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3. Genomic investigations of unexplained acute hepatitis in children

Author

Morfopoulou, Sofia, Buddle, Sarah, Torres Montaguth, Oscar Enrique, Atkinson, Laura, Guerra-Assunção, José Afonso, Moradi Marjaneh, Mahdi, Zennezini Chiozzi, Riccardo, Storey, Nathaniel, Campos, Luis, Hutchinson, J. Ciaran, Counsell, John R., Pollara, Gabriele, Roy, Sunando, Venturini, Cristina, Antinao Diaz, Juan F., Siam, Ala’a, Tappouni, Luke J., Asgarian, Zeinab, Ng, Joanne, Hanlon, Killian S., Lennon, Alexander, McArdle, Andrew, Czap, Agata, Rosenheim, Joshua, Andrade, Catarina, Anderson, Glenn, Lee, Jack C. D., Williams, Rachel, Williams, Charlotte A., Tutill, Helena, Bayzid, Nadua, Martin Bernal, Luz Marina, Macpherson, Hannah, Montgomery, Kylie-Ann, Moore, Catherine, Templeton, Kate, Neill, Claire, Holden, Matt, Gunson, Rory, Shepherd, Samantha J., Shah, Priyen, Cooray, Samantha, Voice, Marie, Steele, Michael, Fink, Colin, Whittaker, Thomas E., Santilli, Giorgia, Gissen, Paul, Kaufer, Benedikt B., Reich, Jana, Andreani, Julien, Simmonds, Peter, Alrabiah, Dimah K., Castellano, Sergi, Chikowore, Primrose, Odam, Miranda, Rampling, Tommy, Houlihan, Catherine, Hoschler, Katja, Talts, Tiina, Celma, Cristina, Gonzalez, Suam, Gallagher, Eileen, Simmons, Ruth, Watson, Conall, Mandal, Sema, Zambon, Maria, Chand, Meera, Hatcher, James, De, Surjo, Baillie, Kenneth, Semple, Malcolm Gracie, Martin, Joanne, Ushiro-Lumb, Ines, Noursadeghi, Mahdad, Deheragoda, Maesha, Hadzic, Nedim, Grammatikopoulos, Tassos, Brown, Rachel, Kelgeri, Chayarani, Thalassinos, Konstantinos, Waddington, Simon N., Jacques, Thomas S., Thomson, Emma, Levin, Michael, Brown, Julianne R., and Breuer, Judith

Published
2023
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4. Rapid synchronous type 1 IFN and virus-specific T cell responses characterize first wave non-severe SARS-CoV-2 infections

Author

Chandran, Aneesh, Rosenheim, Joshua, Nageswaran, Gayathri, Swadling, Leo, Pollara, Gabriele, Gupta, Rishi K., Burton, Alice R., Guerra-Assunção, José Afonso, Woolston, Annemarie, Ronel, Tahel, Pade, Corinna, Gibbons, Joseph M., Sanz-Magallon Duque De Estrada, Blanca, Robert de Massy, Marc, Whelan, Matthew, Semper, Amanda, Brooks, Tim, Altmann, Daniel M., Boyton, Rosemary J., McKnight, Áine, Captur, Gabriella, Manisty, Charlotte, Treibel, Thomas Alexander, Moon, James C., Tomlinson, Gillian S., Maini, Mala K., Chain, Benjamin M., and Noursadeghi, Mahdad

Published
2022
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6. Blood transcriptional biomarkers of acute viral infection for detection of pre-symptomatic SARS-CoV-2 infection: a nested, case-control diagnostic accuracy study

Author

Abbass, Hakam, Abiodun, Aderonke, Alfarih, Mashael, Alldis, Zoe, Altmann, Daniel M, Amin, Oliver E, Andiapen, Mervyn, Artico, Jessica, Augusto, João B, Baca, Georgiana L, Bailey, Sasha NL, Bhuva, Anish N, Boulter, Alex, Bowles, Ruth, Boyton, Rosemary J, Bracken, Olivia V, O'Brien, Ben, Brooks, Tim, Bullock, Natalie, Butler, David K, Captur, Gabriella, Champion, Nicola, Chan, Carmen, Chandran, Aneesh, Collier, David, Couto de Sousa, Jorge, Couto-Parada, Xose, Cutino-Moguel, Teresa, Davies, Rhodri H, Douglas, Brooke, Di Genova, Cecilia, Dieobi-Anene, Keenan, Diniz, Mariana O, Ellis, Anaya, Feehan, Karen, Finlay, Malcolm, Fontana, Marianna, Forooghi, Nasim, Gaier, Celia, Gibbons, Joseph M, Gilroy, Derek, Hamblin, Matt, Harker, Gabrielle, Hewson, Jacqueline, Hickling, Lauren M, Hingorani, Aroon D, Howes, Lee, Hughes, Alun, Hughes, Gemma, Hughes, Rebecca, Itua, Ivie, Jardim, Victor, Lee, Wing-Yiu Jason, Jensen, Melaniepetra, Jones, Jessica, Jones, Meleri, Joy, George, Kapil, Vikas, Kurdi, Hibba, Lambourne, Jonathan, Lin, Kai-Min, Louth, Sarah, Maini, Mala K, Mandadapu, Vineela, Manisty, Charlotte, McKnight, Áine, Menacho, Katia, Mfuko, Celina, Mitchelmore, Oliver, Moon, Christopher, Moon, James C, Munoz Sandoval, Diana, Murray, Sam M, Noursadeghi, Mahdad, Otter, Ashley, Pade, Corinna, Palma, Susana, Parker, Ruth, Patel, Kush, Pawarova, Babita, Petersen, Steffen E, Piniera, Brian, Pieper, Franziska P, Pope, Daniel, Prossora, Maria, Rannigan, Lisa, Rapala, Alicja, Reynolds, Catherine J, Richards, Amy, Robathan, Matthew, Rosenheim, Joshua, Sambile, Genine, Schmidt, Nathalie M, Semper, Amanda, Seraphim, Andreas, Simion, Mihaela, Smit, Angelique, Sugimoto, Michelle, Swadling, Leo, Taylor, Stephen, Temperton, Nigel, Thomas, Stephen, Thornton, George D, Treibel, Thomas A, Tucker, Art, Veerapen, Jessry, Vijayakumar, Mohit, Welch, Sophie, Wodehouse, Theresa, Wynne, Lucinda, Zahedi, Dan, Gupta, Rishi K, Bell, Lucy C, Guerra-Assuncao, Jose A, Pollara, Gabriele, Whelan, Matthew, McKnight, Aine, and Chain, Benjamin M

