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Decoding Glycoproteome Remodeling in Sepsis through Integrative Multi‐Omics Analysis and Parts‐Based Data Representation
Author(s) -
Sorrentino James T.,
Toledo Alejandro Gomez,
Golden Gregory,
Diaz-Peña Ramon,
Campos Alexandre Rosa,
Nizet Victor,
Malmstrom Johan,
Smith Jeffrey W.,
Lewis Nathan E.,
Esko Jeffrey D.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03074
Subject(s) - glycoproteomics , sepsis , glycan , proteomics , computational biology , glycoprotein , biology , bioinformatics , immunology , biochemistry , gene
Sepsis is a major clinical challenge accounting for unacceptably high‐rates of morbidity and mortality in intensive care units around the world. After many years of extensive research, reliable markers for diagnosis and treatment monitoring remain desperately needed. The plasma glycoproteome offers a suitable readout to monitor systemic alterations in the body. Thus, tracking structural changes in plasma glycoproteins may uncover new molecular windows to target bacterial sepsis. Unfortunately, the analytical challenge posed by the large heterogeneity of plasma carbohydrate and protein components has severely limited advancements in this area. Here we show that Staphylococcus aureus bacteremia induces a dramatic shift of the plasma glycoproteome in a murine model of monobacterial sepsis. Significant changes in the levels of plasma glycoproteins in circulation, as well as their associations with vascular surfaces were revealed through an integrative glycomics, chemical proteomics, and glycoproteomics approach. Additionally, the global and site‐specific glycosylation patterns of the plasma N‐ and O‐linked glycoproteome were significantly altered during sepsis. Deconvolution of these changes through non‐negative matrix factorization methods uncovered the co‐existence of discrete patterns of glycoproteome remodeling associated with specific subgroups of glycoproteins. This included changes in the levels of N‐glycan core‐fucosylation, terminal sialylation, and increased protein deglycosylation, including complete glycan truncations. Furthermore, computational analysis demonstrates that these molecular patterns are sufficient to robustly stratify the samples based on their infection status. In short, we show that multi‐Omics integration has the power to dissect local alterations in the plasma glycoproteome during monobacterial sepsis, possibly reflecting the contribution of discrete biological processes of cellular glycosylation. Support or Funding Information This work was supported by grant P01HL131474 to J.D.E. and J.W.S. J.T.S. acknowledges support from the National Institutes of Health, USA (NIH grant T32GM008806) J.W.S. was supported by R01 GM107523. G.G. was supported by Microbial Sciences Graduate Research Fellowship Awards 1‐F17GG and 1‐F18GG.