. 2022 Sep 28;19(1):34.

doi: 10.1186/s12014-022-09371-z.

The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals

Guillaume Butler-Laporte^{1

2}, Edgar Gonzalez-Kozlova³, Chen-Yang Su^{1

4}, Sirui Zhou^{1

2}, Tomoko Nakanishi^{1

5

6

7}, Elsa Brunet-Ratnasingham⁸, David Morrison¹, Laetitia Laurent¹, Jonathan Afilalo^{1

2}, Marc Afilalo⁹, Danielle Henry¹, Yiheng Chen^{1

5}, Julia Carrasco-Zanini¹⁰, Yossi Farjoun¹, Maik Pietzner^{10

11}, Nofar Kimchi¹, Zaman Afrasiabi¹, Nardin Rezk¹, Meriem Bouab¹, Louis Petitjean¹, Charlotte Guzman¹, Xiaoqing Xue¹, Chris Tselios¹, Branka Vulesevic¹, Olumide Adeleye¹, Tala Abdullah¹, Noor Almamlouk¹, Yara Moussa¹, Chantal DeLuca¹, Naomi Duggan¹, Erwin Schurr¹², Nathalie Brassard⁸, Madeleine Durand⁸, Diane Marie Del Valle¹³, Ryan Thompson¹⁴, Mario A Cedillo¹⁵, Eric Schadt¹⁴, Kai Nie¹⁶, Nicole W Simons¹⁴, Konstantinos Mouskas¹⁴, Nicolas Zaki¹⁶, Manishkumar Patel¹³, Hui Xie¹⁶, Jocelyn Harris¹⁶, Robert Marvin¹⁶, Esther Cheng¹⁴, Kevin Tuballes¹³, Kimberly Argueta¹⁶, Ieisha Scott¹⁶; Mount Sinai COVID-19 Biobank Team; Celia M T Greenwood^{1

2}, Clare Paterson¹⁷, Michael Hinterberg¹⁷, Claudia Langenberg^{10

17}, Vincenzo Forgetta¹, Vincent Mooser⁵, Thomas Marron^{3

13

18}, Noam Beckmann¹⁴, Ephraim Kenigsberg¹⁴, Alexander W Charney¹⁹, Seunghee Kim-Schulze¹⁶, Miriam Merad¹³, Daniel E Kaufmann^{8