Published
2021
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10. Functional consequences of HSV-1 infection of dendritic cells

Author

Pollara, Gabriele

Subjects
616.522
Abstract

Herpes simplex virus-1 (HSV-1) infects a significant proportion of the population, causing widespread morbidity and occasional mortality. An understanding of the interaction of this virus with the immune system will aid in the development of vaccines to reduce the prevalence of this infection, and in evaluating its potential role as a vector in immunotherapy. Dendritic cells (DC) are the critical initiators of adaptive immune responses to HSV-1 and are likely to encounter the virus early after infection of the skin or mucosa. This thesis aims to describe the functional consequences of the interaction between HSV-1 and DC. DCs are readily infected by HSV-1. The function of these cells is affected in a multitude of ways. The capacity of infected DC to stimulate T cell proliferation is reduced, following changes in morphology, IL-12 secretion and surface phenotype. However, the infection of DC by HSV-1 also results in activation of both infected and uninfected cells. The secretion and paracrine activity of type IIFN is responsible for the activation of bystander DC and plays an important amplifying role in the secretion of IL-12 by these cells. In contrast, HSV-1 envelope structures bind to the surface of DC and induce maturation directly. The binding of HSV-1 glycoprotein D is critical to the acquisition of this mature phenotype. In the context of natural HSV-1 infection, these findings suggest the hypothesis that the coupling of viral entry to the activation of DC signalling pathways is counterbalanced by viral disruption of DC maturation. This delays the generation of the immune responses to HSV-1. Nonetheless, the parallel release of type I IFN, resulting in paracrine activation, enables other DC to mount an antiviral immune response.

Published
2005

12. Genomic investigations of unexplained acute hepatitis in children

Author

Morfopoulou, Sofia; https://orcid.org/0000-0001-8181-4548, Buddle, Sarah; https://orcid.org/0000-0002-4738-9469, Montaguth, Oscar Enrique Torres, Atkinson, Laura, Guerra-Assunção, José Afonso; https://orcid.org/0000-0001-6593-403X, Marjaneh, Mahdi Moradi; https://orcid.org/0000-0002-9412-9029, Chiozzi, Riccardo Zenezini, Storey, Nathaniel; https://orcid.org/0000-0001-5942-4674, Campos, Luis; https://orcid.org/0000-0002-4317-0013, Hutchinson, J Ciaran, Counsell, John R; https://orcid.org/0000-0001-9208-101X, Pollara, Gabriele; https://orcid.org/0000-0001-5772-0322, Roy, Sunando, Venturini, Cristina, Antinao Diaz, Juan F, Siam, Ala'a, Tappouni, Luke J; https://orcid.org/0000-0003-2397-0512, Asgarian, Zeinab, Ng, Joanne, Hanlon, Killian S, Lennon, Alexander; https://orcid.org/0000-0002-3363-0637, McArdle, Andrew; https://orcid.org/0000-0001-7448-0869, Czap, Agata, Rosenheim, Joshua; https://orcid.org/0000-0003-0171-2053, Andrade, Catarina, Anderson, Glenn, Lee, Jack C D; https://orcid.org/0000-0002-9866-2808, Williams, Rachel, Williams, Charlotte A, Tutill, Helena; https://orcid.org/0000-0002-9977-9012, et al, Morfopoulou, Sofia; https://orcid.org/0000-0001-8181-4548, Buddle, Sarah; https://orcid.org/0000-0002-4738-9469, Montaguth, Oscar Enrique Torres, Atkinson, Laura, Guerra-Assunção, José Afonso; https://orcid.org/0000-0001-6593-403X, Marjaneh, Mahdi Moradi; https://orcid.org/0000-0002-9412-9029, Chiozzi, Riccardo Zenezini, Storey, Nathaniel; https://orcid.org/0000-0001-5942-4674, Campos, Luis; https://orcid.org/0000-0002-4317-0013, Hutchinson, J Ciaran, Counsell, John R; https://orcid.org/0000-0001-9208-101X, Pollara, Gabriele; https://orcid.org/0000-0001-5772-0322, Roy, Sunando, Venturini, Cristina, Antinao Diaz, Juan F, Siam, Ala'a, Tappouni, Luke J; https://orcid.org/0000-0003-2397-0512, Asgarian, Zeinab, Ng, Joanne, Hanlon, Killian S, Lennon, Alexander; https://orcid.org/0000-0002-3363-0637, McArdle, Andrew; https://orcid.org/0000-0001-7448-0869, Czap, Agata, Rosenheim, Joshua; https://orcid.org/0000-0003-0171-2053, Andrade, Catarina, Anderson, Glenn, Lee, Jack C D; https://orcid.org/0000-0002-9866-2808, Williams, Rachel, Williams, Charlotte A, Tutill, Helena; https://orcid.org/0000-0002-9977-9012, and et al

