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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; Malmström, Johan; Lewis, Nathan E; Esko, Jeffrey D; Gómez Toledo, Alejandro.
Afiliação
  • Sorrentino JT; Bioinformatics and Systems Biology Graduate Program, University of California, San Diegogrid.266100.3, La Jolla, California, USA.
  • Golden GJ; Department of Bioengineering, University of California, San Diegogrid.266100.3, La Jolla, California, USA.
  • Morris C; Department of Cellular and Molecular Medicine, University of California, San Diegogrid.266100.3, La Jolla, California, USA.
  • Painter CD; Glycobiology Research and Training Center, University of California, San Diegogrid.266100.3, La Jolla, California, USA.
  • Nizet V; Department of Cellular and Molecular Medicine, University of California, San Diegogrid.266100.3, La Jolla, California, USA.
  • Campos AR; Glycobiology Research and Training Center, University of California, San Diegogrid.266100.3, La Jolla, California, USA.
  • Smith JW; Department of Cellular and Molecular Medicine, University of California, San Diegogrid.266100.3, La Jolla, California, USA.
  • Karlsson C; Glycobiology Research and Training Center, University of California, San Diegogrid.266100.3, La Jolla, California, USA.
  • Malmström J; Department of Pediatrics, University of California, San Diegogrid.266100.3, La Jolla, California, USA.
  • Lewis NE; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diegogrid.266100.3, La Jolla, California, USA.
  • Esko JD; The Cancer Center and The Inflammatory and Infectious Disease Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California, USA.
  • Gómez Toledo A; The Cancer Center and The Inflammatory and Infectious Disease Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California, USA.
mSystems ; 7(4): e0039522, 2022 08 30.
Article em En | MEDLINE | ID: mdl-35913192
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 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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Bacteriemia / Sepse Limite: Animals / Humans Idioma: En Revista: MSystems Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Bacteriemia / Sepse Limite: Animals / Humans Idioma: En Revista: MSystems Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos