Proteomic atlas of organ vasculopathies triggered by Staphylococcus aureus sepsis

Alejandro Gómez Toledo,Victor Nizet,Jeffrey W Smith,Nathan Lewis,Jeffrey D Esko,Gregory Golden,Alexandre Rosa Campos,James Sorrentino,Hector Cuello,Nissi Varki

doi:10.1038/s41467-019-12672-x

Abstract

Sepsis is a life-threatening condition triggered by a dysregulated host response to microbial infection resulting in vascular dysfunction, organ failure and death. Here we provide a semi-quantitative atlas of the murine vascular cell-surface proteome at the organ level, and how it changes during sepsis. Using in vivo chemical labeling and high-resolution mass spectrometry, we demonstrate the presence of a vascular proteome that is perfusable and shared across multiple organs. This proteome is enriched in membrane-anchored proteins, including multiple regulators of endothelial barrier functions and innate immunity. Further, we automated our workflows and applied them to a murine model of methicillin-resistant Staphylococcus aureus (MRSA) sepsis to unravel changes during systemic inflammatory responses. We provide an organ-specific atlas of both systemic and local changes of the vascular proteome triggered by sepsis. Collectively, the data indicates that MRSA-sepsis triggers extensive proteome remodeling of the vascular cell surfaces, in a tissue-specific manner.

Highlights

Sepsis is a life-threatening condition triggered by a dysregulated host response to microbial infection resulting in vascular dysfunction, organ failure and death
We explored the labeling of murine vascular compartments using terminal systemic perfusion with ester derivatives of biotin to tag, purify, and identify proteins normally exposed to the vascular flow
We found a number of proteins involved in lipoprotein remodeling and clearance, including low density lipoprotein receptor (Ldlr), angiopoietinrelated protein 3 (Angptl3), hepatic triglyceride lipase precursor (Lipc), fatty acid binding protein 1 (Fabp1), and LDLR associated protein 1 (Ldlrap1), consistent with the role of the liver as the major target for lipoprotein metabolism and uptake

Summary

Introduction

Sepsis is a life-threatening condition triggered by a dysregulated host response to microbial infection resulting in vascular dysfunction, organ failure and death. We provide a semiquantitative atlas of the murine vascular cell-surface proteome at the organ level, and how it changes during sepsis. Using in vivo chemical labeling and high-resolution mass spectrometry, we demonstrate the presence of a vascular proteome that is perfusable and shared across multiple organs This proteome is enriched in membrane-anchored proteins, including multiple regulators of endothelial barrier functions and innate immunity. Rapid remodeling of the vascular surfaces occurs during systemic inflammatory responses and sepsis[5,6], with increased degradation and shedding of glycocalyx components. The ability to track these processes in vivo with temporal and spatial resolution is key to understanding early events during systemic inflammatory responses Such insights might facilitate the molecular classification of sepsis subtypes based on specific pathogens and/or host vascular responses. ~40% of the proteins expressed on luminal endothelial cell plasma membranes isolated from rat lungs are totally absent in cultured rat lung microvascular endothelial cells, documenting the inadequacy of cell culture models to duplicate the natural environment of endothelial cells[20]

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Results

Conclusion