Abstract

Since its first identification in Scotland, over 1000 cases of unexplained pediatric hepatitis in children have been reported worldwide, including 278 cases in the UK. Here we report investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator subjects, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in liver, blood, plasma or stool from 27/28 cases. We found low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), in 23/31 and 16/23 respectively of the cases tested. In contrast, AAV2 was infrequently detected at low titre in blood or liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded 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 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.

Published
2023

13. Altered IL-6 signalling and risk of tuberculosis disease: a meta-analysis and Mendelian randomisation study

Author

Hamilton, Fergus, Schurz, Haiko, Yates, Tom A., Gilchrist, James J., Möller, Marlo, Naranbhai, Vivek, Ghazal, Peter, Timpson, Nicholas J, Parks, Tom, and Pollara, Gabriele

Subjects
Article
Abstract

SummaryIL-6 responses are ubiquitous inMycobacterium tuberculosis (Mtb)infections, but their role in determining human tuberculosis (TB) disease risk is unknown. We used single nucleotide polymorphisms (SNPs) in and near the IL-6 receptor(IL6R)gene, focusing on the non-synonymous variant, rs2228145, associated with reduced classical IL-6 signalling, to assess the effect of altered IL-6 activity on TB disease risk. We identified 16 genome wide association studies (GWAS) of TB disease collating 17,982 cases of TB disease and 972,389 controls across 4 continents. Meta-analyses and Mendelian randomisation analyses revealed that reduced classical IL-6 signalling was associated with lower odds of TB disease, a finding replicated using multiple, independent SNP instruments and 2 separate exposure variables. Our findings establish a causal relationship between IL-6 signalling and the outcome ofMtbinfection, suggesting IL-6 antagonists do not increase the risk of TB disease and should be investigated as adjuncts in treatment.

Published
2023

15. Blood transcriptional biomarkers of acute viral infection for detection of pre-symptomatic SARS-CoV-2 infection: a nested, case-control diagnostic accuracy study

Author

Gupta, Rishi K, primary, Rosenheim, Joshua, additional, Bell, Lucy C, additional, Chandran, Aneesh, additional, Guerra-Assuncao, Jose A, additional, Pollara, Gabriele, additional, Whelan, Matthew, additional, Artico, Jessica, additional, Joy, George, additional, Kurdi, Hibba, additional, Altmann, Daniel M, additional, Boyton, Rosemary J, additional, Maini, Mala K, additional, McKnight, Aine, additional, Lambourne, Jonathan, additional, Cutino-Moguel, Teresa, additional, Manisty, Charlotte, additional, Treibel, Thomas A, additional, Moon, James C, additional, Chain, Benjamin M, additional, Noursadeghi, Mahdad, additional, Abbass, Hakam, additional, Abiodun, Aderonke, additional, Alfarih, Mashael, additional, Alldis, Zoe, additional, Amin, Oliver E, additional, Andiapen, Mervyn, additional, Augusto, João B, additional, Baca, Georgiana L, additional, Bailey, Sasha NL, additional, Bhuva, Anish N, additional, Boulter, Alex, additional, Bowles, Ruth, additional, Bracken, Olivia V, additional, O'Brien, Ben, additional, Brooks, Tim, additional, Bullock, Natalie, additional, Butler, David K, additional, Captur, Gabriella, additional, Champion, Nicola, additional, Chan, Carmen, additional, Collier, David, additional, Couto de Sousa, Jorge, additional, Couto-Parada, Xose, additional, Davies, Rhodri H, additional, Douglas, Brooke, additional, Di Genova, Cecilia, additional, Dieobi-Anene, Keenan, additional, Diniz, Mariana O, additional, Ellis, Anaya, additional, Feehan, Karen, additional, Finlay, Malcolm, additional, Fontana, Marianna, additional, Forooghi, Nasim, additional, Gaier, Celia, additional, Gibbons, Joseph M, additional, Gilroy, Derek, additional, Hamblin, Matt, additional, Harker, Gabrielle, additional, Hewson, Jacqueline, additional, Hickling, Lauren M, additional, Hingorani, Aroon D, additional, Howes, Lee, additional, Hughes, Alun, additional, Hughes, Gemma, additional, Hughes, Rebecca, additional, Itua, Ivie, additional, Jardim, Victor, additional, Lee, Wing-Yiu Jason, additional, Jensen, Melaniepetra, additional, Jones, Jessica, additional, Jones, Meleri, additional, Kapil, Vikas, additional, Lin, Kai-Min, additional, Louth, Sarah, additional, Mandadapu, Vineela, additional, Manisty,, Charlotte, additional, McKnight, Áine, additional, Menacho, Katia, additional, Mfuko, Celina, additional, Mitchelmore, Oliver, additional, Moon, Christopher, additional, Moon,, James C, additional, Munoz Sandoval, Diana, additional, Murray, Sam M, additional, Otter, Ashley, additional, Pade, Corinna, additional, Palma, Susana, additional, Parker, Ruth, additional, Patel, Kush, additional, Pawarova, Babita, additional, Petersen, Steffen E, additional, Piniera, Brian, additional, Pieper, Franziska P, additional, Pope, Daniel, additional, Prossora, Maria, additional, Rannigan, Lisa, additional, Rapala, Alicja, additional, Reynolds, Catherine J, additional, Richards, Amy, additional, Robathan, Matthew, additional, Sambile, Genine, additional, Schmidt, Nathalie M, additional, Semper, Amanda, additional, Seraphim, Andreas, additional, Simion, Mihaela, additional, Smit, Angelique, additional, Sugimoto, Michelle, additional, Swadling, Leo, additional, Taylor, Stephen, additional, Temperton, Nigel, additional, Thomas, Stephen, additional, Thornton, George D, additional, Tucker, Art, additional, Veerapen, Jessry, additional, Vijayakumar, Mohit, additional, Welch, Sophie, additional, Wodehouse, Theresa, additional, Wynne, Lucinda, additional, and Zahedi, Dan, additional

