Longitudinal immune profiling reveals distinct features of COVID-19 pathogenesis

Elizabeth R. Mann; Madhvi Menon; Sean Blandin Knight; Joanne E. Konkel; Christopher Jagger; Tovah N. Shaw; Siddharth Krishnan; Magnus Rattray; Andrew Ustianowski; Nawar Diar Bakerly; Paul Dark; Graham Lord; Angela Simpson; Timothy Felton; Ling Pei Ho; Marc Feldmann; John R. Grainger; Tracy Hussell; Rohan Ahmed; Halima Ali Shuwa; Miriam Avery; Katharine Birchall; Oliver Brand; Evelyn Charsley; Alistair Chenery; Christine Chew; Richard Clark; Emma Connolly; Karen Connolly; Simon Dawson; Laura Durrans; Hannah Durrington; Jasmine Egan; Claire Fox; Helen Francis; Miriam Franklin; Susannah Glasgow; Nicola Godfrey; Kathryn J. Gray; Seamus Grundy; Jacinta Guerin; Pamela Hackney; Mudassar Iqbal; Chantelle Hayes; Emma Hardy; Jade Harris; Anu John; Bethany Jolly; Verena Kästele; Saba Khan; Gabriella Lindergard; Sylvia Lui; Lesley Lowe; Alex G. Mathioudakis; Flora A. McClure; Joanne Mitchell; Clare Moizer; Katrina Moore; David Morgan; Stuart Moss; Syed Murtuza Baker; Rob Oliver; Grace Padden; Christina Parkinson; Laurence Pearmain; Mike Phuychareon; Ananya Saha; Barbora Salcman; Nicholas A. Scott; Seema Sharma; Jane Shaw; Joanne Shaw; Elizabeth Shepley; Lara Smith; Simon Stephan; Ruth Stephens; Gael Tavernier; Rhys Tudge; Louis Wareing; Roanna Warren; Thomas Williams; Lisa Willmore; Mehwish Younas; Alex Horsley; Tim Harrison; Joanna Porter; Ratko Djukanovic; Stefan Marciniak; Chris Brightling; Ling Pei Ho; Lorcan McGarvey; Jane Davies

doi:10.1101/2020.06.13.20127605

Longitudinal immune profiling reveals distinct features of COVID-19 pathogenesis

Elizabeth R. Mann, Madhvi Menon, Sean Blandin Knight, Joanne E. Konkel, Christopher Jagger, Tovah N. Shaw, Siddharth Krishnan, Magnus Rattray, Andrew Ustianowski, Nawar Diar Bakerly, Paul Dark, Graham Lord, Angela Simpson, Timothy Felton, Ling Pei Ho, Marc Feldmann, John R. Grainger, Tracy Hussell, Rohan Ahmed, Halima Ali ShuwaMiriam Avery, Katharine Birchall, Oliver Brand, Evelyn Charsley, Alistair Chenery, Christine Chew, Richard Clark, Emma Connolly, Karen Connolly, Simon Dawson, Laura Durrans, Hannah Durrington, Jasmine Egan, Claire Fox, Helen Francis, Miriam Franklin, Susannah Glasgow, Nicola Godfrey, Kathryn J. Gray, Seamus Grundy, Jacinta Guerin, Pamela Hackney, Mudassar Iqbal, Chantelle Hayes, Emma Hardy, Jade Harris, Anu John, Bethany Jolly, Verena Kästele, Saba Khan, Gabriella Lindergard, Sylvia Lui, Lesley Lowe, Alex G. Mathioudakis, Flora A. McClure, Joanne Mitchell, Clare Moizer, Katrina Moore, David Morgan, Stuart Moss, Syed Murtuza Baker, Rob Oliver, Grace Padden, Christina Parkinson, Laurence Pearmain, Mike Phuychareon, Ananya Saha, Barbora Salcman, Nicholas A. Scott, Seema Sharma, Jane Shaw, Joanne Shaw, Elizabeth Shepley, Lara Smith, Simon Stephan, Ruth Stephens, Gael Tavernier, Rhys Tudge, Louis Wareing, Roanna Warren, Thomas Williams, Lisa Willmore, Mehwish Younas, Alex Horsley, Tim Harrison, Joanna Porter, Ratko Djukanovic, Stefan Marciniak, Chris Brightling, Ling Pei Ho, Lorcan McGarvey, Jane Davies

