Comprehensive plasma proteomic profiling reveals novel biomarkers for active tuberculosis
File(s)
Author(s)
Type
Journal Article
Abstract
Background
Tuberculosis (TB) kills more people than any other infection and new diagnostic tests to identify active cases are urgently required. We aimed to discover and verify novel markers for TB in non depleted plasma.
Methods
We applied an optimised quantitative proteomics discovery methodology based on multidimensional and orthogonal liquid chromatographic separation hyphenated with high-resolution mass spectrometry (q3D LC-MS) to study non-depleted plasma of 11 patients with active TB compared to 10 healthy control donors. Prioritised candidates were verified in an independent UK-based (n=118) and a South African cohorts (n=203).
Results
We generated the most comprehensive TB plasma proteome to date, profiling 5022 proteins spanning 11 orders-of-magnitude concentration range with diverse biochemical and molecular properties. We
further analysed the predominantly low molecular weight sub-proteome; identifying 46 proteins with significantly increased and 90 with decreased abundance (peptide false discovery rate, FDR ≤1%, q77 value ≤0.05). Biological network analysis showed regulation of new pathways involving lipid and organophosphate ester transport. Verification was performed for novel candidate biomarkers (CFHR5, ILF2) in two independent cohorts. These proteins were elevated in both TB and other respiratory
diseases (ORD). Receiver-operating-characteristics analyses using a 5-protein panel (CFHR5, LRG1, CRP, LBP and SAA1) exhibited discriminatory power in distinguishing between TB and ORD (AUC =0.81).
Conclusions
We report the most comprehensive TB plasma proteome to date, identifying numerous novel markers
with verification in two independent cohorts, which led to a 5-protein biosignature with potential to
improve TB diagnosis. With further development, these biomarkers have potential as a diagnostic
triage test.
Tuberculosis (TB) kills more people than any other infection and new diagnostic tests to identify active cases are urgently required. We aimed to discover and verify novel markers for TB in non depleted plasma.
Methods
We applied an optimised quantitative proteomics discovery methodology based on multidimensional and orthogonal liquid chromatographic separation hyphenated with high-resolution mass spectrometry (q3D LC-MS) to study non-depleted plasma of 11 patients with active TB compared to 10 healthy control donors. Prioritised candidates were verified in an independent UK-based (n=118) and a South African cohorts (n=203).
Results
We generated the most comprehensive TB plasma proteome to date, profiling 5022 proteins spanning 11 orders-of-magnitude concentration range with diverse biochemical and molecular properties. We
further analysed the predominantly low molecular weight sub-proteome; identifying 46 proteins with significantly increased and 90 with decreased abundance (peptide false discovery rate, FDR ≤1%, q77 value ≤0.05). Biological network analysis showed regulation of new pathways involving lipid and organophosphate ester transport. Verification was performed for novel candidate biomarkers (CFHR5, ILF2) in two independent cohorts. These proteins were elevated in both TB and other respiratory
diseases (ORD). Receiver-operating-characteristics analyses using a 5-protein panel (CFHR5, LRG1, CRP, LBP and SAA1) exhibited discriminatory power in distinguishing between TB and ORD (AUC =0.81).
Conclusions
We report the most comprehensive TB plasma proteome to date, identifying numerous novel markers
with verification in two independent cohorts, which led to a 5-protein biosignature with potential to
improve TB diagnosis. With further development, these biomarkers have potential as a diagnostic
triage test.
Date Issued
2020-09-17
Date Acceptance
2020-07-31
Citation
JCI Insight, 2020, 5 (18), pp.1-20
ISSN
2379-3708
Publisher
American Society for Clinical Investigation
Start Page
1
End Page
20
Journal / Book Title
JCI Insight
Volume
5
Issue
18
Copyright Statement
© 2020, Garay-Baquero et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License https://creativecommons.org/licenses/by/4.0/.
License URL
Sponsor
Wellcome Trust
Royal College of Physicians
European and Developing Countries Clinical Trial Partnership
Wellcome Trust
Identifier
https://insight.jci.org/articles/view/137427
Grant Number
104803/Z/14/Z
n/a
SRIA2015-1065
WDAI_P83556
Subjects
Diagnostics
Infectious disease
Proteomics
Tuberculosis
Publication Status
Published
Date Publish Online
2020-09-17