Large-Scale Inference of Protein Tissue Origin in Sepsis Plasma Using Quantitative Targeted Proteomics

Johan Malmström
Department of Clinical Sciences, Lund, Lund University, Sweden

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Johan Malmström (Presenter) Department of Clinical Sciences

Presenter Bio: Johan Malmström is a Professor at the Department of Clinical Sciences, Lund University where he is heading the infection medicine proteomics group (IMP). Dr Malmström’s main research focus is to develop new mass spectrometry-based proteomics methods and systems biology applications to systematically investigate molecular mechanisms behind the development of invasive infectious diseases. This is expected to lead to a more complete understanding of the biochemical processes behind the development of severe infectious disease and to the development of new preventive, diagnostic and treatment opportunities.

Johan Malmström received his PhD in 2003, at Lund University in collaboration with AstraZeneca R&D. Between 2004 and 2007 Johan completed two post-doctoral fellowships first at the Institute of Systems Biology in Seattle, WA, USA and then at the Institute for Molecular Systems Biology

Relevant Financial Disclosures (within past 24 months) No relevant financial relationship(s) to disclose. Discussing Products? NO, presenter will NOT present educational content related to products/services of the ineligible company(ies) listed above. Conflict mitigation NOT REQUIRED.

The blood plasma proteome is maintained by influx and efflux of proteins from surrounding cells and organs. The liver secretes the majority of the highly abundant plasma proteins, the so-called classical plasma proteins, involved in the principal functions of plasma such as serving as transport medium, provide colloid osmotic pressure and maintaining hemostasis through the complement and coagulation systems. Blood plasma also contains numerous tissue proteins that most likely do not contribute to the principal functions of blood plasma. This group of proteins is more numerous than the classical plasma proteins and their role, if any, in the plasma is unclear. A subset of these proteins may be waste products resulting from the turnover of proteins and cells under physiological and pathological conditions.
To investigate the complex processes that control the composition of the plasma proteome, we have developed a mass spectrometry-based proteomics strategy to infer the most likely tissue origin of the proteins detected in blood plasma. The strategy relies on the construction of a large-scale protein tissue distribution atlas from cells and highly vascularized organs using shotgun mass spectrometry. The protein tissue atlas was subsequently transformed to a spectral library to enable sensitive and reproducible quantification of tissue-enriched proteins directly in plasma using SWATH-like data-independent mass spectrometry analysis. Here, we show that analysis of septic blood plasma reveals a drastic reorganization of the blood plasma proteome related to disease severity, where part of the plasma proteome followed a disease-dependent reorganization. On the contrary, certain tissue-enriched proteins were increased predominately in the most severely ill subjects. The increase of tissue proteins in critically ill subjects may indicate early signs of organ failure, a hallmark of sepsis pathology.