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7 results on '"Barnes, Josephine L"'

1. Human SARS-CoV-2 challenge uncovers local and systemic response dynamics.

Author

Lindeboom RGH, Worlock KB, Dratva LM, Yoshida M, Scobie D, Wagstaffe HR, Richardson L, Wilbrey-Clark A, Barnes JL, Kretschmer L, Polanski K, Allen-Hyttinen J, Mehta P, Sumanaweera D, Boccacino JM, Sungnak W, Elmentaite R, Huang N, Mamanova L, Kapuge R, Bolt L, Prigmore E, Killingley B, Kalinova M, Mayer M, Boyers A, Mann A, Swadling L, Woodall MNJ, Ellis S, Smith CM, Teixeira VH, Janes SM, Chambers RC, Haniffa M, Catchpole A, Heyderman R, Noursadeghi M, Chain B, Mayer A, Meyer KB, Chiu C, Nikolić MZ, and Teichmann SA

Subjects
Female, Humans, Male, Epithelial Cells immunology, Gene Expression Profiling, Interferons immunology, Macrophages immunology, Macrophages virology, Nasopharynx virology, Nasopharynx immunology, T-Lymphocytes cytology, T-Lymphocytes immunology, T-Lymphocytes metabolism, T-Lymphocytes virology, Time Factors, Virus Replication, COVID-19 genetics, COVID-19 immunology, COVID-19 pathology, COVID-19 virology, Multiomics, SARS-CoV-2 growth & development, SARS-CoV-2 immunology, SARS-CoV-2 pathogenicity, SARS-CoV-2 physiology, Single-Cell Analysis
Abstract

The COVID-19 pandemic is an ongoing global health threat, yet our understanding of the dynamics of early cellular responses to this disease remains limited 1 . Here in our SARS-CoV-2 human challenge study, we used single-cell multi-omics profiling of nasopharyngeal swabs and blood to temporally resolve abortive, transient and sustained infections in seronegative individuals challenged with pre-Alpha SARS-CoV-2. Our analyses revealed rapid changes in cell-type proportions and dozens of highly dynamic cellular response states in epithelial and immune cells associated with specific time points and infection status. We observed that the interferon response in blood preceded the nasopharyngeal response. Moreover, nasopharyngeal immune infiltration occurred early in samples from individuals with only transient infection and later in samples from individuals with sustained infection. High expression of HLA-DQA2 before inoculation was associated with preventing sustained infection. Ciliated cells showed multiple immune responses and were most permissive for viral replication, whereas nasopharyngeal T cells and macrophages were infected non-productively. We resolved 54 T cell states, including acutely activated T cells that clonally expanded while carrying convergent SARS-CoV-2 motifs. Our new computational pipeline Cell2TCR identifies activated antigen-responding T cells based on a gene expression signature and clusters these into clonotype groups and motifs. Overall, our detailed time series data can serve as a Rosetta stone for epithelial and immune cell responses and reveals early dynamic responses associated with protection against infection., (© 2024. The Author(s).)

Published
2024
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2. Mapping interindividual dynamics of innate immune response at single-cell resolution.

Author

Kumasaka N, Rostom R, Huang N, Polanski K, Meyer KB, Patel S, Boyd R, Gomez C, Barnett SN, Panousis NI, Schwartzentruber J, Ghoussaini M, Lyons PA, Calero-Nieto FJ, Göttgens B, Barnes JL, Worlock KB, Yoshida M, Nikolić MZ, Stephenson E, Reynolds G, Haniffa M, Marioni JC, Stegle O, Hagai T, and Teichmann SA

Subjects
Humans, Genome-Wide Association Study, Immunity, Innate, COVID-19, Autoimmune Diseases
Abstract