Published
2021
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16. C-reactive protein-guided use of procalcitonin in COVID-19

Author

Houghton, Rebecca, primary, Moore, Nathan, additional, Williams, Rebecca, additional, El-Bakri, Fatima, additional, Peters, Jonathan, additional, Mori, Matilde, additional, Vernet, Gabrielle, additional, Lynch, Jessica, additional, Lewis, Henry, additional, Tavener, Maryanna, additional, Durham, Tom, additional, Bowyer, Jack, additional, Saeed, Kordo, additional, and Pollara, Gabriele, additional

Published
2021
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17. Blood transcriptional biomarkers of acute viral infection for detection of pre-symptomatic SARS-CoV-2 infection: a nested, case-control diagnostic accuracy study

Author

Gupta, Rishi K, Rosenheim, Joshua, Bell, Lucy C, Chandran, Aneesh, Guerra-Assuncao, Jose A, Pollara, Gabriele, Whelan, Matthew, Artico, Jessica, Joy, George, Kurdi, Hibba, Altmann, Daniel M, Boyton, Rosemary J, Maini, Mala K, McKnight, Aine, Lambourne, Jonathan, Cutino-Moguel, Teresa, Manisty, Charlotte, Treibel, Thomas A, Moon, James C, Chain, Benjamin M, Noursadeghi, Mahdad, Abbass, Hakam, Abiodun, Aderonke, Alfarih, Mashael, Alldis, Zoe, Amin, Oliver E, Andiapen, Mervyn, Augusto, João B, Baca, Georgiana L, Bailey, Sasha NL, Bhuva, Anish N, Boulter, Alex, Bowles, Ruth, Bracken, Olivia V, O'Brien, Ben, Brooks, Tim, Bullock, Natalie, Butler, David K, Captur, Gabriella, Champion, Nicola, Chan, Carmen, Collier, David, Couto de Sousa, Jorge, Couto-Parada, Xose, Davies, Rhodri H, Douglas, Brooke, Di Genova, Cecilia, Dieobi-Anene, Keenan, Diniz, Mariana O, Ellis, Anaya, Feehan, Karen, Finlay, Malcolm, Fontana, Marianna, Forooghi, Nasim, Gaier, Celia, Gibbons, Joseph M, Gilroy, Derek, Hamblin, Matt, Harker, Gabrielle, Hewson, Jacqueline, Hickling, Lauren M, Hingorani, Aroon D, Howes, Lee, Hughes, Alun, Hughes, Gemma, Hughes, Rebecca, Itua, Ivie, Jardim, Victor, Lee, Wing-Yiu Jason, Jensen, Melaniepetra, Jones, Jessica, Jones, Meleri, Kapil, Vikas, Lin, Kai-Min, Louth, Sarah, Mandadapu, Vineela, Manisty,, Charlotte, McKnight, Áine, Menacho, Katia, Mfuko, Celina, Mitchelmore, Oliver, Moon, Christopher, Moon,, James C, Munoz Sandoval, Diana, Murray, Sam M, Otter, Ashley, Pade, Corinna, Palma, Susana, Parker, Ruth, Patel, Kush, Pawarova, Babita, Petersen, Steffen E, Piniera, Brian, Pieper, Franziska P, Pope, Daniel, Prossora, Maria, Rannigan, Lisa, Rapala, Alicja, Reynolds, Catherine J, Richards, Amy, Robathan, Matthew, Sambile, Genine, Schmidt, Nathalie M, Semper, Amanda, Seraphim, Andreas, Simion, Mihaela, Smit, Angelique, Sugimoto, Michelle, Swadling, Leo, Taylor, Stephen, Temperton, Nigel J., Thomas, Stephen, Thornton, George D, Tucker, Art, Veerapen, Jessry, Vijayakumar, Mohit, Welch, Sophie, Wodehouse, Theresa, Wynne, Lucinda, Zahedi, Dan, Gupta, Rishi K, Rosenheim, Joshua, Bell, Lucy C, Chandran, Aneesh, Guerra-Assuncao, Jose A, Pollara, Gabriele, Whelan, Matthew, Artico, Jessica, Joy, George, Kurdi, Hibba, Altmann, Daniel M, Boyton, Rosemary J, Maini, Mala K, McKnight, Aine, Lambourne, Jonathan, Cutino-Moguel, Teresa, Manisty, Charlotte, Treibel, Thomas A, Moon, James C, Chain, Benjamin M, Noursadeghi, Mahdad, Abbass, Hakam, Abiodun, Aderonke, Alfarih, Mashael, Alldis, Zoe, Amin, Oliver E, Andiapen, Mervyn, Augusto, João B, Baca, Georgiana L, Bailey, Sasha NL, Bhuva, Anish N, Boulter, Alex, Bowles, Ruth, Bracken, Olivia V, O'Brien, Ben, Brooks, Tim, Bullock, Natalie, Butler, David K, Captur, Gabriella, Champion, Nicola, Chan, Carmen, Collier, David, Couto de Sousa, Jorge, Couto-Parada, Xose, Davies, Rhodri H, Douglas, Brooke, Di Genova, Cecilia, Dieobi-Anene, Keenan, Diniz, Mariana O, Ellis, Anaya, Feehan, Karen, Finlay, Malcolm, Fontana, Marianna, Forooghi, Nasim, Gaier, Celia, Gibbons, Joseph M, Gilroy, Derek, Hamblin, Matt, Harker, Gabrielle, Hewson, Jacqueline, Hickling, Lauren M, Hingorani, Aroon D, Howes, Lee, Hughes, Alun, Hughes, Gemma, Hughes, Rebecca, Itua, Ivie, Jardim, Victor, Lee, Wing-Yiu Jason, Jensen, Melaniepetra, Jones, Jessica, Jones, Meleri, Kapil, Vikas, Lin, Kai-Min, Louth, Sarah, Mandadapu, Vineela, Manisty,, Charlotte, McKnight, Áine, Menacho, Katia, Mfuko, Celina, Mitchelmore, Oliver, Moon, Christopher, Moon,, James C, Munoz Sandoval, Diana, Murray, Sam M, Otter, Ashley, Pade, Corinna, Palma, Susana, Parker, Ruth, Patel, Kush, Pawarova, Babita, Petersen, Steffen E, Piniera, Brian, Pieper, Franziska P, Pope, Daniel, Prossora, Maria, Rannigan, Lisa, Rapala, Alicja, Reynolds, Catherine J, Richards, Amy, Robathan, Matthew, Sambile, Genine, Schmidt, Nathalie M, Semper, Amanda, Seraphim, Andreas, Simion, Mihaela, Smit, Angelique, Sugimoto, Michelle, Swadling, Leo, Taylor, Stephen, Temperton, Nigel J., Thomas, Stephen, Thornton, George D, Tucker, Art, Veerapen, Jessry, Vijayakumar, Mohit, Welch, Sophie, Wodehouse, Theresa, Wynne, Lucinda, and Zahedi, Dan