20}, Sacha Gnjatic¹⁶, J Brent Richards^{21

22

23

24

25

26}

Collaborators, Affiliations

Collaborators

Mount Sinai COVID-19 Biobank Team:
Charuta Agashe, Priyal Agrawal, Alara Akyatan, Kasey Alesso-Carra, Eziwoma Alibo, Kelvin Alvarez, Angelo Amabile, Carmen Argmann, Kimberly Argueta, Steven Ascolillo, Rasheed Bailey, Craig Batchelor, Noam D Beckmann, Aviva G Beckmann, Priya Begani, Jessica Le Berichel, Dusan Bogunovic, Swaroop Bose, Cansu Cimen Bozkus, Paloma Bravo, Mark Buckup, Larissa Burka, Sharlene Calorossi, Lena Cambron, Guillermo Carbonell, Gina Carrara, Mario A Cedillo, Christie Chang, Serena Chang, Alexander W Charney, Steven T Chen, Esther Cheng, Jonathan Chien, Mashkura Chowdhury, Jonathan Chung, Phillip H Comella, Dana Cosgrove, Francesca Cossarini, Liam Cotter, Arpit Dave, Travis Dawson, Bheesham Dayal, Diane Marie Del Valle, Maxime Dhainaut, Rebecca Dornfeld, Katie Dul, Melody Eaton, Nissan Eber, Cordelia Elaiho, Ethan Ellis, Frank Fabris, Jeremiah Faith, Dominique Falci, Susie Feng, Brian Fennessy, Marie Fernandes, Nataly Fishman, Nancy J Francoeur, Sandeep Gangadharan, Daniel Geanon, Bruce D Gelb, Benjamin S Glicksberg, Sacha Gnjatic, Joanna Grabowska, Gavin Gyimesi, Maha Hamdani, Diana Handler, Jocelyn Harris, Matthew Hartnett, Sandra Hatem, Manon Herbinet, Elva Herrera, Arielle Hochman, Gabriel E Hoffman, Jaime Hook, Laila Horta, Etienne Humblin, Suraj Jaladanki, Hajra Jamal, Jessica S Johnson, Gurpawan Kang, Neha Karekar, Subha Karim, Geoffrey Kelly, Jong Kim, Seunghee Kim-Schulze, Edgar Kozlova, Arvind Kumar, Jose Lacunza, Alona Lansky, Dannielle Lebovitch, Brian Lee, Grace Lee, Gyu Ho Lee, Jacky Lee, John Leech, Lauren Lepow, Michael B Leventhal, Lora E Liharska, Katherine Lindblad, Alexandra Livanos, Bojan Losic, Rosalie Machado, Kent Madrid, Zafar Mahmood, Kelcey Mar, Thomas U Marron, Glenn Martin, Robert Marvin, Shrisha Maskey, Paul Matthews, Katherine Meckel, Saurabh Mehandru, Miriam Merad, Cynthia Mercedes, Elyze Merzier, Dara Meyer, Gurkan Mollaoglu, Sarah Morris, Konstantinos Mouskas, Emily Moya, Naa-Akomaah Yeboah, Girish Nadkarni, Kai Nie, Marjorie Nisenholtz, George Ofori-Amanfo, Kenan Onel, Merouane Ounadjela, Manishkumar Patel, Vishwendra Patel, Cassandra Pruitt, Adeeb Rahman, Shivani Rathi, Jamie Redes, Ivan Reyes-Torres, Alcina Rodrigues, Alfonso Rodriguez, Vladimir Roudko, Panagiotis Roussos, Evelyn Ruiz, Pearl Scalzo, Eric E Schadt, Ieisha Scott, Robert Sebra, Hardik Shah, Mark Shervey, Pedro Silva, Nicole W Simons, Melissa Smith, Alessandra Soares-Schanoski, Juan Soto, Shwetha Hara Sridhar, Stacey-Ann Brown, Hiyab Stefanos, Meghan Straw, Robert Sweeney, Alexandra Tabachnikova, Collin Teague, Ryan Thompson, Manying Tin, Kevin Tuballes, Scott R Tyler, Bhaskar Upadhyaya, Akhil Vaid, Verena Van Der Heide, Natalie Vaninov, Konstantinos Vlachos, Daniel Wacker, Laura Walker, Hadley Walsh, Wenhui Wang, Bo Wang, C Matthias Wilk, Lillian Wilkins, Karen M Wilson, Jessica Wilson, Hui Xie, Li Xue, Nancy Yi, Ying-Chih Wang, Mahlet Yishak, Sabina Young, Alex Yu, Nina Zaks, Renyuan Zha

Affiliations

¹ Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
² Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Québec, Canada.
³ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Department of Computer Science, McGill University, Montréal, Québec, Canada.
⁵ Department of Human Genetics, McGill University, Montréal, Québec, Canada.
⁶ Graduate School of Medicine, McGill International Collaborative School in Genomic Medicine, Kyoto University, KyotoKyoto, Japan.
⁷ Japan Society for the Promotion of Science, Tokyo, Japan.
⁸ Research Centre of the Centre Hospitalier de L'Université de Montréal, Montréal, Québec, Canada.
⁹ Department of Emergency Medicine, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
¹⁰ MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
¹¹ Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹² Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.
¹³ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵ Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁷ SomaLogic Inc, Boulder, CO, USA.
¹⁸ Early Phase Trials Unit, Mount Sinai Hospital, New York, NY, USA.
¹⁹ Mount Sinai Clinical Intelligence Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁰ Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
²¹ Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca.
²² Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca.
²³ Department of Human Genetics, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca.
²⁴ Department of Twin Research, King's College London, London, UK. brent.richards@mcgill.ca.
²⁵ 5 Prime Sciences, Montreal, Québec, Canada. brent.richards@mcgill.ca.
²⁶ McGill University, King's College London (Honorary), Jewish General Hospital, Pavilion H-4133755 Côte-Ste-Catherine, Montréal, Québec, H3T 1E2, Canada. brent.richards@mcgill.ca.

