A pharmacoproteomic landscape of organotypic intervention responses in Gram-negative sepsis
(2023) In Nature Communications 14. p.1-17- Abstract
Sepsis is the major cause of mortality across intensive care units globally, yet details of accompanying pathological molecular events remain unclear. This knowledge gap has resulted in ineffective biomarker development and suboptimal treatment regimens to prevent and manage organ dysfunction/damage. Here, we used pharmacoproteomics to score time-dependent treatment impact in a murine Escherichia coli sepsis model after administering beta-lactam antibiotic meropenem (Mem) and/or the immunomodulatory glucocorticoid methylprednisolone (Gcc). Three distinct proteome response patterns were identified, which depended on the underlying proteotype for each organ. Gcc enhanced some positive proteome responses of Mem, including superior... (More)
Sepsis is the major cause of mortality across intensive care units globally, yet details of accompanying pathological molecular events remain unclear. This knowledge gap has resulted in ineffective biomarker development and suboptimal treatment regimens to prevent and manage organ dysfunction/damage. Here, we used pharmacoproteomics to score time-dependent treatment impact in a murine Escherichia coli sepsis model after administering beta-lactam antibiotic meropenem (Mem) and/or the immunomodulatory glucocorticoid methylprednisolone (Gcc). Three distinct proteome response patterns were identified, which depended on the underlying proteotype for each organ. Gcc enhanced some positive proteome responses of Mem, including superior reduction of the inflammatory response in kidneys and partial restoration of sepsis-induced metabolic dysfunction. Mem introduced sepsis-independent perturbations in the mitochondrial proteome that Gcc counteracted. We provide a strategy for the quantitative and organotypic assessment of treatment effects of candidate therapies in relationship to dosing, timing, and potential synergistic intervention combinations during sepsis.
(Less)
- author
- Mohanty, Tirthankar
LU
; Karlsson, Christofer A Q
LU
; Chao, Yashuan
LU
; Malmström, Erik
LU
; Bratanis, Eleni
LU
; Grentzmann, Andrietta
LU
; Mørch, Martina
LU
; Nizet, Victor
; Malmström, Lars
LU
; Linder, Adam
LU
; Shannon, Oonagh
LU
and Malmström, Johan
LU
(Less) - organization
-
- Translational Sepsis research (research group)
- Infection Medicine Proteomics (research group)
- Immunomodulatory effects of platelets during inflammation and infection (research group)
- Experimental Infection Medicine, Malmö (research group)
- epIgG (research group)
- Cardiovascular Research - Immunity and Atherosclerosis (research group)
- Infection Medicine (BMC)
- Heparin bindning protein in cardiothoracic surgery (research group)
- SEBRA Sepsis and Bacterial Resistance Alliance (research group)
- LTH Profile Area: Engineering Health
- BioMS (research group)
- publishing date
- 2023-06-17
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Mice, Animals, Anti-Bacterial Agents/pharmacology, Proteome, Meropenem/pharmacology, Sepsis/drug therapy, Gram-Negative Bacterial Infections/drug therapy, Bacteremia/drug therapy
- in
- Nature Communications
- volume
- 14
- article number
- 3603
- pages
- 1 - 17
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85162163280
- pmid:37330510
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-023-39269-9
- language
- English
- LU publication?
- yes
- additional info
- © 2023. The Author(s).
- id
- cd7109bf-fda5-48ba-b198-2e297fc80fcf
- date added to LUP
- 2023-06-26 21:35:07
- date last changed
- 2024-04-19 23:06:35
@article{cd7109bf-fda5-48ba-b198-2e297fc80fcf,
abstract = {{<p>Sepsis is the major cause of mortality across intensive care units globally, yet details of accompanying pathological molecular events remain unclear. This knowledge gap has resulted in ineffective biomarker development and suboptimal treatment regimens to prevent and manage organ dysfunction/damage. Here, we used pharmacoproteomics to score time-dependent treatment impact in a murine Escherichia coli sepsis model after administering beta-lactam antibiotic meropenem (Mem) and/or the immunomodulatory glucocorticoid methylprednisolone (Gcc). Three distinct proteome response patterns were identified, which depended on the underlying proteotype for each organ. Gcc enhanced some positive proteome responses of Mem, including superior reduction of the inflammatory response in kidneys and partial restoration of sepsis-induced metabolic dysfunction. Mem introduced sepsis-independent perturbations in the mitochondrial proteome that Gcc counteracted. We provide a strategy for the quantitative and organotypic assessment of treatment effects of candidate therapies in relationship to dosing, timing, and potential synergistic intervention combinations during sepsis.</p>}},
author = {{Mohanty, Tirthankar and Karlsson, Christofer A Q and Chao, Yashuan and Malmström, Erik and Bratanis, Eleni and Grentzmann, Andrietta and Mørch, Martina and Nizet, Victor and Malmström, Lars and Linder, Adam and Shannon, Oonagh and Malmström, Johan}},
issn = {{2041-1723}},
keywords = {{Mice; Animals; Anti-Bacterial Agents/pharmacology; Proteome; Meropenem/pharmacology; Sepsis/drug therapy; Gram-Negative Bacterial Infections/drug therapy; Bacteremia/drug therapy}},
language = {{eng}},
month = {{06}},
pages = {{1--17}},
publisher = {{Nature Publishing Group}},
series = {{Nature Communications}},
title = {{A pharmacoproteomic landscape of organotypic intervention responses in Gram-negative sepsis}},
url = {{http://dx.doi.org/10.1038/s41467-023-39269-9}},
doi = {{10.1038/s41467-023-39269-9}},
volume = {{14}},
year = {{2023}},
}