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Title: Application of multiplexed ion mobility spectrometry towards the identification of host protein signatures of treatment effect in pulmonary tuberculosis

Here, the monitoring of TB treatments in clinical practice and clinical trials relies on traditional sputum-based culture status indicators at specific time points. Accurate, predictive, blood-based protein markers would provide a simpler and more informative view of patient health and response to treatment. We utilized sensitive, high throughput multiplexed ion mobility-mass spectrometry (IM-MS) to characterize the serum proteome of TB patients at the start of and at 8 weeks of rifamycin-based treatment. We sought to identify treatment specific signatures within patients as well as correlate the proteome signatures to various clinical markers of treatment efficacy. Serum samples were collected from 289 subjects enrolled in CDC TB Trials Consortium Study 29 at time of enrollment and at the end of the intensive phase (after 40 doses of TB treatment). Serum proteins were immunoaffinity-depleted of high abundant components, digested to peptides and analyzed for data acquisition utilizing a unique liquid chromatography IM-MS platform (LC-IM-MS). Linear mixed models were utilized to identify serum protein changes in the host response to antibiotic treatment as well as correlations with culture status end points. A total of 10,137 peptides corresponding to 872 proteins were identified, quantified, and used for statistical analysis across the longitudinal patient cohort.more » In response to TB treatment, 244 proteins were significantly altered. Pathway/network comparisons helped visualize the interconnected proteins, identifying up regulated (lipid transport, coagulation cascade, endopeptidase activity) and down regulated (acute phase) processes and pathways in addition to other cross regulated networks (inflammation, cell adhesion, extracellular matrix). Detection of possible lung injury serum proteins such as HPSE, significantly downregulated upon treatment. Analyses of microbiologic data over time identified a core set of serum proteins (TTHY, AFAM, CRP, RET4, SAA1, PGRP2) which change in response to treatment and also strongly correlate with culture status. A similar set of proteins at baseline were found to be predictive of week 6 and 8 culture status.« less
Authors:
 [1] ;  [1] ; ORCiD logo [1] ;  [1] ; ORCiD logo [2] ;  [3] ; ORCiD logo [1] ; ORCiD logo [1] ;  [1] ;  [4] ;  [5] ;  [6] ;  [1] ;  [1] ; ORCiD logo [2]
  1. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Biological Sciences Division and Environmental Molecular Sciences Lab.
  2. Univ. of California San Francisco, San Francisco, CA (United States). Div. of Pulmonary and Critical Care Medicine
  3. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Computational and Statistical Analysis Div.
  4. Oregon Health & Science Univ., Portland, OR (United States). Pulmonary and Critical Care Medicine
  5. Meso Scale Diagnostics, Rockville, MD (United States)
  6. Univ. of Texas Health Science Center at San Antonio and the South Texas VAMC, San Antonio, TX (United States)
Publication Date:
Report Number(s):
PNNL-SA-126570
Journal ID: ISSN 1472-9792; PII: S1472979218301264
Grant/Contract Number:
1R01AI104589; 200-2009-32597; GM103493; AC05-76RL01830
Type:
Accepted Manuscript
Journal Name:
Tuberculosis
Additional Journal Information:
Journal Volume: none; Journal Issue: none; Journal ID: ISSN 1472-9792
Publisher:
Elsevier
Research Org:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Ion mobility spectrometry; Proteomics; Tuberculosis; Antibiotic treatment
OSTI Identifier:
1461645

Kedia, Komal, Wendler, Jason, Baker, Erin S., Burnum-Johnson, Kristin E., Jarsberg, Leah G., Stratton, Kelly G., Wright, Aaron T., Piehowski, Paul D., Gritsenko, Marina A., Lewinsohn, David M., Sigal, George B., Weiner, Marc H., Smith, Richard D., Jacobs, Jon M., and Nahid, Payam. Application of multiplexed ion mobility spectrometry towards the identification of host protein signatures of treatment effect in pulmonary tuberculosis. United States: N. p., Web. doi:10.1016/J.TUBE.2018.07.005.
