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101. Transcriptional profiling unveils type I and II interferon networks in blood and tissues across diseases

Author

Singhania, Akul, primary, Graham, Christine M., additional, Gabryšová, Leona, additional, Moreira-Teixeira, Lúcia, additional, Stavropoulos, Evangelos, additional, Pitt, Jonathan M., additional, Chakravarty, Probir, additional, Warnatsch, Annika, additional, Branchett, William J., additional, Conejero, Laura, additional, Lin, Jing-Wen, additional, Davidson, Sophia, additional, Wilson, Mark S., additional, Bancroft, Gregory, additional, Langhorne, Jean, additional, Frickel, Eva, additional, Sesay, Abdul K., additional, Priestnall, Simon L., additional, Herbert, Eleanor, additional, Ioannou, Marianna, additional, Wang, Qian, additional, Humphreys, Ian R., additional, Dodd, Jonathan, additional, Openshaw, Peter J. M., additional, Mayer-Barber, Katrin D., additional, Jankovic, Dragana, additional, Sher, Alan, additional, Lloyd, Clare M., additional, Baldwin, Nicole, additional, Chaussabel, Damien, additional, Papayannopoulos, Venizelos, additional, Wack, Andreas, additional, Banchereau, Jacques F., additional, Pascual, Virginia M., additional, and O’Garra, Anne, additional

Published
2019
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106. Genetic mechanisms of critical illness in COVID-19

Author

Pairo-Castineira, Erola, Clohisey, Sara, Klaric, Lucija, Bretherick, Andrew D., Rawlik, Konrad, Pasko, Dorota, Walker, Susan, Parkinson, Nick, Fourman, Max Head, Russell, Clark D., Furniss, James, Richmond, Anne, Gountouna, Elvina, Wrobel, Nicola, Harrison, David, Wang, Bo, Wu, Yang, Meynert, Alison, Griffiths, Fiona, Oosthuyzen, Wilna, Kousathanas, Athanasios, Moutsianas, Loukas, Yang, Zhijian, Zhai, Ranran, Zheng, Chenqing, Grimes, Graeme, Beale, Rupert, Millar, Jonathan, Shih, Barbara, Keating, Sean, Zechner, Marie, Haley, Chris, Porteous, David J., Hayward, Caroline, Yang, Jian, Knight, Julian, Summers, Charlotte, Shankar-Hari, Manu, Klenerman, Paul, Turtle, Lance, Ho, Antonia, Moore, Shona C., Hinds, Charles, Horby, Peter, Nichol, Alistair, Maslove, David, Ling, Lowell, McAuley, Danny, Montgomery, Hugh, Walsh, Timothy, Pereira, Alexandre C., Renieri, Alessandra, Shen, Xia, Ponting, Chris P., Fawkes, Angie, Tenesa, Albert, Caulfield, Mark, Scott, Richard, Rowan, Kathy, Murphy, Lee, Openshaw, Peter J. M., Semple, Malcolm G., Law, Andrew, Vitart, Veronique, Wilson, James F., and Baillie, J. Kenneth

Abstract

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P= 1.65 × 10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2and OAS3); on chromosome 19p13.2 (rs74956615, P= 2.3 × 10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P= 3.98 ×  10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P= 4.99 × 10−8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptor CCR2is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.

Published
2021
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107. Broad and strong memory CD4+and CD8+T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19

