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1. 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

2. 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
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3. 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 C. S., Goh, Issac, Horsfall, Dave, McGrath, Jim, Webb, Simone, Mather, Michael W., Lindeboom, Rik G. H., 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 C. D., 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., Rostron, Anthony J., Simpson, A. John, Hambleton, Sophie, Laurenti, Elisa, Lyons, Paul A., Meyer, Kerstin B., Nikolić, Marko Z., Duncan, Christopher J. A., Smith, Kenneth G. C., Teichmann, Sarah A., Clatworthy, Menna R., Marioni, John C., Göttgens, Berthold, and Haniffa, Muzlifah

Subjects
Proteome, COVID-19, Cross-Sectional Studies, Humans, Monocytes, Receptors, Antigen, B-Cell, Receptors, Antigen, T-Cell, SARS-CoV-2, Single-Cell Analysis, T-Lymphocytes, Transcriptome, CD34, Biology, Peripheral blood mononuclear cell, Article, General Biochemistry, Genetics and Molecular Biology, Immune system, Antigen, Receptors, Platelet activation, Progenitor cell, B-Cell, RNA sequencing, General Medicine, T-Cell, Haematopoiesis, Viral infection, Immunology, Infection, CD8
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., Transcriptomic and proteomic profiling of blood samples from individuals with COVID-19 reveals immune cell and hematopoietic progenitor cell alterations that are differentially associated with disease severity.

Published
2021
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4. 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 C. S., Goh, Issac, Horsfall, Dave, McGrath, Jim, Webb, Simone, Mather, Michael W., Lindeboom, Rik G. H., 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 C. D., 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., Rostron, Anthony J., Simpson, A. John, Hambleton, Sophie, Laurenti, Elisa, Lyons, Paul A., Meyer, Kerstin B., Nikolić, Marko Z., Duncan, Christopher J. A., Teichmann, Sarah A., Clatworthy, Menna R., Marioni, John C., Göttgens, Berthold, Haniffa, Muzlifah, Baker, Stephen, Bradley, John R., Dougan, Gordon, Goodfellow, Ian G., Gupta, Ravindra K., Hess, Christoph, Kingston, Nathalie, Lehner, Paul J., Matheson, Nicholas J., Owehand, Willem H., Saunders, Caroline, Smith, Kenneth G. C., Summers, Charlotte, Thaventhiran, James E. D., Toshner, Mark, Weekes, Michael P., Bucke, Ashlea, Calder, Jo, Canna, Laura, Domingo, Jason, Elmer, Anne, Fuller, Stewart, Harris, Julie, Hewitt, Sarah, Kennet, Jane, Jose, Sherly, Kourampa, Jenny, Meadows, Anne, O’Brien, Criona, Price, Jane, Publico, Cherry, Rastall, Rebecca, Ribeiro, Carla, Rowlands, Jane, Ruffolo, Valentina, Tordesillas, Hugo, Bullman, Ben, Dunmore, Benjamin J., Fawke, Stuart, Gräf, Stefan, Hodgson, Josh, Huang, Christopher, Hunter, Kelvin, Jones, Emma, Legchenko, Ekaterina, Matara, Cecilia, Martin, Jennifer, O’Donnell, Ciara, Pointon, Linda, Pond, Nicole, Shih, Joy, Sutcliffe, Rachel, Tilly, Tobias, Treacy, Carmen, Tong, Zhen, Wood, Jennifer, Wylot, Marta, Betancourt, Ariana, Bower, Georgie, De Sa, Aloka, Epping, Madeline, Huhn, Oisin, Jackson, Sarah, Jarvis, Isobel, Marsden, Jimmy, Nice, Francesca, Okecha, Georgina, Omarjee, Ommar, Perera, Marianne, Richoz, Nathan, Sharma, Rahul, Turner, Lori, De Bie, Eckart M. D. D., Bunclark, Katherine, Josipovic, Masa, Mackay, Michael, Michael, Alice, Rossi, Sabrina, Selvan, Mayurun, Spencer, Sarah, Yong, Cissy, Ansaripour, Ali, Mwaura, Lucy, Patterson, Caroline, Polwarth, Gary, Polgarova, Petra, Stefano, Giovanni Di, Allison, John, Butcher, Helen, Caputo, Daniela, Clapham-Riley, Debbie, Dewhurst, Eleanor, Furlong, Anita, Graves, Barbara, Gray, Jennifer, Ivers, Tasmin, Kasanicki, Mary, Gresley, Emma Le, Linger, Rachel, Meloy, Sarah, Muldoon, Francesca, Ovington, Nigel, Papadia, Sofia, Phelan, Isabel, Stark, Hannah, Stirrups, Kathleen E., Townsend, Paul, Walker, Neil, Webster, Jennifer, 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 C. S. [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 G. H. [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 C. D. [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 G. C. [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
692/699/255/2514, 631/208/514/1949, article, 631/250/232, 631/250/254, 631/326/596/4130
Abstract