Common genetic variants across individuals modulate the cellular response to pathogens and are implicated in diverse immune pathologies, yet how they dynamically alter the response upon infection is not well understood. Here, we triggered antiviral responses in human fibroblasts from 68 healthy donors, and profiled tens of thousands of cells using single-cell RNA-sequencing. We developed GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity), a statistical approach designed to identify nonlinear dynamic genetic effects across transcriptional trajectories of cells. This approach identified 1,275 expression quantitative trait loci (local false discovery rate 10%) that manifested during the responses, many of which were colocalized with susceptibility loci identified by genome-wide association studies of infectious and autoimmune diseases, including the OAS1 splicing quantitative trait locus in a COVID-19 susceptibility locus. In summary, our analytical approach provides a unique framework for delineation of the genetic variants that shape a wide spectrum of transcriptional responses at single-cell resolution., (© 2023. The Author(s).)

Published
2023
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3. Local and systemic responses to SARS-CoV-2 infection in children and adults.

Author

Yoshida M, Worlock KB, Huang N, Lindeboom RGH, Butler CR, Kumasaka N, Dominguez Conde C, Mamanova L, Bolt L, Richardson L, Polanski K, Madissoon E, Barnes JL, Allen-Hyttinen J, Kilich E, Jones BC, de Wilton A, Wilbrey-Clark A, Sungnak W, Pett JP, Weller J, Prigmore E, Yung H, Mehta P, Saleh A, Saigal A, Chu V, Cohen JM, Cane C, Iordanidou A, Shibuya S, Reuschl AK, Herczeg IT, Argento AC, Wunderink RG, Smith SB, Poor TA, Gao CA, Dematte JE, Reynolds G, Haniffa M, Bowyer GS, Coates M, Clatworthy MR, Calero-Nieto FJ, Göttgens B, O'Callaghan C, Sebire NJ, Jolly C, De Coppi P, Smith CM, Misharin AV, Janes SM, Teichmann SA, Nikolić MZ, and Meyer KB

Subjects
Adult, Bronchi immunology, Bronchi virology, COVID-19 pathology, Chicago, Cohort Studies, Disease Progression, Epithelial Cells cytology, Epithelial Cells immunology, Epithelial Cells virology, Female, Humans, Immunity, Innate, London, Male, Nasal Mucosa immunology, Nasal Mucosa virology, SARS-CoV-2 growth & development, Single-Cell Analysis, Trachea virology, Young Adult, COVID-19 blood, COVID-19 immunology, Dendritic Cells immunology, Interferons immunology, Killer Cells, Natural immunology, SARS-CoV-2 immunology, T-Lymphocytes, Cytotoxic immunology
Abstract

It is not fully understood why COVID-19 is typically milder in children 1-3 . Here, to examine the differences between children and adults in their response to SARS-CoV-2 infection, we analysed paediatric and adult patients with COVID-19 as well as healthy control individuals (total n = 93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In the airways of healthy paediatric individuals, we observed cells that were already in an interferon-activated state, which after SARS-CoV-2 infection was further induced especially in airway immune cells. We postulate that higher paediatric innate interferon responses restrict viral replication and disease progression. The systemic response in children was characterized by increases in naive lymphocytes and a depletion of natural killer cells, whereas, in adults, cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signalling in early infection, and identify epithelial cell states associated with COVID-19 and age. Our matching nasal and blood data show a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were substantially reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children., (© 2021. The Author(s).)

Published
2022
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4. Single-cell multi-omics analysis of the immune response in COVID-19.

Author

Stephenson E, Reynolds G, Botting RA, Calero-Nieto FJ, Morgan MD, Tuong ZK, Bach K, Sungnak W, Worlock KB, Yoshida M, Kumasaka N, Kania K, Engelbert J, Olabi B, Spegarova JS, Wilson NK, Mende N, Jardine L, Gardner LCS, Goh I, Horsfall D, McGrath J, Webb S, Mather MW, Lindeboom RGH, Dann E, Huang N, Polanski K, Prigmore E, Gothe F, Scott J, Payne RP, Baker KF, Hanrath AT, Schim van der Loeff ICD, Barr AS, Sanchez-Gonzalez A, Bergamaschi L, Mescia F, Barnes JL, Kilich E, de Wilton A, Saigal A, Saleh A, Janes SM, Smith CM, Gopee N, Wilson C, Coupland P, Coxhead JM, Kiselev VY, van Dongen S, Bacardit J, King HW, Rostron AJ, Simpson AJ, Hambleton S, Laurenti E, Lyons PA, Meyer KB, Nikolić MZ, Duncan CJA, Smith KGC, Teichmann SA, Clatworthy MR, Marioni JC, Göttgens B, and Haniffa M