Author

Peng, Yanchun, Mentzer, Alexander J., Liu, Guihai, Yao, Xuan, Yin, Zixi, Dong, Danning, Dejnirattisai, Wanwisa, Rostron, Timothy, Supasa, Piyada, Liu, Chang, López-Camacho, César, Slon-Campos, Jose, Zhao, Yuguang, Stuart, David I., Paesen, Guido C., Grimes, Jonathan M., Antson, Alfred A., Bayfield, Oliver W., Hawkins, Dorothy E. D. P., Ker, De-Sheng, Wang, Beibei, Turtle, Lance, Subramaniam, Krishanthi, Thomson, Paul, Zhang, Ping, Dold, Christina, Ratcliff, Jeremy, Simmonds, Peter, de Silva, Thushan, Sopp, Paul, Wellington, Dannielle, Rajapaksa, Ushani, Chen, Yi-Ling, Salio, Mariolina, Napolitani, Giorgio, Paes, Wayne, Borrow, Persephone, Kessler, Benedikt M., Fry, Jeremy W., Schwabe, Nikolai F., Semple, Malcolm G., Baillie, J. Kenneth, Moore, Shona C., Openshaw, Peter J. M., Ansari, M. Azim, Dunachie, Susanna, Barnes, Eleanor, Frater, John, Kerr, Georgina, Goulder, Philip, Lockett, Teresa, Levin, Robert, Zhang, Yonghong, Jing, Ronghua, Ho, Ling-Pei, Cornall, Richard J., Conlon, Christopher P., Klenerman, Paul, Screaton, Gavin R., Mongkolsapaya, Juthathip, McMichael, Andrew, Knight, Julian C., Ogg, Graham, and Dong, Tao

Abstract

The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4+and/or CD8+epitopes, including six immunodominant regions. Six optimized CD8+epitopes were defined, with peptide–MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8+T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design.

Published
2020
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108. Regulatory T Cells Prevent Th2 Immune Responses and Pulmonary Eosinophilia during Respiratory Syncytial Virus Infection in Mice

Author

Durant, Lydia R., Makris, Spyridon, Voorburg, Cornelia Maaike, Loebbermann, Jens, Johansson, Cecilia, and Openshaw, Peter J. M.

Subjects
CD4-Positive T-Lymphocytes, Interleukin-13, Forkhead Transcription Factors, Mice, Transgenic, Respiratory Syncytial Virus Infections, respiratory system, CD8-Positive T-Lymphocytes, T-Lymphocytes, Regulatory, Mice, Inbred C57BL, Disease Models, Animal, Mice, Th2 Cells, Gene Knockdown Techniques, Pathogenesis and Immunity, Animals, Pulmonary Eosinophilia
Abstract

During viral infection, inflammation and recovery are tightly controlled by competing proinflammatory and regulatory immune pathways. Respiratory syncytial virus (RSV) is the leading global cause of infantile bronchiolitis, which is associated with recurrent wheeze and asthma diagnosis in later life. Th2-driven disease has been well described under some conditions for RSV-infected mice. In the present studies, we used the Foxp3(DTR) mice (which allow specific conditional depletion of Foxp3(+) T cells) to investigate the functional effects of regulatory T cells (Tregs) during A2-strain RSV infection. Infected Treg-depleted mice lost significantly more weight than wild-type mice, indicating enhanced disease. This enhancement was characterized by increased cellularity in the bronchoalveolar lavage (BAL) fluid and notable lung eosinophilia not seen in control mice. This was accompanied by abundant CD4(+) and CD8(+) T cells exhibiting an activated phenotype and induction of interleukin 13 (IL-13)- and GATA3-expressing Th2-type CD4(+) T cells that remained present in the airways even 14 days after infection. Therefore, Treg cells perform vital anti-inflammatory functions during RSV infection, suppressing pathogenic T cell responses and inhibiting lung eosinophilia. These findings provide additional evidence that dysregulation of normal immune responses to viral infection may contribute to severe RSV disease.

Published
2013

116. Open source clinical science for emerging infections

Author

Dunning, Jake W, primary, Merson, Laura, additional, Rohde, Gernot G U, additional, Gao, Zhancheng, additional, Semple, Malcolm G, additional, Tran, Dat, additional, Gordon, Anthony, additional, Olliaro, Piero L, additional, Khoo, Saye H, additional, Bruzzone, Roberto, additional, Horby, Peter, additional, Cobb, J Perren, additional, Longuere, Kajsa-Stina, additional, Kellam, Paul, additional, Nichol, Alistair, additional, Brett, Stephen, additional, Everett, Dean, additional, Walsh, Timothy S, additional, Hien, Tran-Tinh, additional, Yu, Hongjie, additional, Zambon, Maria, additional, Ruiz-Palacios, Guillermo, additional, Lang, Trudie, additional, Akhvlediani, Tamuna, additional, Hayden, Frederick G, additional, Marshall, John, additional, Webb, Steve, additional, Angus, Derek C, additional, Shindo, Nahoko, additional, van der Werf, Sylvie, additional, Openshaw, Peter J M, additional, Farrar, Jeremy, additional, Carson, Gail, additional, and Baillie, J Kenneth, additional