Kedia, Komal, Wendler, Jason, Baker, Erin S., Burnum-Johnson, Kristin E., Jarsberg, Leah G., Stratton, Kelly G., Wright, Aaron T., Piehowski, Paul D., Gritsenko, Marina A., Lewinsohn, David M., Sigal, George B., Weiner, Marc H., Smith, Richard D., Jacobs, Jon M., & Nahid, Payam. Application of multiplexed ion mobility spectrometry towards the identification of host protein signatures of treatment effect in pulmonary tuberculosis. United States. doi:10.1016/J.TUBE.2018.07.005.
Kedia, Komal, Wendler, Jason, Baker, Erin S., Burnum-Johnson, Kristin E., Jarsberg, Leah G., Stratton, Kelly G., Wright, Aaron T., Piehowski, Paul D., Gritsenko, Marina A., Lewinsohn, David M., Sigal, George B., Weiner, Marc H., Smith, Richard D., Jacobs, Jon M., and Nahid, Payam. 2018. "Application of multiplexed ion mobility spectrometry towards the identification of host protein signatures of treatment effect in pulmonary tuberculosis". United States. doi:10.1016/J.TUBE.2018.07.005. https://www.osti.gov/servlets/purl/1461645.
@article{osti_1461645,
title = {Application of multiplexed ion mobility spectrometry towards the identification of host protein signatures of treatment effect in pulmonary tuberculosis},
author = {Kedia, Komal and Wendler, Jason and Baker, Erin S. and Burnum-Johnson, Kristin E. and Jarsberg, Leah G. and Stratton, Kelly G. and Wright, Aaron T. and Piehowski, Paul D. and Gritsenko, Marina A. and Lewinsohn, David M. and Sigal, George B. and Weiner, Marc H. and Smith, Richard D. and Jacobs, Jon M. and Nahid, Payam},
abstractNote = {Here, the monitoring of TB treatments in clinical practice and clinical trials relies on traditional sputum-based culture status indicators at specific time points. Accurate, predictive, blood-based protein markers would provide a simpler and more informative view of patient health and response to treatment. We utilized sensitive, high throughput multiplexed ion mobility-mass spectrometry (IM-MS) to characterize the serum proteome of TB patients at the start of and at 8 weeks of rifamycin-based treatment. We sought to identify treatment specific signatures within patients as well as correlate the proteome signatures to various clinical markers of treatment efficacy. Serum samples were collected from 289 subjects enrolled in CDC TB Trials Consortium Study 29 at time of enrollment and at the end of the intensive phase (after 40 doses of TB treatment). Serum proteins were immunoaffinity-depleted of high abundant components, digested to peptides and analyzed for data acquisition utilizing a unique liquid chromatography IM-MS platform (LC-IM-MS). Linear mixed models were utilized to identify serum protein changes in the host response to antibiotic treatment as well as correlations with culture status end points. A total of 10,137 peptides corresponding to 872 proteins were identified, quantified, and used for statistical analysis across the longitudinal patient cohort. In response to TB treatment, 244 proteins were significantly altered. Pathway/network comparisons helped visualize the interconnected proteins, identifying up regulated (lipid transport, coagulation cascade, endopeptidase activity) and down regulated (acute phase) processes and pathways in addition to other cross regulated networks (inflammation, cell adhesion, extracellular matrix). Detection of possible lung injury serum proteins such as HPSE, significantly downregulated upon treatment. Analyses of microbiologic data over time identified a core set of serum proteins (TTHY, AFAM, CRP, RET4, SAA1, PGRP2) which change in response to treatment and also strongly correlate with culture status. A similar set of proteins at baseline were found to be predictive of week 6 and 8 culture status.},
doi = {10.1016/J.TUBE.2018.07.005},
journal = {Tuberculosis},
number = none,
volume = none,
place = {United States},
year = {2018},
month = {7}
}