Subjects
Cross-Sectional Studies, Humans, Monocytes immunology, Receptors, Antigen, B-Cell immunology, Receptors, Antigen, T-Cell immunology, T-Lymphocytes immunology, COVID-19 immunology, Proteome, SARS-CoV-2 immunology, Single-Cell Analysis methods, Transcriptome
Abstract

Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16 + C1QA/B/C + ) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34 + hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8 + T cells and an increased ratio of CD8 + effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.

Published
2021
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5. Mapping interindividual dynamics of innate immune response at single-cell resolution

Author

Kumasaka, Natsuhiko, Rostom, Raghd, Huang, Ni, Polanski, Krzysztof, Meyer, Kerstin B, Patel, Sharad, Boyd, Rachel, Gomez, Celine, Barnett, Sam N, Panousis, Nikolaos I, Schwartzentruber, Jeremy, Ghoussaini, Maya, Lyons, Paul A, Calero-Nieto, Fernando J, Göttgens, Berthold, Barnes, Josephine L, Worlock, Kaylee B, Yoshida, Masahiro, Nikolić, Marko Z, Stephenson, Emily, Reynolds, Gary, Haniffa, Muzlifah, Marioni, John C, Stegle, Oliver, Hagai, Tzachi, Teichmann, Sarah A, Kumasaka, Natsuhiko [0000-0002-3557-0375], Polanski, Krzysztof [0000-0002-2586-9576], Meyer, Kerstin B. [0000-0001-5906-1498], Barnett, Sam N. [0000-0002-8968-4319], Ghoussaini, Maya [0000-0002-2415-2143], Lyons, Paul A. [0000-0001-7035-8997], Calero-Nieto, Fernando J. [0000-0003-3358-8253], Göttgens, Berthold [0000-0001-6302-5705], Barnes, Josephine L. [0000-0001-9938-3176], Worlock, Kaylee B. [0000-0002-5656-7634], Yoshida, Masahiro [0000-0002-3521-5322], Nikolić, Marko Z. [0000-0001-6304-6848], Reynolds, Gary [0000-0002-8142-8708], Haniffa, Muzlifah [0000-0002-3927-2084], Marioni, John C. [0000-0001-9092-0852], Stegle, Oliver [0000-0002-8818-7193], Hagai, Tzachi [0000-0002-4575-6624], Teichmann, Sarah A. [0000-0002-6294-6366], Apollo - University of Cambridge Repository, Meyer, Kerstin B [0000-0001-5906-1498], Barnett, Sam N [0000-0002-8968-4319], Lyons, Paul A [0000-0001-7035-8997], Calero-Nieto, Fernando J [0000-0003-3358-8253], Barnes, Josephine L [0000-0001-9938-3176], Worlock, Kaylee B [0000-0002-5656-7634], Nikolić, Marko Z [0000-0001-6304-6848], Marioni, John C [0000-0001-9092-0852], and Teichmann, Sarah A [0000-0002-6294-6366]

Subjects
Humans, COVID-19, Pentaerythritol Tetranitrate, Immunity, Innate, Genome-Wide Association Study, Autoimmune Diseases
Abstract

Common genetic variants across individuals modulate the cellular response to pathogens and are implicated in diverse immune pathologies, yet how they dynamically alter the response upon infection is not well understood. Here, we triggered antiviral responses in human fibroblasts from 68 healthy donors, and profiled tens of thousands of cells using single-cell RNA-sequencing. We developed GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity), a statistical approach designed to identify nonlinear dynamic genetic effects across transcriptional trajectories of cells. This approach identified 1,275 expression quantitative trait loci (local false discovery rate 10%) that manifested during the responses, many of which were colocalized with susceptibility loci identified by genome-wide association studies of infectious and autoimmune diseases, including the OAS1 splicing quantitative trait locus in a COVID-19 susceptibility locus. In summary, our analytical approach provides a unique framework for delineation of the genetic variants that shape a wide spectrum of transcriptional responses at single-cell resolution.