Published
2014
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117. Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza

Author

Dunning, Jake, Blankley, Simon, Hoang, Long T., Cox, Mike, Graham, Christine M., James, Philip L., Bloom, Chloe I., Chaussabel, Damien, Banchereau, Jacques, Brett, Stephen J., Moffatt, Miriam F., O’Garra, Anne, and Openshaw, Peter J. M.

Abstract

Transcriptional profiles and host-response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole-blood mRNA signatures and concentrations of local and systemic immunological mediators in 131 adults hospitalized with influenza, from whom extensive clinical and investigational data were obtained by MOSAIC investigators. Signatures reflective of interferon-related antiviral pathways were common up to day 4 of symptoms in patients who did not require mechanical ventilator support; in those who needed mechanical ventilation, an inflammatory, activated-neutrophil and cell-stress or death (‘bacterial’) pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this ‘bacterial’ signature but was able to enhance its development while attenuating the early ‘viral’ signature. Our findings emphasize the importance of timing and severity in the interpretation of host responses to acute viral infection and identify specific patterns of immune-system activation that might enable the development of novel diagnostic and therapeutic tools for severe influenza.

Published
2018
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121. An Evaluation of Community Assessment Tools (CATs) in Predicting Use of Clinical Interventions and Severe Outcomes during the A(H1N1)pdm09 Pandemic

Author

Semple, Malcolm G., primary, Myles, Puja R., additional, Nicholson, Karl G., additional, Lim, Wei Shen, additional, Read, Robert C., additional, Taylor, Bruce L., additional, Brett, Stephen J., additional, Openshaw, Peter J. M., additional, Enstone, Joanne E., additional, McMenamin, James, additional, Bannister, Barbara, additional, and Nguyen-Van-Tam, Jonathan S., additional

Published
2013
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122. The Helminth-Derived Immunomodulator AvCystatin Reduces Virus Enhanced Inflammation by Induction of Regulatory IL-10+ T Cells.

Author

Schuijs, Martijn J., Hartmann, Susanne, Selkirk, Murray E., Roberts, Luke B., Openshaw, Peter J. M., and Schnoeller, Corinna

Subjects
HELMINTHS, IMMUNOLOGICAL adjuvants, CYSTATINS, INFLAMMATION, T cells, INTERLEUKIN-10, RESPIRATORY syncytial virus
Abstract

Respiratory Syncytial Virus (RSV) is a major pathogen causing low respiratory tract disease (bronchiolitis), primarily in infants. Helminthic infections may alter host immune responses to both helminths and to unrelated immune triggers. For example, we have previously shown that filarial cystatin (AvCystatin/Av17) ameliorates allergic airway inflammation. However, helminthic immunomodulators have so far not been tested in virus-induced disease. We now report that AvCystatin prevents Th2-based immunopathology in vaccine-enhanced RSV lung inflammation, a murine model for bronchiolitis. AvCystatin ablated eosinophil influx, reducing both weight loss and neutrophil recruitment without impairing anti-viral immune responses. AvCystatin also protected mice from excessive inflammation following primary RSV infection, significantly reducing neutrophil influx and cytokine production in the airways. Interestingly, we found that AvCystatin induced an influx of CD4+ FoxP3+ interleukin-10-producing T cells in the airway and lungs, correlating with immunoprotection, and the corresponding cells could also be induced by adoptive transfer of AvCystatin-primed F4/80+ macrophages. Thus, AvCystatin ameliorates enhanced RSV pathology without increasing susceptibility to, or persistence of, viral infection and warrants further investigation as a possible therapy for virus-induced airway disease. [ABSTRACT FROM AUTHOR]

