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Vascular Proteome Responses Precede Organ Dysfunction in a Murine Model of Staphylococcus aureus Bacteremia

Sorrentino, James T ; Golden, Gregory J ; Morris, Claire ; Painter, Chelsea D ; Nizet, Victor ; Campos, Alexandre Rosa ; Smith, Jeffrey W ; Karlsson, Christofer LU ; Malmström, Johan LU orcid and Lewis, Nathan E , et al. (2022) In mSystems 7(4).
Abstract

Vascular dysfunction and organ failure are two distinct, albeit highly interconnected, clinical outcomes linked to morbidity and mortality in human sepsis. The mechanisms driving vascular and parenchymal damage are dynamic and display significant molecular cross talk between organs and tissues. Therefore, assessing their individual contribution to disease progression is technically challenging. Here, we hypothesize that dysregulated vascular responses predispose the organism to organ failure. To address this hypothesis, we have evaluated four major organs in a murine model of Staphylococcus aureus sepsis by combining
in vivo labeling of the endothelial cell surface proteome, data-independent acquisition (DIA) mass spectrometry, and... (More)

Vascular dysfunction and organ failure are two distinct, albeit highly interconnected, clinical outcomes linked to morbidity and mortality in human sepsis. The mechanisms driving vascular and parenchymal damage are dynamic and display significant molecular cross talk between organs and tissues. Therefore, assessing their individual contribution to disease progression is technically challenging. Here, we hypothesize that dysregulated vascular responses predispose the organism to organ failure. To address this hypothesis, we have evaluated four major organs in a murine model of Staphylococcus aureus sepsis by combining
in vivo labeling of the endothelial cell surface proteome, data-independent acquisition (DIA) mass spectrometry, and an integrative computational pipeline. The data reveal, with unprecedented depth and throughput, that a septic insult evokes organ-specific proteome responses that are highly compartmentalized, synchronously coordinated, and significantly correlated with the progression of the disease. These responses include abundant vascular shedding, dysregulation of the intrinsic pathway of coagulation, compartmentalization of the acute phase response, and abundant upregulation of glycocalyx components. Vascular cell surface proteome changes were also found to precede bacterial invasion and leukocyte infiltration into the organs, as well as to precede changes in various well-established cellular and biochemical correlates of systemic coagulopathy and tissue dysfunction. Importantly, our data suggest a potential role for the vascular proteome as a determinant of the susceptibility of the organs to undergo failure during sepsis.
IMPORTANCE Sepsis is a life-threatening response to infection that results in immune dysregulation, vascular dysfunction, and organ failure. New methods are needed for the identification of diagnostic and therapeutic targets. Here, we took a systems-wide approach using data-independent acquisition (DIA) mass spectrometry to track the progression of bacterial sepsis in the vasculature leading to organ failure. Using a murine model of S. aureus sepsis, we were able to quantify thousands of proteins across the plasma and parenchymal and vascular compartments of multiple organs in a time-resolved fashion. We showcase the profound proteome remodeling triggered by sepsis over time and across these compartments. Importantly, many vascular proteome alterations precede changes in traditional correlates of organ dysfunction, opening a molecular window for the discovery of early markers of sepsis progression.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
DIA mass spectrometry, glycocalyx, proteome, sepsis, Staphylococcus aureus, vascular, vascular glycocalyx
in
mSystems
volume
7
issue
4
article number
e0039522
publisher
American Society for Microbiology
external identifiers
  • pmid:35913192
  • scopus:85137046741
  • pmid:35913192
ISSN
2379-5077
DOI
10.1128/msystems.00395-22
language
English
LU publication?
yes
id
054e2f31-0b2c-49bf-94a4-0e415f15e9f1
date added to LUP
2022-09-26 08:38:02
date last changed
2024-06-13 14:00:36
@article{054e2f31-0b2c-49bf-94a4-0e415f15e9f1,
  abstract     = {{<p>Vascular dysfunction and organ failure are two distinct, albeit highly interconnected, clinical outcomes linked to morbidity and mortality in human sepsis. The mechanisms driving vascular and parenchymal damage are dynamic and display significant molecular cross talk between organs and tissues. Therefore, assessing their individual contribution to disease progression is technically challenging. Here, we hypothesize that dysregulated vascular responses predispose the organism to organ failure. To address this hypothesis, we have evaluated four major organs in a murine model of Staphylococcus aureus sepsis by combining<br>
 in vivo labeling of the endothelial cell surface proteome, data-independent acquisition (DIA) mass spectrometry, and an integrative computational pipeline. The data reveal, with unprecedented depth and throughput, that a septic insult evokes organ-specific proteome responses that are highly compartmentalized, synchronously coordinated, and significantly correlated with the progression of the disease. These responses include abundant vascular shedding, dysregulation of the intrinsic pathway of coagulation, compartmentalization of the acute phase response, and abundant upregulation of glycocalyx components. Vascular cell surface proteome changes were also found to precede bacterial invasion and leukocyte infiltration into the organs, as well as to precede changes in various well-established cellular and biochemical correlates of systemic coagulopathy and tissue dysfunction. Importantly, our data suggest a potential role for the vascular proteome as a determinant of the susceptibility of the organs to undergo failure during sepsis. <br>
 IMPORTANCE Sepsis is a life-threatening response to infection that results in immune dysregulation, vascular dysfunction, and organ failure. New methods are needed for the identification of diagnostic and therapeutic targets. Here, we took a systems-wide approach using data-independent acquisition (DIA) mass spectrometry to track the progression of bacterial sepsis in the vasculature leading to organ failure. Using a murine model of S. aureus sepsis, we were able to quantify thousands of proteins across the plasma and parenchymal and vascular compartments of multiple organs in a time-resolved fashion. We showcase the profound proteome remodeling triggered by sepsis over time and across these compartments. Importantly, many vascular proteome alterations precede changes in traditional correlates of organ dysfunction, opening a molecular window for the discovery of early markers of sepsis progression.<br>
 </p>}},
  author       = {{Sorrentino, James T and Golden, Gregory J and Morris, Claire and Painter, Chelsea D and Nizet, Victor and Campos, Alexandre Rosa and Smith, Jeffrey W and Karlsson, Christofer and Malmström, Johan and Lewis, Nathan E and Esko, Jeffrey D and Gómez Toledo, Alejandro}},
  issn         = {{2379-5077}},
  keywords     = {{DIA mass spectrometry; glycocalyx; proteome; sepsis; Staphylococcus aureus; vascular; vascular glycocalyx}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{4}},
  publisher    = {{American Society for Microbiology}},
  series       = {{mSystems}},
  title        = {{Vascular Proteome Responses Precede Organ Dysfunction in a Murine Model of Staphylococcus aureus Bacteremia}},
  url          = {{http://dx.doi.org/10.1128/msystems.00395-22}},
  doi          = {{10.1128/msystems.00395-22}},
  volume       = {{7}},
  year         = {{2022}},
}