Published
2023

6. Local and systemic responses to SARS-CoV-2 infection in children and adults

Author

Yoshida, Masahiro, Worlock, Kaylee B., Huang, Ni, Lindeboom, Rik G. H., Butler, Colin R., Kumasaka, Natsuhiko, Dominguez Conde, Cecilia, Mamanova, Lira, Bolt, Liam, Richardson, Laura, Polanski, Krzysztof, Madissoon, Elo, Barnes, Josephine L., Allen-Hyttinen, Jessica, Kilich, Eliz, Jones, Brendan C., de Wilton, Angus, Wilbrey-Clark, Anna, Sungnak, Waradon, Pett, J. Patrick, Weller, Juliane, Prigmore, Elena, Yung, Henry, Mehta, Puja, Saleh, Aarash, Saigal, Anita, Chu, Vivian, Cohen, Jonathan M., Cane, Clare, Iordanidou, Aikaterini, Shibuya, Soichi, Reuschl, Ann-Kathrin, Herczeg, Iván T., Argento, A. Christine, Wunderink, Richard G., Smith, Sean B., Poor, Taylor A., Gao, Catherine A., Dematte, Jane E., Budinger, G. R. Scott, Donnelly, Helen K., Markov, Nikolay S., Lu, Ziyan, Reynolds, Gary, Haniffa, Muzlifah, Bowyer, Georgina S., Coates, Matthew, Clatworthy, Menna R., Calero-Nieto, Fernando J., Göttgens, Berthold, O’Callaghan, Christopher, Sebire, Neil J., Jolly, Clare, De Coppi, Paolo, Smith, Claire M., Misharin, Alexander V., Janes, Sam M., Teichmann, Sarah A., Nikolić, Marko Z., and Meyer, Kerstin B.

Subjects
Multidisciplinary Sciences, Science & Technology, Multidisciplinary, Science & Technology - Other Topics, COVID-19, CELL
Abstract

It is not fully understood why COVID-19 is typically milder in children1–3. Here, to examine the differences between children and adults in their response to SARS-CoV-2 infection, we analysed paediatric and adult patients with COVID-19 as well as healthy control individuals (total n = 93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In the airways of healthy paediatric individuals, we observed cells that were already in an interferon-activated state, which after SARS-CoV-2 infection was further induced especially in airway immune cells. We postulate that higher paediatric innate interferon responses restrict viral replication and disease progression. The systemic response in children was characterized by increases in naive lymphocytes and a depletion of natural killer cells, whereas, in adults, cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signalling in early infection, and identify epithelial cell states associated with COVID-19 and age. Our matching nasal and blood data show a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were substantially reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children.

Published
2021
Full Text
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7. Single-cell multi-omics analysis of the immune response in COVID-19