PMID: 36171541
PMCID: PMC9516500
DOI: 10.1186/s12014-022-09371-z

The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals

Guillaume Butler-Laporte et al. Clin Proteomics. 2022.

. 2022 Sep 28;19(1):34.

doi: 10.1186/s12014-022-09371-z.

Authors

Collaborators

Mount Sinai COVID-19 Biobank Team:
Charuta Agashe, Priyal Agrawal, Alara Akyatan, Kasey Alesso-Carra, Eziwoma Alibo, Kelvin Alvarez, Angelo Amabile, Carmen Argmann, Kimberly Argueta, Steven Ascolillo, Rasheed Bailey, Craig Batchelor, Noam D Beckmann, Aviva G Beckmann, Priya Begani, Jessica Le Berichel, Dusan Bogunovic, Swaroop Bose, Cansu Cimen Bozkus, Paloma Bravo, Mark Buckup, Larissa Burka, Sharlene Calorossi, Lena Cambron, Guillermo Carbonell, Gina Carrara, Mario A Cedillo, Christie Chang, Serena Chang, Alexander W Charney, Steven T Chen, Esther Cheng, Jonathan Chien, Mashkura Chowdhury, Jonathan Chung, Phillip H Comella, Dana Cosgrove, Francesca Cossarini, Liam Cotter, Arpit Dave, Travis Dawson, Bheesham Dayal, Diane Marie Del Valle, Maxime Dhainaut, Rebecca Dornfeld, Katie Dul, Melody Eaton, Nissan Eber, Cordelia Elaiho, Ethan Ellis, Frank Fabris, Jeremiah Faith, Dominique Falci, Susie Feng, Brian Fennessy, Marie Fernandes, Nataly Fishman, Nancy J Francoeur, Sandeep Gangadharan, Daniel Geanon, Bruce D Gelb, Benjamin S Glicksberg, Sacha Gnjatic, Joanna Grabowska, Gavin Gyimesi, Maha Hamdani, Diana Handler, Jocelyn Harris, Matthew Hartnett, Sandra Hatem, Manon Herbinet, Elva Herrera, Arielle Hochman, Gabriel E Hoffman, Jaime Hook, Laila Horta, Etienne Humblin, Suraj Jaladanki, Hajra Jamal, Jessica S Johnson, Gurpawan Kang, Neha Karekar, Subha Karim, Geoffrey Kelly, Jong Kim, Seunghee Kim-Schulze, Edgar Kozlova, Arvind Kumar, Jose Lacunza, Alona Lansky, Dannielle Lebovitch, Brian Lee, Grace Lee, Gyu Ho Lee, Jacky Lee, John Leech, Lauren Lepow, Michael B Leventhal, Lora E Liharska, Katherine Lindblad, Alexandra Livanos, Bojan Losic, Rosalie Machado, Kent Madrid, Zafar Mahmood, Kelcey Mar, Thomas U Marron, Glenn Martin, Robert Marvin, Shrisha Maskey, Paul Matthews, Katherine Meckel, Saurabh Mehandru, Miriam Merad, Cynthia Mercedes, Elyze Merzier, Dara Meyer, Gurkan Mollaoglu, Sarah Morris, Konstantinos Mouskas, Emily Moya, Naa-Akomaah Yeboah, Girish Nadkarni, Kai Nie, Marjorie Nisenholtz, George Ofori-Amanfo, Kenan Onel, Merouane Ounadjela, Manishkumar Patel, Vishwendra Patel, Cassandra Pruitt, Adeeb Rahman, Shivani Rathi, Jamie Redes, Ivan Reyes-Torres, Alcina Rodrigues, Alfonso Rodriguez, Vladimir Roudko, Panagiotis Roussos, Evelyn Ruiz, Pearl Scalzo, Eric E Schadt, Ieisha Scott, Robert Sebra, Hardik Shah, Mark Shervey, Pedro Silva, Nicole W Simons, Melissa Smith, Alessandra Soares-Schanoski, Juan Soto, Shwetha Hara Sridhar, Stacey-Ann Brown, Hiyab Stefanos, Meghan Straw, Robert Sweeney, Alexandra Tabachnikova, Collin Teague, Ryan Thompson, Manying Tin, Kevin Tuballes, Scott R Tyler, Bhaskar Upadhyaya, Akhil Vaid, Verena Van Der Heide, Natalie Vaninov, Konstantinos Vlachos, Daniel Wacker, Laura Walker, Hadley Walsh, Wenhui Wang, Bo Wang, C Matthias Wilk, Lillian Wilkins, Karen M Wilson, Jessica Wilson, Hui Xie, Li Xue, Nancy Yi, Ying-Chih Wang, Mahlet Yishak, Sabina Young, Alex Yu, Nina Zaks, Renyuan Zha