Funder: Lister Institute of Preventive Medicine; doi: https://doi.org/10.13039/501100001255, Funder: University College London, Birkbeck MRC Doctoral Training Programme, Funder: The Jikei University School of Medicine, Funder: Action Medical Research (GN2779), Funder: NIHR Clinical Lectureship (CL-2017-01-004), Funder: NIHR (ACF-2018-01-004) and the BMA Foundation, Funder: Chan Zuckerberg Initiative (grant 2017-174169) and from Wellcome (WT211276/Z/18/Z and Sanger core grant WT206194), Funder: UKRI Innovation/Rutherford Fund Fellowship allocated by the MRC and the UK Regenerative Medicine Platform (MR/5005579/1 to M.Z.N.). M.Z.N. and K.B.M. have been funded by the Rosetrees Trust (M944), Funder: Barbour Foundation, Funder: ERC Consolidator and EU MRG-Grammar awards, Funder: Versus Arthritis Cure Challenge Research Grant (21777), and an NIHR Research Professorship (RP-2017-08-ST2-002), Funder: European Molecular Biology Laboratory (EMBL), 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

5. 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

6. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes

Author

Sungnak, Waradon, Huang, Ni, Bécavin, Christophe, Berg, Marijn, Queen, Rachel, Litvinukova, Monika, Talavera-López, Carlos, Maatz, Henrike, Reichart, Daniel, Sampaziotis, Fotios, Worlock, Kaylee B, Yoshida, Masahiro, Barnes, Josephine L, and HCA Lung Biological Network

Subjects
HCA Lung Biological Network, 3. Good health
Abstract

We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells' potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org.

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

Author

Gottgens, Berthold, Yoshida, Masahiro, Worlock, Kaylee, Yoshida, Masahiro [0000-0002-3521-5322], Worlock, Kaylee B [0000-0002-5656-7634], Lindeboom, Rik GH [0000-0002-3660-504X], Kumasaka, Natsuhiko [0000-0002-3557-0375], Dominguez Conde, Cecilia [0000-0002-8684-4655], Mamanova, Lira [0000-0003-1463-8622], Bolt, Liam [0000-0001-7293-0774], Richardson, Laura [0000-0002-8075-3816], Polanski, Krzysztof [0000-0002-2586-9576], Barnes, Josephine L [0000-0001-9938-3176], Allen-Hyttinen, Jessica [0000-0003-4644-0362], Jones, Brendan C [0000-0002-2637-8859], Sungnak, Waradon [0000-0002-0136-4960], Pett, J Patrick [0000-0002-5249-444X], Weller, Juliane [0000-0002-1310-6168], Prigmore, Elena [0000-0001-8870-0316], Chu, Vivian [0000-0003-1376-1186], Cohen, Jonathan M [0000-0003-1004-5598], Cane, Clare [0000-0002-3545-768X], Shibuya, Soichi [0000-0002-4274-1312], Herczeg, Iván T [0000-0003-1281-3634], Wunderink, Richard G [0000-0002-8527-4195], Gao, Catherine A [0000-0001-5576-3943], Reynolds, Gary [0000-0002-8142-8708], Haniffa, Muzlifah [0000-0002-3927-2084], Bowyer, Georgina S [0000-0002-2058-4045], Calero-Nieto, Fernando J [0000-0003-3358-8253], Göttgens, Berthold [0000-0001-6302-5705], Jolly, Clare [0000-0002-4603-2281], De Coppi, Paolo [0000-0002-1659-0207], Smith, Claire M [0000-0002-8913-0009], Misharin, Alexander V [0000-0003-2879-3789], Janes, Sam M [0000-0002-6634-5939], Teichmann, Sarah A [0000-0002-6294-6366], Nikolić, Marko Z [0000-0001-6304-6848], Meyer, Kerstin B [0000-0001-5906-1498], and Apollo - University of Cambridge Repository

Subjects
Cambridge Stem Cell Institute
Abstract

It is not fully understood why COVID-19 is typically milder in children To examine differences in response to SARS-CoV-2 infection in children and adults, we analysed paediatric and adult COVID-19 patients and healthy controls (total n=93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In healthy paediatric airways, we observed cells already in an interferon-activated state, that upon 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 characterised by increases in naive lymphocytes and a depletion of natural killer cells, while in adults cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signaling in early infection, and identify novel epithelial cell states that associate with COVID-19 and age. Our matching nasal and blood data showed a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were massively reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children.

Published
2022

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