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Abstract

Background The pathogenesis of COVID-19, caused by a novel strain of coronavirus (SARS-CoV-2), involves a complex host-virus interaction and is characterised by an exaggerated immune response, the specific components of which are poorly understood. Here we report the outcome of a longitudinal immune profiling study in hospitalised patients during the peak of the COVID-19 pandemic in the UK and show the relationship between immune responses and severity of the clinical presentation. Methods The Coronavirus Immune Response and Clinical Outcomes (CIRCO) study was conducted at four hospitals in Greater Manchester. Patients with SARS-CoV-2 infection, recruited as close to admission as possible, provided peripheral blood samples at enrolment and sequentially thereafter. Fresh samples were assessed for immune cells and proteins in whole blood and serum. Some samples were also stimulated for 3 hours with LPS and analysed for intracellular proteins. Results were stratified based on patient-level data including severity of symptoms and date of reported symptom onset. Findings Longitudinal analysis showed a very high neutrophil to T cell ratio and abnormal activation of monocytes in the blood, which displayed high levels of the cell cycle marker, Ki67 and low COX-2. These properties all reverted in patient with good outcome. Unexpectedly, multiple aspects of inflammation were diminished as patients progressed in severity and time, even in ITU patients not recovering. Interpretation This is the first detailed longitudinal analysis of COVID-19 patients of varying severity and outcome, revealing common features and aspects that track with severity. Patients destined for a severe outcome can be identified at admission when still displaying mild-moderate symptoms. We provide clues concerning pathogenesis that should influence clinical trials and therapeutics. Targeting pathways involved in neutrophil and monocyte release from the bone marrow should be tested in patients with COVID-19.

Original language	English
Journal	medRxiv
DOIs	https://doi.org/10.1101/2020.06.13.20127605
Publication status	Published - 16 Jun 2020

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10.1101/2020.06.13.20127605

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Mann, E. R., Menon, M., Knight, S. B., Konkel, J. E., Jagger, C., Shaw, T. N., Krishnan, S., Rattray, M., Ustianowski, A., Bakerly, N. D., Dark, P., Lord, G., Simpson, A., Felton, T., Ho, L. P., Feldmann, M., Grainger, J. R., Hussell, T., Ahmed, R., ... Davies, J. (2020). Longitudinal immune profiling reveals distinct features of COVID-19 pathogenesis. medRxiv. https://doi.org/10.1101/2020.06.13.20127605

@article{65820fc8faa64e8585a1433cabc1821f,

title = "Longitudinal immune profiling reveals distinct features of COVID-19 pathogenesis",

abstract = "Background The pathogenesis of COVID-19, caused by a novel strain of coronavirus (SARS-CoV-2), involves a complex host-virus interaction and is characterised by an exaggerated immune response, the specific components of which are poorly understood. Here we report the outcome of a longitudinal immune profiling study in hospitalised patients during the peak of the COVID-19 pandemic in the UK and show the relationship between immune responses and severity of the clinical presentation. Methods The Coronavirus Immune Response and Clinical Outcomes (CIRCO) study was conducted at four hospitals in Greater Manchester. Patients with SARS-CoV-2 infection, recruited as close to admission as possible, provided peripheral blood samples at enrolment and sequentially thereafter. Fresh samples were assessed for immune cells and proteins in whole blood and serum. Some samples were also stimulated for 3 hours with LPS and analysed for intracellular proteins. Results were stratified based on patient-level data including severity of symptoms and date of reported symptom onset. Findings Longitudinal analysis showed a very high neutrophil to T cell ratio and abnormal activation of monocytes in the blood, which displayed high levels of the cell cycle marker, Ki67 and low COX-2. These properties all reverted in patient with good outcome. Unexpectedly, multiple aspects of inflammation were diminished as patients progressed in severity and time, even in ITU patients not recovering. Interpretation This is the first detailed longitudinal analysis of COVID-19 patients of varying severity and outcome, revealing common features and aspects that track with severity. Patients destined for a severe outcome can be identified at admission when still displaying mild-moderate symptoms. We provide clues concerning pathogenesis that should influence clinical trials and therapeutics. Targeting pathways involved in neutrophil and monocyte release from the bone marrow should be tested in patients with COVID-19.",