Abstract

Background We hypothesised that host-response biomarkers of viral infections might contribute to early identification of individuals infected with SARS-CoV-2, which is critical to breaking the chains of transmission. We aimed to evaluate the diagnostic accuracy of existing candidate whole-blood transcriptomic signatures for viral infection to predict positivity of nasopharyngeal SARS-CoV-2 PCR testing.Methods We did a nested case-control diagnostic accuracy study among a prospective cohort of health-care workers (aged ≥18 years) at St Bartholomew’s Hospital (London, UK) undergoing weekly blood and nasopharyngeal swab sampling for whole-blood RNA sequencing and SARS-CoV-2 PCR testing, when fit to attend work. We identified candidate blood transcriptomic signatures for viral infection through a systematic literature search. We searched MEDLINE for articles published between database inception and Oct 12, 2020, using comprehensive MeSH and keyword terms for “viral infection”, “transcriptome”, “biomarker”, and “blood”. We reconstructed signature scores in blood RNA sequencing data and evaluated their diagnostic accuracy for contemporaneous SARS-CoV-2 infection, compared with the gold standard of SARS-CoV-2 PCR testing, by quantifying the area under the receiver operating characteristic curve (AUROC), sensitivities, and specificities at a standardised Z score of at least 2 based on the distribution of signature scores in test-negative controls. We used pairwise DeLong tests compared with the most discriminating signature to identify the subset of best performing biomarkers. We evaluated associations between signature expression, viral load (using PCR cycle thresholds), and symptom status visually and using Spearman rank correlation. The primary outcome was the AUROC for discriminating between samples from participants who tested negative throughout the study (test-negative controls) and samples from participants with PCR-confirmed SARS-CoV-2 infection (test-positive part

Published
2021

18. Vitamin D3replacement enhances antigen-specific immunity in older adults

Author

Chambers, Emma S., Vukmanovic-Stejic, Milica, Turner, Carolin T., Shih, Barbara B., Trahair, Hugh, Pollara, Gabriele, Tsaliki, Evdokia, Rustin, Malcolm, Freeman, Tom C., Mabbott, Neil A., Noursadeghi, Mahdad, Martineau, Adrian R., Akbar, Arne N., Chambers, Emma S., Vukmanovic-Stejic, Milica, Turner, Carolin T., Shih, Barbara B., Trahair, Hugh, Pollara, Gabriele, Tsaliki, Evdokia, Rustin, Malcolm, Freeman, Tom C., Mabbott, Neil A., Noursadeghi, Mahdad, Martineau, Adrian R., and Akbar, Arne N.

