M, Hadzic N, Grammatikopoulos T, Brown R, Kelgeri C, Thalassinos K, Waddington SN, Jacques TS, Thomson E, Levin M, Brown JR, Breuer Jet al., 2023, Genomic investigations of unexplained acute hepatitis in children, Nature, Vol: 617, Pages: 564-573, ISSN: 0028-0836

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.

Journal article

Postma MJ, Cheng C-Y, Buyukkaramikli NC, Pastor LH, Vandersmissen I, Van Effelterre T, Openshaw P, Simoens Set al., 2023, Predicted Public Health and Economic Impact of Respiratory Syncytial Virus Vaccination with Variable Duration of Protection for Adults =60 Years in Belgium, VACCINES, Vol: 11

Journal article

Liew F, Efstathiou C, Openshaw PJM, 2023, Long COVID: clues about causes, EUROPEAN RESPIRATORY JOURNAL, Vol: 61, ISSN: 0903-1936

Journal article

Cable J, Sun J, Cheon IS, Vaughan AE, Castro IA, Stein SR, López CB, Gostic KM, Openshaw PJM, Ellebedy AH, Wack A, Hutchinson E, Thomas MM, Langlois RA, Lingwood D, Baker SF, Folkins M, Foxman EF, Ward AB, Schwemmle M, Russell AB, Chiu C, Ganti K, Subbarao K, Sheahan TP, Penaloza-MacMaster P, Eddens Tet al., 2023, Respiratory viruses: New frontiers-a Keystone Symposia report., Annals of the New York Academy of Sciences, Vol: 1522, Pages: 60-73, ISSN: 0077-8923

Respiratory viruses are a common cause of morbidity and mortality around the world. Viruses like influenza, RSV, and most recently SARS-CoV-2 can rapidly spread through a population, causing acute infection and, in vulnerable populations, severe or chronic disease. Developing effective treatment and prevention strategies often becomes a race against ever-evolving viruses that develop resistance, leaving therapy efficacy either short-lived or relevant for specific viral strains. On June 29 to July 2, 2022, researchers met for the Keystone symposium "Respiratory Viruses: New Frontiers." Researchers presented new insights into viral biology and virus-host interactions to understand the mechanisms of disease and identify novel treatment and prevention approaches that are effective, durable, and broad.

Journal article

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