Distinct subsets of neutrophils crosstalk with cytokines and metabolites in patients with sepsis
Upasana Parthasarathy,
Yi Kuang,
Gunjan Thakur,
John D. Hogan,
Thomas P. Wyche,
James E. Norton, Jr.,
Jason R. Killough,
Theodore R. Sana,
Caroline Beakes,
BaoJen Shyong,
Rena N. Zhang,
Dario A. Gutierrez,
Michael Filbin,
David C. Christiani,
Alex G. Therien,
Christopher H. Woelk,
Cory H. White,
Roberta Martinelli
Affiliations
Upasana Parthasarathy
Discovery Immunology, Merck & Co.,Inc., Cambridge, MA, USA
Yi Kuang
Discovery Immunology, Merck & Co.,Inc., Cambridge, MA, USA
Gunjan Thakur
Data and Genome Sciences, Merck & Co.,Inc., Cambridge, MA, USA
John D. Hogan
Data and Genome Sciences, Merck & Co.,Inc., Cambridge, MA, USA
Thomas P. Wyche
Mass Spectrometry & Biophysics, Merck & Co.,Inc., Cambridge, MA, USA
James E. Norton, Jr.
Quantitative Biosciences, Merck & Co.,Inc., West Point, PA, USA
Jason R. Killough
Discovery Immunology, Merck & Co.,Inc., Cambridge, MA, USA
Theodore R. Sana
Mass Spectrometry & Biophysics, Merck & Co.,Inc., Cambridge, MA, USA
Caroline Beakes
Pulmonary and Critical Care Division, Massachusetts General Hospital, Boston, MA, USA
BaoJen Shyong
Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co.,Inc., West Point, PA, USA
Rena N. Zhang
Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co.,Inc., West Point, PA, USA
Dario A. Gutierrez
Discovery Immunology, Merck & Co.,Inc., Cambridge, MA, USA
Michael Filbin
Pulmonary and Critical Care Division, Massachusetts General Hospital, Boston, MA, USA
David C. Christiani
Pulmonary and Critical Care Division, Massachusetts General Hospital, Boston, MA, USA; Department of Environmental Health and Epidemiology, Harvard School of Public Health, Boston, MA, USA
Alex G. Therien
Discovery Immunology, Merck & Co.,Inc., Cambridge, MA, USA
Christopher H. Woelk
Discovery Immunology, Merck & Co.,Inc., Cambridge, MA, USA
Cory H. White
Data and Genome Sciences, Merck & Co.,Inc., Cambridge, MA, USA; Corresponding author
Roberta Martinelli
Discovery Immunology, Merck & Co.,Inc., Cambridge, MA, USA; Corresponding author
Summary: Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Despite continued efforts to understand the pathophysiology of sepsis, no effective therapies are currently available. While singular components of the aberrant immune response have been investigated, comprehensive studies linking different data layers are lacking. Using an integrated systems immunology approach, we evaluated neutrophil phenotypes and concomitant changes in cytokines and metabolites in patients with sepsis. Our findings identify differentially expressed mature and immature neutrophil subsets in patients with sepsis. These subsets correlate with various proteins, metabolites, and lipids, including pentraxin-3, angiopoietin-2, and lysophosphatidylcholines, in patients with sepsis. These results enabled the construction of a statistical model based on weighted multi-omics linear regression analysis for sepsis biomarker identification. These findings could help inform early patient stratification and treatment options, and facilitate further mechanistic studies targeting the trifecta of surface marker expression, cytokines, and metabolites.