Abstract

Introduction: Ageing is associated with increased number of infections, decreased vaccine efficacy and increased systemic inflammation termed inflammageing. These changes are reflected by reduced recall responses to varicella zoster virus (VZV) challenge in the skin of older adults. Vitamin D deficiency is more common in the old and has been associated with frailty and increased inflammation. In addition, vitamin D increases immunoregulatory mechanisms and therefore has the potential to inhibit inflammageing. Objectives: We investigated the use of vitamin D3 replacement to enhance cutaneous antigen-specific immunity in older adults (≥65 years). Methods: Vitamin D insufficient older adults (n = 18) were administered 6400IU of vitamin D3/day orally for 14 weeks. Antigen-specific immunity to VZV was assessed by clinical score assessment of the injection site and transcriptional analysis of skin biopsies collected from challenged injection sites pre- and post-vitamin D3 replacement. Results: We showed that older adults had reduced VZV-specific cutaneous immune response and increased non-specific inflammation as compared to young. Increased non-specific inflammation observed in the skin of older adults negatively correlated with vitamin D sufficiency. We showed that vitamin D3 supplementation significantly increased the response to cutaneous VZV antigen challenge in older adults. This enhancement was associated with a reduction in inflammatory monocyte infiltration with a concomitant enhancement of T cell recruitment to the site of antigen challenge in the skin. Conclusion: Vitamin D3 replacement can boost antigen-specific immunity in older adults with sub-optimal vitamin D status.

Published
2021

21. Vitamin D3 replacement enhances antigen-specific immunity in older adults

Author

Chambers, Emma S, primary, Vukmanovic-Stejic, Milica, additional, Turner, Carolin T, additional, Shih, Barbara B, additional, Trahair, Hugh, additional, Pollara, Gabriele, additional, Tsaliki, Evdokia, additional, Rustin, Malcolm, additional, Freeman, Tom C, additional, Mabbott, Neil A, additional, Noursadeghi, Mahdad, additional, Martineau, Adrian R, additional, and Akbar, Arne N, additional

Published
2020
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26. Intravenous catheter-related adverse events exceed drug-related adverse events in outpatient parenteral antimicrobial therapy

Author

Underwood, Jonathan, Marks, Michael, Collins, Steve, Logan, Sarah, and Pollara, Gabriele

Abstract

Background\ud\udDrug-related adverse events (AEs) are reported to be common amongst patients receiving outpatient parenteral antimicrobial therapy (OPAT). However, comparative data regarding intravenous (iv) catheter-related AEs are lacking.\ud\ud\udObjectives\ud\udTo compare drug- and iv catheter-related AEs from a large UK OPAT centre.\ud\ud\udPatients and methods\ud\udWe reviewed 544 OPAT episodes [median (IQR) age: 57 (39–71) years, 60% male, 13% with diabetes] with a median (IQR) duration of 7 (2–18) days. Clinically significant drug- and iv catheter-related AEs were calculated as a percentage of OPAT episodes with an AE and also as AEs per 1000 iv drug/catheter days.\ud\ud\udResults\ud\udDrug-related AEs complicated 13 (2.4%) OPAT episodes at 1.7 (95% CI 0.9–2.9) per 1000 drug days. Catheter-related AEs occurred more frequently, complicating 32 (5.9%) episodes at 5.7 (95% CI 4.2–7.9) per 1000 iv catheter days (χ2 test for difference in AE rate: P

Published
2018

27. Tissue Metabolic Changes Drive Cytokine Responses to Mycobacterium tuberculosis

Author

Lachmandas, E.L., Rios-Miguel, Ana B., Kooken, Valerie A.C.M., Pasch, Eva van der, Kumar, V., Matzaraki, V., Oosting, M., Joosten, L.A.B., Notebaart, R.A., Netea, M.G., Crevel, R. van, and Pollara, Gabriele

Subjects
All institutes and research themes of the Radboud University Medical Center, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9]
Abstract

Contains fulltext : 192645.pdf (Publisher’s version ) (Open Access)

Published
2018

30. Tissue Metabolic Changes Drive Cytokine Responses to Mycobacterium tuberculosis

Author

Lachmandas, Ekta, Rios-Miguel, Ana B., Koeken, Valerie A.C.M., van der Pasch, Eva, Kumar, Vinod, Matzaraki, Vasiliki, Li, Yang, Oosting, Marije, Joosten, Leo A.B., Notebaart, Richard A., Noursadeghi, Mahdad, Netea, Mihai G., van Crevel, Reinout, Pollara, Gabriele, Lachmandas, Ekta, Rios-Miguel, Ana B., Koeken, Valerie A.C.M., van der Pasch, Eva, Kumar, Vinod, Matzaraki, Vasiliki, Li, Yang, Oosting, Marije, Joosten, Leo A.B., Notebaart, Richard A., Noursadeghi, Mahdad, Netea, Mihai G., van Crevel, Reinout, and Pollara, Gabriele

Abstract

Cellular metabolism can influence host immune responses to Mycobacterium tuberculosis. Using a systems biology approach, differential expression of 292 metabolic genes involved in glycolysis, glutathione, pyrimidine, and inositol phosphate pathways was evident at the site of a human tuberculin skin test challenge in patients with active tuberculosis infection. For 28 metabolic genes, we identified single nucleotide polymorphisms that were trans-acting for in vitro cytokine responses to M. tuberculosis stimulation, including glutathione and pyrimidine metabolism genes that alter production of Th1 and Th17 cytokines. Our findings identify novel therapeutic targets in host metabolism that may shape protective immunity to tuberculosis.

