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

doi:10.1016/j.isci.2023.105948

Distinct subsets of neutrophils crosstalk with cytokines and metabolites in patients with sepsis

iScience. 2023 Jan 7;26(2):105948. doi: 10.1016/j.isci.2023.105948. eCollection 2023 Feb 17.

Authors

Upasana Parthasarathy¹, Yi Kuang¹, Gunjan Thakur², John D Hogan², Thomas P Wyche³, James E Norton Jr⁴, Jason R Killough¹, Theodore R Sana³, Caroline Beakes⁵, BaoJen Shyong⁶, Rena N Zhang⁶, Dario A Gutierrez¹, Michael Filbin⁵, David C Christiani^{5

7}, Alex G Therien¹, Christopher H Woelk¹, Cory H White², Roberta Martinelli¹

Affiliations

¹ Discovery Immunology, Merck & Co.,Inc., Cambridge, MA, USA.
² Data and Genome Sciences, Merck & Co.,Inc., Cambridge, MA, USA.
³ Mass Spectrometry & Biophysics, Merck & Co.,Inc., Cambridge, MA, USA.
⁴ Quantitative Biosciences, Merck & Co.,Inc., West Point, PA, USA.
⁵ Pulmonary and Critical Care Division, Massachusetts General Hospital, Boston, MA, USA.
⁶ Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co.,Inc., West Point, PA, USA.
⁷ Department of Environmental Health and Epidemiology, Harvard School of Public Health, Boston, MA, USA.

Abstract

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.

Keywords: Cell biology; Components of the immune system; Immunity; Systems biology.