Sepsis, the dysregulated host response to infection causing life-threatening organ dysfunction, is an unmet global health challenge. Here we apply high-throughput tandem mass spectrometry to delineate the plasma proteome for sepsis and comparator groups (non-infected critical illness, post-operative inflammation and healthy volunteers) involving 2622 samples and 4553 liquid chromatography-mass spectrometry analyses in a single batch, at 100 samples/day. We show how this scale of data can establish shared and specific proteins, pathways and co-expression modules in sepsis, and be integrated with paired leukocyte transcriptomic data (n=837 samples) using matrix decomposition. We map the landscape of the host response in sepsis including changes over time, and identify features relating to etiology, clinical phenotypes and severity. This work reveals novel subphenotypes informative for sepsis response state, disease processes and outcome, highlights potential biomarkers, pathways and processes for drug targets, and advances a systems-based precision medicine approach to sepsis.

ACG has received consulting fees from AstraZeneca, unrelated to this project. Other authors declare no competing interests.

Research was supported by the National Institute for Health and Care Research (NIHR) through the Comprehensive Clinical Research Network for patient recruitment. This research and participating researchers were funded by the Wellcome Trust (Wellcome Trust Investigator Award (204969/Z/16/Z) (J.C.K), core funding to the Wellcome Centre for Human Genetics (090532/Z/09/Z, 203141/Z/16/Z) and Wellcome Sanger Institute (206194, 108413/A/15/D), Medical Research Council (MR/V002503/1) (J.C.K., E.E.D., A.C.G.), CAMS IFMS 2018-I2M-2-002 (J.C.K.), China Scholarship Council-University of Oxford Scholarship (Y.M.), BJA/RCA Career Development Award (G.L.A.), British Oxygen Company (G.L.A.), British Heart Foundation (RG/14/4/30736 and RG/19/5/34463) (G.L.A.), NIHR Advanced Fellowship (NIHR 300097) (G.L.A.), NIHR Oxford Biomedical Research Centre (J.C.K., Oxford BioBank and Oxford Bioresource), NIHR Imperial Biomedical Research Centre (D.A., R.D., D.J.P.O, P.P., A.C.G., BIONIC), NIHR Research Professor award (RP-2015-06-018) (A.C.G), NIHR Research for Patient Benefit awards (MONGRAMS, PB-PG-0613-31073 and VANISH, PB-PG-0610-22350), Intensive Care Foundation Young Investigators Awards (TACE and MONOGRAMS), the National Institute of Academic Anaesthesia (BIONIC, BJA/RCoA Project Grant WKR0-2020-0019), European Society of Anaesthesiologists (BIONIC), and NIHR Academic Clinical Fellowship (ACF-2019-21-011) (H.D.T.).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethical approval for this work was given by the following UK Research Ethics Committees: Scotland A Research Ethics Committee (05/MRE00/38), Berkshire Research Ethics Committee (08/H0505/78), South Central - Oxford A Research Ethics Committee (12/SC/0014), South Central - Oxford C Research Ethics Committee (18/SC/0588), London - Stanmore Research Ethics Committee (16/LO/0635), East Midlands - Nottingham 2 Research Ethics Committee (14/EM/1223), London - Harrow Research Ethics Committee (14/LO/2004), London - Camden and Kings Cross Research Ethics Committee (15/LO/0933), and North London Research Ethics Committee (10/H0709/77).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

The raw and processed timsTOF mass spectrometry data are publicly available on the Proteomics Identification Database (PRIDE) (deposition in progress, accession ID TBC). RNAseq gene expression data for GAinS study samples will be made available in the European Genome-Phenome Archive before publication. Microarray gene expression data for GAinS study samples are publicly available in ArrayExpress (E-MTAB-4421, E-MTAB-4451, E-MTAB-5273, and E-MTAB-5274).

https://www.ebi.ac.uk/arrayexpress/

https://ega-archive.org/