Published
2018

31. Tumor Necrosis Factor (TNF) bioactivity at the site of an acute cell-mediated immune response Is preserved in rheumatoid arthritis patients responding to Anti-TNF therapy

Author

Byng-Maddick, Rachel, Turner, Carolin T., Pollara, Gabriele, Ellis, Matthew, Guppy, Naomi J., Bell, Lucy C. K., Ehrenstein, Michael R., and Noursadeghi, Mahdad

Subjects
rheumatoid arthritis, anti-tumor necrosis factor, tumor necrosis factor, Immunology, Immunology and Allergy, tuberculin skin test, transcriptional profiling
Abstract

The impact of anti-tumor necrosis factor (TNF) therapies on inducible TNF-dependent activity in humans has never been evaluated in vivo. We aimed to test the hypothesis that patients responding to anti-TNF treatments exhibit attenuated TNF-dependent immune responses at the site of an immune challenge. We developed and validated four context-specific TNF-inducible transcriptional signatures to quantify TNF bioactivity in transcriptomic data. In anti-TNF treated rheumatoid arthritis (RA) patients, we measured the expression of these biosignatures in blood, and in skin biopsies from the site of tuberculin skin tests (TSTs) as a human experimental model of multivariate cell-mediated immune responses. In blood, anti-TNF therapies attenuated TNF bioactivity following ex vivo stimulation. However, at the site of the TST, TNF-inducible gene expression and genome-wide transcriptional changes associated with cell-mediated immune responses were comparable to that of RA patients receiving methotrexate only. These data demonstrate that anti-TNF agents in RA patients do not inhibit inducible TNF activity at the site of an acute inflammatory challenge in vivo, as modeled by the TST. We hypothesize instead that their therapeutic effects are limited to regulating TNF activity in chronic inflammation or by alternative non-canonical pathways.

Published
2017

32. Molecular Signatures of Regression of the Canine Transmissible Venereal Tumor

Author

Frampton, Dan, primary, Schwenzer, Hagen, additional, Marino, Gabriele, additional, Butcher, Lee M., additional, Pollara, Gabriele, additional, Kriston-Vizi, Janos, additional, Venturini, Cristina, additional, Austin, Rachel, additional, de Castro, Karina Ferreira, additional, Ketteler, Robin, additional, Chain, Benjamin, additional, Goldstein, Richard A., additional, Weiss, Robin A., additional, Beck, Stephan, additional, and Fassati, Ariberto, additional

Published
2018
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33. Attitudes and Behaviours to Antimicrobial Prescribing following Introduction of a Smartphone App

Author

Panesar, Preet, Jones, Alisdair, Aldous, Alicia, Kranzer, Katharina, Halpin, Eamus, Fifer, Helen, Macrae, Bruce, Curtis, Carmel, and Pollara, Gabriele

Subjects
Questionnaires, Computer and Information Sciences, Medical Doctors, Attitude of Health Personnel, Health Care Providers, Equipment, lcsh:Medicine, Inappropriate Prescribing, Research and Analysis Methods, Microbiology, Drug Prescriptions, Anti-Infective Agents, Microbial Control, Physicians, Surveys and Questionnaires, Medicine and Health Sciences, Humans, Practice Patterns, Physicians', lcsh:Science, Communication Equipment, Pharmacology, Survey Research, Antimicrobials, Computers, lcsh:R, Drugs, Biology and Life Sciences, Mobile Applications, United Kingdom, Health Care, Professions, Cross-Sectional Studies, Research Design, People and Places, Practice Guidelines as Topic, Engineering and Technology, Population Groupings, lcsh:Q, Antimicrobial Resistance, Smartphone, Cell Phones, Research Article
Abstract

OBJECTIVES: Our hospital replaced the format for delivering portable antimicrobial prescribing guidance from a paper-based pocket guide to a smartphone application (app). We used this opportunity to assess the relationship between its use and the attitudes and behaviours of antimicrobial prescribers. METHODS: We used 2 structured cross-sectional questionnaires issued just prior to and 3 months following the launch of the smartphone app. Ordinal Likert scale responses to both frequencies of use and agreement statements permitted quantitative assessment of the relationship between variables. RESULTS: The smartphone app was used more frequently than the pocket guide it replaced (p < 0.01), and its increased use was associated with sentiments that the app was useful, easy to navigate and its content relevant. Users who used the app more frequently were more likely to agree that the app encouraged them to challenge inappropriate prescribing by their colleagues (p = 0.001) and were more aware of the importance of antimicrobial stewardship (p = 0.005). Reduced use of the app was associated with agreement that senior physicians' preferences for antimicrobial prescribing would irrespectively overrule guideline recommendations (p = 0.0002). CONCLUSIONS: Smartphone apps are an effective and acceptable format to deliver guidance on antimicrobial prescribing. Our findings suggest that they may empower users to challenge incorrect prescribing, breaking well-established behaviours, and thus supporting vital stewardship efforts in an era of increased antimicrobial resistance. Future work will need to focus on the direct impact on drug prescriptions as well as identifying barriers to implementing smartphone apps in other clinical settings.