Author

Stephenson, Emily, Reynolds, Gary, Botting, Rachel A, Calero-Nieto, Fernando J, Morgan, Michael D, Tuong, Zewen Kelvin, Bach, Karsten, Sungnak, Waradon, Worlock, Kaylee B, Yoshida, Masahiro, Kumasaka, Natsuhiko, Kania, Katarzyna, Engelbert, Justin, Olabi, Bayanne, Spegarova, Jarmila Stremenova, Wilson, Nicola K, Mende, Nicole, Jardine, Laura, Gardner, Louis CS, Goh, Issac, Horsfall, Dave, McGrath, Jim, Webb, Simone, Mather, Michael W, Lindeboom, Rik GH, Dann, Emma, Huang, Ni, Polanski, Krzysztof, Prigmore, Elena, Gothe, Florian, Scott, Jonathan, Payne, Rebecca P, Baker, Kenneth F, Hanrath, Aidan T, Schim Van Der Loeff, Ina CD, Barr, Andrew S, Sanchez-Gonzalez, Amada, Bergamaschi, Laura, Mescia, Federica, Barnes, Josephine L, Kilich, Eliz, De Wilton, Angus, Saigal, Anita, Saleh, Aarash, Janes, Sam M, Smith, Claire M, Gopee, Nusayhah, Wilson, Caroline, Coupland, Paul, Coxhead, Jonathan M, Kiselev, Vladimir Yu, Van Dongen, Stijn, Bacardit, Jaume, King, Hamish W, Cambridge Institute Of Therapeutic Immunology And Infectious Disease-National Institute Of Health Research (CITIID-NIHR) COVID-19 BioResource Collaboration, Rostron, Anthony J, Simpson, A John, Hambleton, Sophie, Laurenti, Elisa, Lyons, Paul A, Meyer, Kerstin B, Nikolić, Marko Z, Duncan, Christopher JA, Smith, Kenneth GC, Teichmann, Sarah A, Clatworthy, Menna R, Marioni, John C, Göttgens, Berthold, Haniffa, Muzlifah, Calero-Nieto, Fernando J [0000-0003-3358-8253], Morgan, Michael D [0000-0003-0757-0711], Tuong, Zewen Kelvin [0000-0002-6735-6808], Sungnak, Waradon [0000-0002-0136-4960], Yoshida, Masahiro [0000-0002-3521-5322], Kumasaka, Natsuhiko [0000-0002-3557-0375], Spegarova, Jarmila Stremenova [0000-0002-0710-9266], Wilson, Nicola K [0000-0003-0865-7333], Mende, Nicole [0000-0002-5078-2333], Gardner, Louis CS [0000-0002-7200-978X], Goh, Issac [0000-0002-6397-3518], Horsfall, Dave [0000-0002-8086-812X], Webb, Simone [0000-0003-3058-8952], Mather, Michael W [0000-0001-7972-7111], Lindeboom, Rik GH [0000-0002-3660-504X], Dann, Emma [0000-0002-7400-7438], Polanski, Krzysztof [0000-0002-2586-9576], Payne, Rebecca P [0000-0002-9037-7367], Baker, Kenneth F [0000-0002-6735-2911], Schim van der Loeff, Ina CD [0000-0003-1196-6196], Barr, Andrew S [0000-0002-8084-7644], Mescia, Federica [0000-0002-2759-4027], Barnes, Josephine L [0000-0001-9938-3176], Janes, Sam M [0000-0002-6634-5939], Smith, Claire M [0000-0002-8913-0009], Coupland, Paul [0000-0002-2871-3374], Bacardit, Jaume [0000-0002-2692-7205], King, Hamish W [0000-0001-5972-8926], Rostron, Anthony J [0000-0002-9336-1723], Simpson, A John [0000-0003-4731-7294], Hambleton, Sophie [0000-0001-7954-3267], Laurenti, Elisa [0000-0002-9917-9092], Lyons, Paul A [0000-0001-7035-8997], Meyer, Kerstin B [0000-0001-5906-1498], Nikolić, Marko Z [0000-0001-6304-6848], Smith, Kenneth GC [0000-0003-3829-4326], Teichmann, Sarah A [0000-0002-6294-6366], Clatworthy, Menna R [0000-0002-3340-9828], Marioni, John C [0000-0001-9092-0852], Göttgens, Berthold [0000-0001-6302-5705], Haniffa, Muzlifah [0000-0002-3927-2084], and Apollo - University of Cambridge Repository

Subjects
Cross-Sectional Studies, Proteome, SARS-CoV-2, T-Lymphocytes, Receptors, Antigen, T-Cell, COVID-19, Humans, Receptors, Antigen, B-Cell, Single-Cell Analysis, Transcriptome, Monocytes
Abstract

Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.

Published
2021
Full Text
View/download PDF

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