author = "Mann, {Elizabeth R.} and Madhvi Menon and Knight, {Sean Blandin} and Konkel, {Joanne E.} and Christopher Jagger and Shaw, {Tovah N.} and Siddharth Krishnan and Magnus Rattray and Andrew Ustianowski and Bakerly, {Nawar Diar} and Paul Dark and Graham Lord and Angela Simpson and Timothy Felton and Ho, {Ling Pei} and Marc Feldmann and Grainger, {John R.} and Tracy Hussell and Rohan Ahmed and Shuwa, {Halima Ali} and Miriam Avery and Katharine Birchall and Oliver Brand and Evelyn Charsley and Alistair Chenery and Christine Chew and Richard Clark and Emma Connolly and Karen Connolly and Simon Dawson and Laura Durrans and Hannah Durrington and Jasmine Egan and Claire Fox and Helen Francis and Miriam Franklin and Susannah Glasgow and Nicola Godfrey and Gray, {Kathryn J.} and Seamus Grundy and Jacinta Guerin and Pamela Hackney and Mudassar Iqbal and Chantelle Hayes and Emma Hardy and Jade Harris and Anu John and Bethany Jolly and Verena K{\"a}stele and Saba Khan and Gabriella Lindergard and Sylvia Lui and Lesley Lowe and Mathioudakis, {Alex G.} and McClure, {Flora A.} and Joanne Mitchell and Clare Moizer and Katrina Moore and David Morgan and Stuart Moss and Baker, {Syed Murtuza} and Rob Oliver and Grace Padden and Christina Parkinson and Laurence Pearmain and Mike Phuychareon and Ananya Saha and Barbora Salcman and Scott, {Nicholas A.} and Seema Sharma and Jane Shaw and Joanne Shaw and Elizabeth Shepley and Lara Smith and Simon Stephan and Ruth Stephens and Gael Tavernier and Rhys Tudge and Louis Wareing and Roanna Warren and Thomas Williams and Lisa Willmore and Mehwish Younas and Alex Horsley and Tim Harrison and Joanna Porter and Ratko Djukanovic and Stefan Marciniak and Chris Brightling and Ho, {Ling Pei} and Lorcan McGarvey and Jane Davies",

