The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals
Authors: Butler-Laporte Guillaume , Gonzalez-Kozlova Edgar , Su Chen-Yang , Zhou Sirui , Nakanishi Tomoko , Brunet-Ratnasingham Elsa , Morrison David , Laurent Laetitia , Afilalo Jonathan , Afilalo Marc , Henry Danielle , Chen Yiheng , Carrasco-Zanini Julia , Farjoun Yossi , Pietzner Maik , Kimchi Nofar , Afrasiabi Zaman , Rezk Nardin , Bouab Meriem , Petitjean Louis , Guzman Charlotte , Xue Xiaoqing , Tselios Chris , Vulesevic Branka , Adeleye Olumide , Abdullah Tala , Almamlouk Noor , Moussa Yara , DeLuca Chantal , Duggan Naomi , Schurr Erwin , Brassard Nathalie , Durand Madeleine , Del Valle Diane Marie , Thompson Ryan , Cedillo Mario A. , Schadt Eric , Nie Kai , Simons Nicole W. , Mouskas Konstantinos , Zaki Nicolas , Patel Manishkumar , Xie Hui , Harris Jocelyn , Marvin Robert , Cheng Esther , Tuballes Kevin , Argueta Kimberly , Scott Ieisha ,   The Mount Sinai COVID-19 Biobank Team, Agashe Charuta , Agrawal Priyal , Akyatan Alara , Alesso-Carra Kasey , Alibo Eziwoma , Alvarez Kelvin , Amabile Angelo , Argmann Carmen , Argueta Kimberly , Ascolillo Steven , Bailey Rasheed , Batchelor Craig , Beckmann Noam D , Beckmann Aviva G , Begani Priya , Berichel Jessica Le , Bogunovic Dusan , Bose Swaroop , Bozkus Cansu Cimen , Bravo Paloma , Buckup Mark , Burka Larissa , Calorossi Sharlene , Cambron Lena , Carbonell Guillermo , Carrara Gina , Cedillo Mario A. , Chang Christie , Chang Serena , Charney Alexander W. , Chen Steven T. , Cheng Esther , Chien Jonathan , Chowdhury Mashkura , Chung Jonathan , Comella Phillip H , Cosgrove Dana , Cossarini Francesca , Cotter Liam , Dave Arpit , Dawson Travis , Dayal Bheesham , Valle Diane Marie Del , Dhainaut Maxime , Dornfeld Rebecca , Dul Katie , Eaton Melody , Eber Nissan , Elaiho Cordelia , Ellis Ethan , Fabris Frank , Faith Jeremiah , Falci Dominique , Feng Susie , Fennessy Brian , Fernandes Marie , Fishman Nataly , Francoeur Nancy J. , Gangadharan Sandeep , Geanon Daniel , Gelb Bruce D. , Glicksberg Benjamin S , Gnjatic Sacha , Grabowska Joanna , Gyimesi Gavin , Hamdani Maha , Handler Diana , Harris Jocelyn , Hartnett Matthew , Hatem Sandra , Herbinet Manon , Herrera Elva , Hochman Arielle , Hoffman Gabriel E. , Hook Jaime , Horta Laila , Humblin Etienne , Jaladanki Suraj , Jamal Hajra , Johnson Jessica S. , Kang Gurpawan , Karekar Neha , Karim Subha , Kelly Geoffrey , Kim Jong , Kim-Schulze Seunghee , Kozlova Edgar , Kumar Arvind , Lacunza Jose , Lansky Alona , Lebovitch Dannielle , Lee Brian , Lee Grace , Lee Gyu Ho , Lee Jacky , Leech John , Lepow Lauren , Leventhal Michael B , Liharska Lora E , Lindblad Katherine , Livanos Alexandra , Losic Bojan , Machado Rosalie , Madrid Kent , Mahmood Zafar , Mar Kelcey , Marron Thomas U. , Martin Glenn , Marvin Robert , Maskey Shrisha , Matthews Paul , Meckel Katherine , Mehandru Saurabh , Merad Miriam , Mercedes Cynthia , Merzier Elyze , Meyer Dara , Mollaoglu Gurkan , Morris Sarah , Mouskas Konstantinos , Moya Emily , Yeboah Naa-akomaah , Nadkarni Girish , Nie Kai , Nisenholtz Marjorie , Ofori-Amanfo George , Onel Kenan , Ounadjela Merouane , Patel Manishkumar , Patel Vishwendra , Pruitt Cassandra , Rahman Adeeb , Rathi Shivani , Redes Jamie , Reyes-Torres Ivan , Rodrigues Alcina , Rodriguez Alfonso , Roudko Vladimir , Roussos Panagiotis , Ruiz Evelyn , Scalzo Pearl , Schadt Eric E. , Scott Ieisha , Sebra Robert , Shah Hardik , Shervey Mark , Silva Pedro , Simons Nicole W. , Smith Melissa , Soares-Schanoski Alessandra , Soto Juan , Sridhar Shwetha Hara , Brown Stacey-Ann , Stefanos Hiyab , Straw Meghan , Sweeney Robert , Tabachnikova Alexandra , Teague Collin , Thompson Ryan , Tin Manying , Tuballes Kevin , Tyler Scott R. , Upadhyaya Bhaskar , Vaid Akhil , Van Der Heide Verena , Vaninov Natalie , Vlachos Konstantinos , Wacker Daniel , Walker Laura , Walsh Hadley , Wang Wenhui , Wang Bo , Wilk C. Matthias , Wilkins Lillian , Wilson Karen M. , Wilson Jessica , Xie Hui , Xue Li , Yi Nancy , Wang Ying-chih , Yishak Mahlet , Young Sabina , Yu Alex , Zaks Nina , Zha Renyuan , Greenwood Celia M. T. , Paterson Clare , Hinterberg Michael , Langenberg Claudia , Forgetta Vincenzo , Mooser Vincent , Marron Thomas , Beckmann Noam , Kenigsberg Ephraim , Charney Alexander W. , Kim-schulze Seunghee , Merad Miriam , Kaufmann Daniel E. , Gnjatic Sacha , Richards J Brent 
Published: September 2022

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.