Affiliations

¹ Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
² Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Québec, Canada.
³ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Department of Computer Science, McGill University, Montréal, Québec, Canada.
⁵ Department of Human Genetics, McGill University, Montréal, Québec, Canada.
⁶ Graduate School of Medicine, McGill International Collaborative School in Genomic Medicine, Kyoto University, KyotoKyoto, Japan.
⁷ Japan Society for the Promotion of Science, Tokyo, Japan.
⁸ Research Centre of the Centre Hospitalier de L'Université de Montréal, Montréal, Québec, Canada.
⁹ Department of Emergency Medicine, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
¹⁰ MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
¹¹ Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹² Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.
¹³ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵ Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁷ SomaLogic Inc, Boulder, CO, USA.
¹⁸ Early Phase Trials Unit, Mount Sinai Hospital, New York, NY, USA.
¹⁹ Mount Sinai Clinical Intelligence Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁰ Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
²¹ Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca.
²² Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca.
²³ Department of Human Genetics, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca.
²⁴ Department of Twin Research, King's College London, London, UK. brent.richards@mcgill.ca.
²⁵ 5 Prime Sciences, Montreal, Québec, Canada. brent.richards@mcgill.ca.
²⁶ McGill University, King's College London (Honorary), Jewish General Hospital, Pavilion H-4133755 Côte-Ste-Catherine, Montréal, Québec, H3T 1E2, Canada. brent.richards@mcgill.ca.

PMID: 36171541
PMCID: PMC9516500
DOI: 10.1186/s12014-022-09371-z

Erratum in

Correction: The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals.
Butler-Laporte G, Gonzalez-Kozlova E, Su CY, Zhou S, Nakanishi T, Brunet-Ratnasingham E, Morrison D, Laurent L, Aflalo J, Aflalo M, Henry D, Chen Y, Carrasco-Zanini J, Farjoun Y, Pietzner M, Kimchi N, Afrasiabi Z, Rezk N, Bouab M, Petitjean L, Guzman C, Xue X, Tselios C, Vulesevic B, Adeleye O, Abdullah T, Almamlouk N, Moussa Y, DeLuca C, Duggan N, Schurr E, Brassard N, Durand M, Del Valle DM, Thompson R, Cedillo MA, Schadt E, Nie K, Simons NW, Mouskas K, Zaki N, Patel M, Xie H, Harris J, Marvin R, Cheng E, Tuballes K, Argueta K, Scott I; Mount Sinai COVID-19 Biobank Team; Greenwood CMT, Paterson C, Hinterberg M, Langenberg C, Forgetta V, Mooser V, Marron T, Beckmann ND, Kenigsberg E, Charney AW, Kim-Schulze S, Merad M, Kaufmann DE, Gnjatic S, Richards JB. Butler-Laporte G, et al. Clin Proteomics. 2022 Nov 15;19(1):40. doi: 10.1186/s12014-022-09378-6. Clin Proteomics. 2022. PMID: 36376796 Free PMC article. No abstract available.

Abstract

Introduction: Severe COVID-19 leads to important changes in circulating immune-related proteins. To date it has been difficult to understand their temporal relationship and identify cytokines that are drivers of severe COVID-19 outcomes and underlie differences in outcomes between sexes. Here, we measured 147 immune-related proteins during acute COVID-19 to investigate these questions.