year = "2020",

month = jun,

day = "16",

doi = "10.1101/2020.06.13.20127605",

language = "English",

journal = "medRxiv",

publisher = "Cold Spring Harbor Laboratory Press",

}

Mann, ER , Menon, M , Knight, SB , Konkel, JE, Jagger, C, Shaw, TN, Krishnan, S, Rattray, M, Ustianowski, A, Bakerly, ND, Dark, P, Lord, G, Simpson, A , Felton, T, Ho, LP, Feldmann, M, Grainger, JR, Hussell, T, Ahmed, R, Shuwa, HA, Avery, M, Birchall, K, Brand, O, Charsley, E, Chenery, A, Chew, C, Clark, R, Connolly, E, Connolly, K, Dawson, S, Durrans, L, Durrington, H, Egan, J, Fox, C, Francis, H, Franklin, M, Glasgow, S, Godfrey, N, Gray, KJ, Grundy, S, Guerin, J, Hackney, P, Iqbal, M, Hayes, C, Hardy, E, Harris, J, John, A, Jolly, B, Kästele, V, Khan, S, Lindergard, G, Lui, S, Lowe, L, Mathioudakis, AG, McClure, FA, Mitchell, J, Moizer, C, Moore, K, Morgan, D, Moss, S, Baker, SM, Oliver, R, Padden, G, Parkinson, C, Pearmain, L, Phuychareon, M, Saha, A, Salcman, B, Scott, NA, Sharma, S, Shaw, J, Shaw, J, Shepley, E, Smith, L, Stephan, S, Stephens, R, Tavernier, G, Tudge, R, Wareing, L, Warren, R, Williams, T, Willmore, L, Younas, M, Horsley, A, Harrison, T, Porter, J, Djukanovic, R, Marciniak, S, Brightling, C, Ho, LP, McGarvey, L & Davies, J 2020, 'Longitudinal immune profiling reveals distinct features of COVID-19 pathogenesis', medRxiv. https://doi.org/10.1101/2020.06.13.20127605

TY - JOUR

T1 - Longitudinal immune profiling reveals distinct features of COVID-19 pathogenesis

AU - Mann, Elizabeth R.

AU - Menon, Madhvi

AU - Knight, Sean Blandin

AU - Konkel, Joanne E.

AU - Jagger, Christopher

AU - Shaw, Tovah N.

AU - Krishnan, Siddharth

AU - Rattray, Magnus

AU - Ustianowski, Andrew

AU - Bakerly, Nawar Diar

AU - Dark, Paul

AU - Lord, Graham

AU - Simpson, Angela

AU - Felton, Timothy

AU - Ho, Ling Pei

AU - Feldmann, Marc

AU - Grainger, John R.

AU - Hussell, Tracy

AU - Ahmed, Rohan

AU - Shuwa, Halima Ali

AU - Avery, Miriam

AU - Birchall, Katharine

AU - Brand, Oliver

AU - Charsley, Evelyn

AU - Chenery, Alistair

AU - Chew, Christine

AU - Clark, Richard

AU - Connolly, Emma

AU - Connolly, Karen

AU - Dawson, Simon

AU - Durrans, Laura

AU - Durrington, Hannah

AU - Egan, Jasmine

AU - Fox, Claire

AU - Francis, Helen

AU - Franklin, Miriam

AU - Glasgow, Susannah

AU - Godfrey, Nicola

AU - Gray, Kathryn J.

AU - Grundy, Seamus

AU - Guerin, Jacinta

AU - Hackney, Pamela

AU - Iqbal, Mudassar

AU - Hayes, Chantelle

AU - Hardy, Emma

AU - Harris, Jade

AU - John, Anu

AU - Jolly, Bethany

AU - Kästele, Verena

AU - Khan, Saba

AU - Lindergard, Gabriella

AU - Lui, Sylvia

AU - Lowe, Lesley

AU - Mathioudakis, Alex G.

AU - McClure, Flora A.

AU - Mitchell, Joanne

AU - Moizer, Clare

AU - Moore, Katrina

AU - Morgan, David

AU - Moss, Stuart

AU - Baker, Syed Murtuza

AU - Oliver, Rob

AU - Padden, Grace

AU - Parkinson, Christina

AU - Pearmain, Laurence

AU - Phuychareon, Mike

AU - Saha, Ananya

AU - Salcman, Barbora

AU - Scott, Nicholas A.