Published
2016
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123. Comparison of CATs, CURB-65 and PMEWS as Triage Tools in Pandemic Influenza Admissions to UK Hospitals: Case Control Analysis Using Retrospective Data

Author

Myles, Puja R., primary, Nguyen-Van-Tam, Jonathan S., additional, Lim, Wei Shen, additional, Nicholson, Karl G., additional, Brett, Stephen J., additional, Enstone, Joanne E., additional, McMenamin, James, additional, Openshaw, Peter J. M., additional, Read, Robert C., additional, Taylor, Bruce L., additional, Bannister, Barbara, additional, and Semple, Malcolm G., additional

Published
2012
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128. Interleukin 18 Coexpression during Respiratory Syncytial Virus Infection Results in Enhanced Disease Mediated by Natural Killer Cells

Author

Harker, James A., primary, Godlee, Alexandra, additional, Wahlsten, Jennifer L., additional, Lee, Debbie C. P., additional, Thorne, Lucy G., additional, Sawant, Devika, additional, Tregoning, John S., additional, Caspi, Rachel R., additional, Bukreyev, Alexander, additional, Collins, Peter L., additional, and Openshaw, Peter J. M., additional

Published
2010
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136. Role of CCL5 (RANTES) in Viral Lung Disease

Author

Culley, Fiona J., primary, Pennycook, Alasdair M. J., additional, Tregoning, John S., additional, Dodd, Jonathan S., additional, Walzl, Gerhard, additional, Wells, Timothy N., additional, Hussell, Tracy, additional, and Openshaw, Peter J. M., additional

Published
2006
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150. The Comparative Clinical Course of Pregnant and Non-Pregnant Women Hospitalised with Influenza A(H1N1)pdm09 Infection.

Author

Dolan, Gayle P., Myles, Puja R., Brett, Stephen J., Enstone, Joanne E., Read, Robert C., Openshaw, Peter J. M., Semple, Malcolm G., Wei Shen Lim, Taylor, Bruce L., McMenamin, James, Nicholson, Karl G., Bannister, Barbara, Nguyen-Van-Tam, Jonathan S., and Cowling, Benjamin J.

Subjects
INFLUENZA research, H1N1 influenza, INFLUENZA A virus, H1N1 subtype, PREGNANCY complications, RESPIRATORY infections, DATA extraction
Abstract

Introduction: The Influenza Clinical Information Network (FLU-CIN) was established to gather detailed clinical and epidemiological information about patients with laboratory confirmed A(H1 N1)pdm09 infection in UK hospitals. This report focuses on the clinical course and outcomes of infection in pregnancy. Methods: A standardised data extraction form was used to obtain detailed clinical information from hospital case notes and electronic records, for patients with PCR-confirmed A(H1N1)pdm09 infection admitted to 13 sentinel hospitals in five clinical 'hubs' and a further 62 non-sentinel hospitals, between 11th May 2009 and 31st January 2010.Outcomes were compared for pregnant and non-pregnant women aged 15-44 years, using univariate and multivariable techniques. Results: Of the 395 women aged 15-44 years, 82 (21%) were pregnant; 73 (89%) in the second or third trimester. Pregnant women were significantly less likely to exhibit severe respiratory distress at initial assessment (OR = 0.49 (95% CI: 0.30-0.82)), require supplemental oxygen on admission (OR = 0.40 (95% CI: 0.20-0.80)), or have underlying co-morbidities (p-trend <0.001). However, they were equally likely to be admitted to high dependency (Level 2) or intensive care (Level 3) and/or to die, after adjustment for potential confounders (adj. OR = 0.93 (95% CI: 0.46-1.92). Of 11 pregnant women needing Level 2/3 care, 10 required mechanical ventilation and three died. Conclusions: Since the expected prevalence of pregnancy in the source population was 6%, our data suggest that pregnancy greatly increased the likelihood of hospital admission with A(H1N1)pdm09. Pregnant women were less likely than non-pregnant women to have respiratory distress on admission, but severe outcomes were equally likely in both groups. [ABSTRACT FROM AUTHOR]

Published
2012
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