TLR4-independent effects of LPS identified using longitudinal serum proteomics

Erin Harberts , Tao Liang , Sung Hwan Yoon , Belita N. Opene , Melinda A. McFarland , David Goodlett , Robert K. Ernst

Abstract

Sepsis remains one of the most lethal and costly conditions treated in U.S. hospitals, with approximately 50% of cases caused by Gram-negative bacterial infections. Septic shock is induced when lipopolysaccharide (LPS), a main component of Gram-negative outer bacterial membranes, signals through the Toll-like receptor 4 (TLR4) complex. Lethal endotoxemia, a model for septic shock, was induced in WT C57BL6 and TLR4-/- mice by administration of Escherichia coli LPS. WT LPS treated mice showed high morbidity while PBS treated LPS and treated TLR4-/- mice did not. ANOVA analysis of label-free quantification (LFQ) of longitudinal serum proteome revealed 182 out of 324 proteins in LPS injected WT mice that were significantly changed across four time points (0, 6, 12 and 18h). No significant changes were identified in the two control groups. From the 182 identified proteins, examples of known sepsis biomarkers were validated by ELISA which showed similar trends as MS proteomics data. Longitudinal analysis within individual mice produced 3-fold more significantly changed proteins than pair-wise comparison. A subsequent global analysis of WT and TLR4-/- mice identified pathways activated independent of TLR4. These pathways represent possible compensatory mechanisms that allow for control of Gram-negative bacterial infection regardless of host immune status.
Publication typeIn press (online first, early view)
Author Erin Harberts
Erin Harberts,,
-
, Tao Liang
Tao Liang,,
-
, Sung Hwan Yoon
Sung Hwan Yoon,,
-
, Belita N. Opene
Belita N. Opene,,
-
, Melinda A. McFarland
Melinda A. McFarland,,
-
, David Goodlett (ICCVS)
David Goodlett,,
- International Centre for Cancer Vaccine Science
, Robert K. Ernst
Robert K. Ernst,,
-
Journal seriesJournal of Proteome Research, ISSN 1535-3893, e-ISSN 1535-3907, (N/A 100 pkt)
Issue year2020
Noonline first
Pages1-30
Publication size in sheets1.45
Keywords in EnglishTLR4, LPS, mass spectrometry, serum proteomics, sepsis, endotoxemia
ASJC Classification1303 Biochemistry; 1600 General Chemistry
DOIDOI:10.1021/acs.jproteome.9b00765
URL https://doi.org/10.1021/acs.jproteome.9b00765
Languageen angielski
Score (nominal)100
Score sourcejournalList
ScoreMinisterial score = 100.0, 21-02-2020, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2018 = 0.940; WoS Impact Factor: 2018 = 3.780 (2) - 2018=3.917 (5)
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