AU - Sharma, Seema

AU - Shaw, Jane

AU - Shaw, Joanne

AU - Shepley, Elizabeth

AU - Smith, Lara

AU - Stephan, Simon

AU - Stephens, Ruth

AU - Tavernier, Gael

AU - Tudge, Rhys

AU - Wareing, Louis

AU - Warren, Roanna

AU - Williams, Thomas

AU - Willmore, Lisa

AU - Younas, Mehwish

AU - Horsley, Alex

AU - Harrison, Tim

AU - Porter, Joanna

AU - Djukanovic, Ratko

AU - Marciniak, Stefan

AU - Brightling, Chris

AU - Ho, Ling Pei

AU - McGarvey, Lorcan

AU - Davies, Jane

PY - 2020/6/16

Y1 - 2020/6/16

N2 - Background The pathogenesis of COVID-19, caused by a novel strain of coronavirus (SARS-CoV-2), involves a complex host-virus interaction and is characterised by an exaggerated immune response, the specific components of which are poorly understood. Here we report the outcome of a longitudinal immune profiling study in hospitalised patients during the peak of the COVID-19 pandemic in the UK and show the relationship between immune responses and severity of the clinical presentation. Methods The Coronavirus Immune Response and Clinical Outcomes (CIRCO) study was conducted at four hospitals in Greater Manchester. Patients with SARS-CoV-2 infection, recruited as close to admission as possible, provided peripheral blood samples at enrolment and sequentially thereafter. Fresh samples were assessed for immune cells and proteins in whole blood and serum. Some samples were also stimulated for 3 hours with LPS and analysed for intracellular proteins. Results were stratified based on patient-level data including severity of symptoms and date of reported symptom onset. Findings Longitudinal analysis showed a very high neutrophil to T cell ratio and abnormal activation of monocytes in the blood, which displayed high levels of the cell cycle marker, Ki67 and low COX-2. These properties all reverted in patient with good outcome. Unexpectedly, multiple aspects of inflammation were diminished as patients progressed in severity and time, even in ITU patients not recovering. Interpretation This is the first detailed longitudinal analysis of COVID-19 patients of varying severity and outcome, revealing common features and aspects that track with severity. Patients destined for a severe outcome can be identified at admission when still displaying mild-moderate symptoms. We provide clues concerning pathogenesis that should influence clinical trials and therapeutics. Targeting pathways involved in neutrophil and monocyte release from the bone marrow should be tested in patients with COVID-19.

AB - Background The pathogenesis of COVID-19, caused by a novel strain of coronavirus (SARS-CoV-2), involves a complex host-virus interaction and is characterised by an exaggerated immune response, the specific components of which are poorly understood. Here we report the outcome of a longitudinal immune profiling study in hospitalised patients during the peak of the COVID-19 pandemic in the UK and show the relationship between immune responses and severity of the clinical presentation. Methods The Coronavirus Immune Response and Clinical Outcomes (CIRCO) study was conducted at four hospitals in Greater Manchester. Patients with SARS-CoV-2 infection, recruited as close to admission as possible, provided peripheral blood samples at enrolment and sequentially thereafter. Fresh samples were assessed for immune cells and proteins in whole blood and serum. Some samples were also stimulated for 3 hours with LPS and analysed for intracellular proteins. Results were stratified based on patient-level data including severity of symptoms and date of reported symptom onset. Findings Longitudinal analysis showed a very high neutrophil to T cell ratio and abnormal activation of monocytes in the blood, which displayed high levels of the cell cycle marker, Ki67 and low COX-2. These properties all reverted in patient with good outcome. Unexpectedly, multiple aspects of inflammation were diminished as patients progressed in severity and time, even in ITU patients not recovering. Interpretation This is the first detailed longitudinal analysis of COVID-19 patients of varying severity and outcome, revealing common features and aspects that track with severity. Patients destined for a severe outcome can be identified at admission when still displaying mild-moderate symptoms. We provide clues concerning pathogenesis that should influence clinical trials and therapeutics. Targeting pathways involved in neutrophil and monocyte release from the bone marrow should be tested in patients with COVID-19.

UR - https://www.mendeley.com/catalogue/20a7a731-18c8-35f1-8a57-07a06a0a4e47/

U2 - 10.1101/2020.06.13.20127605

DO - 10.1101/2020.06.13.20127605

M3 - Article

JO - medRxiv

JF - medRxiv

ER -

Longitudinal immune profiling reveals distinct features of COVID-19 pathogenesis

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