Methods: We measured circulating protein abundances using the SOMAscan nucleic acid aptamer panel in two large independent hospital-based COVID-19 cohorts in Canada and the United States. We fit generalized additive models with cubic splines from the start of symptom onset to identify protein levels over the first 14 days of infection which were different between severe cases and controls, adjusting for age and sex. Severe cases were defined as individuals with COVID-19 requiring invasive or non-invasive mechanical respiratory support.

Results: 580 individuals were included in the analysis. Mean subject age was 64.3 (sd 18.1), and 47% were male. Of the 147 proteins, 69 showed a significant difference between cases and controls (p < 3.4 × 10^-4). Three clusters were formed by 108 highly correlated proteins that replicated in both cohorts, making it difficult to determine which proteins have a true causal effect on severe COVID-19. Six proteins showed sex differences in levels over time, of which 3 were also associated with severe COVID-19: CCL26, IL1RL2, and IL3RA, providing insights to better understand the marked differences in outcomes by sex.

Conclusions: Severe COVID-19 is associated with large changes in 69 immune-related proteins. Further, five proteins were associated with sex differences in outcomes. These results provide direct insights into immune-related proteins that are strongly influenced by severe COVID-19 infection.

Keywords: COVID-19; Immunity; Proteomics; SOMAscan.

PubMed Disclaimer

Conflict of interest statement

J.B.R. has served as an advisor to GlaxoSmithKline and Deerfield Capital and is the Founder of 5 Prime Sciences. The Lady Davis Institute has previously received funding from GlaxoSmithKline, Eli Lilly, and Biogen for research programs at Dr. Richards’ laboratory unrelated to this manuscript. C.P. and M.H. are employees of SomaLogic.

Figures

**Fig. 1**
Spearman correlations for three clusters (A, B and C) of proteins in the BQC (left) and the MSB (right). Only correlations with p-values less than 0.05 shown. Proteins with asterisks (***) showed a statistically significant differences between cases and controls (Bonferroni threshold 0.05/147). Full spearman correlation heatmap available in Additional file 3

**Fig. 2**
Smoothed curves for cluster-representative immune-related proteins, as a function of days since symptoms onset (x-axis), and separately for severe COVID cases and controls. Estimated curves are shown for 65-year-old. Y-axis is standardized to a mean of 0 and standard deviation of 1. Full results are shown in Additional final 5. Blue: controls. Red: severe COVID-19. Asterisks (***): p < 3.4 × 10^–4 for case–control difference in protein levels

**Fig. 3**
Smoothed protein level curves showing time-related and sex-related differences as a function of days since symptoms onset (x-axis) in a 65-year-old patient (p < 3.4 × 10^–4 for sex differences in cytokine levels). Y-axis is standardized to a mean of 0 and standard deviation of 1 F: female. M: male. Blue: controls. Red: severe COVID-19

See this image and copyright information in PMC

References

1. Tang Y, Liu J, Zhang D, Xu Z, Ji J, Wen C. Cytokine storm in COVID-19: the current evidence and treatment strategies. Front Immunol. 2020;11:1708. doi: 10.3389/fimmu.2020.01708. - DOI - PMC - PubMed
1. Sinha P, Matthay MA, Calfee CS. Is a “cytokine storm” relevant to COVID-19? JAMA Intern Med. 2020 doi: 10.1001/jamainternmed.2020.3313. - DOI - PubMed
1. Lucas C, Wong P, Klein J, et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature. 2020;584:463–469. doi: 10.1038/s41586-020-2588-y. - DOI - PMC - PubMed
1. Del Valle DM, Kim-Schulze S, Huang H-H, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020;26:1636–1643. doi: 10.1038/s41591-020-1051-9. - DOI - PMC - PubMed
1. Blanco-Melo D, Nilsson-Payant BE, Liu W-C, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020;181:1036–1045.e9. doi: 10.1016/j.cell.2020.04.026. - DOI - PMC - PubMed

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The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals

Collaborators

Affiliations

The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals

Authors

Collaborators

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

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