Published
2016

39. In Vivo Molecular Dissection of the Effects of HIV-1 in Active Tuberculosis

Author

Bell, Lucy C. K., primary, Pollara, Gabriele, additional, Pascoe, Mellissa, additional, Tomlinson, Gillian S., additional, Lehloenya, Rannakoe J., additional, Roe, Jennifer, additional, Meldau, Richard, additional, Miller, Robert F., additional, Ramsay, Alan, additional, Chain, Benjamin M., additional, Dheda, Keertan, additional, and Noursadeghi, Mahdad, additional

Published
2016
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40. Transcriptional response modules characterise IL-1β and IL-6 activity in COVID-19.

Author

Bell LC, Meydan C, Kim J, Foox J, Butler D, Mason CE, Shapira SD, Noursadeghi M, and Pollara G

Abstract

Dysregulated IL-1β and IL-6 responses have been implicated in the pathogenesis of severe Coronavirus Disease 2019 (COVID-19). Innovative approaches for evaluating the biological activity of these cytokines in vivo are urgently needed to complement clinical trials of therapeutic targeting of IL-1β and IL-6 in COVID-19. We show that the expression of IL-1β or IL-6 inducible transcriptional signatures (modules) reflects the bioactivity of these cytokines in immunopathology modelled by juvenile idiopathic arthritis (JIA) and rheumatoid arthritis. In COVID-19, elevated expression of IL-1β and IL-6 response modules, but not the cytokine transcripts themselves, is a feature of infection in the nasopharynx and blood, but is not associated with severity of COVID-19 disease, length of stay or mortality. We propose that IL-1β and IL-6 transcriptional response modules provide a dynamic readout of functional cytokine activity in vivo , aiding quantification of the biological effects of immunomodulatory therapies in COVID-19., Competing Interests: Competing interests No competing interests exist.

Published
2020
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41. Vitamin D 3 replacement enhances antigen-specific immunity in older adults.

Author

Chambers ES, Vukmanovic-Stejic M, Turner CT, Shih BB, Trahair H, Pollara G, Tsaliki E, Rustin M, Freeman TC, Mabbott NA, Noursadeghi M, Martineau AR, and Akbar AN

Abstract

Introduction: Ageing is associated with increased number of infections, decreased vaccine efficacy and increased systemic inflammation termed inflammageing. These changes are reflected by reduced recall responses to varicella zoster virus (VZV) challenge in the skin of older adults. Vitamin D deficiency is more common in the old and has been associated with frailty and increased inflammation. In addition, vitamin D increases immunoregulatory mechanisms and therefore has the potential to inhibit inflammageing., Objectives: We investigated the use of vitamin D 3 replacement to enhance cutaneous antigen-specific immunity in older adults (≥65 years)., Methods: Vitamin D insufficient older adults ( n = 18) were administered 6400IU of vitamin D 3 /day orally for 14 weeks. Antigen-specific immunity to VZV was assessed by clinical score assessment of the injection site and transcriptional analysis of skin biopsies collected from challenged injection sites pre- and post-vitamin D 3 replacement., Results: We showed that older adults had reduced VZV-specific cutaneous immune response and increased non-specific inflammation as compared to young. Increased non-specific inflammation observed in the skin of older adults negatively correlated with vitamin D sufficiency. We showed that vitamin D 3 supplementation significantly increased the response to cutaneous VZV antigen challenge in older adults. This enhancement was associated with a reduction in inflammatory monocyte infiltration with a concomitant enhancement of T cell recruitment to the site of antigen challenge in the skin., Conclusion: Vitamin D 3 replacement can boost antigen-specific immunity in older adults with sub-optimal vitamin D status., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Immunology.)

Published
2020
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42. The differential influence of allogeneic tumor cell death via DNA damage on dendritic cell maturation and antigen presentation.

Author

Rad AN, Pollara G, Sohaib SM, Chiang C, Chain BM, and Katz DR

Subjects
Antigens, CD analysis, Antineoplastic Agents, Alkylating pharmacology, B7-2 Antigen, Cell Death, Coculture Techniques, Humans, Interleukin-12 metabolism, Lymphocyte Activation, Membrane Glycoproteins analysis, Neoplasms immunology, Neoplasms pathology, T-Lymphocytes immunology, U937 Cells, Up-Regulation, Antigen Presentation, DNA Damage, Dendritic Cells physiology, Neoplasms drug therapy
Abstract

Dendritic cells (DCs) respond to danger signals from tissue injury by amplifying their immune-inducing capacity. In the cancer context, this may lead to in vivo antitumor synergism between DCs and DNA-damaging chemotherapeutic agents. Neither the interaction between DCs and dying tumor cells nor whether different ways of inducing cell injury can deliver danger signals of different strength to DCs nor the potential role of damaged DNA as a danger signal has been studied rigorously. Here we report that coculture of immature DCs with tumor cells treated with the alkylating agents melphalan and chlorambucil leads to enhanced autologous and allogeneic T-cell activation, up-regulation of surface expression of MHC and costimulatory molecules, and increased interleukin (IL)-12 secretion. Exposure of the same DCs to tumor cells killed by cytarabine or by freeze-thaw (primary necrosis) resulted in significantly less T-cell proliferation and IL-12 production, indicating that DCs are able to sense and respond differentially to the mode of cell death. Exposure of DCs to DNA purified from tumor cells treated with alkylating agents also increased their T-cell-stimulating capacity, expression of CD86, and IL-12 secretion, supporting the hypothesis that the activating effects of tumor cells are linked to the nature of the DNA damage. This is the first study that shows that DCs respond differentially to killed tumor cells, depending upon the mechanism of DNA damage and consequent cell death.

Published
2003

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