Abstract
Introduction Host lipids play important roles in tuberculosis (TB) pathogenesis. Whether host lipids at TB treatment initiation (baseline) affect subsequent treatment outcomes has not been well characterised. We used unbiased lipidomics to study the prospective association of host lipids with TB treatment failure.
Methods A case–control study (n=192), nested within a prospective cohort study, was used to investigate the association of baseline plasma lipids with TB treatment failure among adults with pulmonary TB. Cases (n=46) were defined as TB treatment failure, while controls (n=146) were those without failure. Complex lipids and inflammatory lipid mediators were measured using liquid chromatography mass spectrometry techniques. Adjusted least-square regression was used to assess differences in groups. In addition, machine learning identified lipids with highest area under the curve (AUC) to classify cases and controls.
Results Baseline levels of 32 lipids differed between controls and those with treatment failure after false discovery rate adjustment. Treatment failure was associated with lower baseline levels of cholesteryl esters and oxylipin, and higher baseline levels of ceramides and triglycerides compared to controls. Two cholesteryl ester lipids combined in a unique classifier model provided an AUC of 0.79 (95% CI 0.65–0.93) in the test dataset for prediction of TB treatment failure.
Conclusions We identified lipids, some with known roles in TB pathogenesis, associated with TB treatment failure. In addition, a lipid signature with prognostic accuracy for TB treatment failure was identified. These lipids could be potential targets for risk-stratification, adjunct therapy and treatment monitoring.
Abstract
In this study, unbiased lipidomics were used to identify host lipids prospectively associated with TB treatment failure. These lipids, some with known roles in TB pathogenesis, could be potential targets for adjunct therapy and treatment monitoring. https://bit.ly/3vHZ0Ec
Footnotes
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Author contributions: R. Shivakoti designed the study, oversaw the scientific and logistical aspects of the study, and wrote the primary version of the manuscript. J.W. Newman, K. Borkowski and O. Fiehn conducted the laboratory assessments of lipids, data processing and provided interpretation of the findings. J.W. Newman and K. Borkowski also conducted the data analysis and contributed to manuscript writing and review. L.E. Hanna, A.N. Gupte, M. Paradkar, P. Satyamurthi, V. Kulkarni, M. Selva, N. Pradhan, S.V.B.Y. Shivakumar, S. Natarajan, R. Karunaianantham, N. Gupte, K. Thiruvengadam, R. Bharadwaj, A. Kagal, S. Gaikwad, S. Sangle, J.E. Golub and V. Mave contributed to cohort study design and implementation, data collection and data management. A.T.L. Queiroz and B.B. Andrade helped with the data analysis, created the statistical scripts used to plots the analyses and graphs, and also provided interpretation of the findings. A. Gupta and C. Padmapriyadarsini led the parent study design, and also contributed to the design, implementation and interpretation of this study. All authors read and approved the final manuscript.
Conflict of interest: R. Shivakoti reports grants from NIH, during the conduct of the study.
Conflict of interest: J.W. Newman has nothing to disclose.
Conflict of interest: L.E. Hanna has nothing to disclose.
Conflict of interest: A.T.L. Queiroz has nothing to disclose.
Conflict of interest: K. Borkowski has nothing to disclose.
Conflict of interest: A.N. Gupte has nothing to disclose.
Conflict of interest: M. Paradkar has nothing to disclose.
Conflict of interest: P. Satyamurthi has nothing to disclose.
Conflict of interest: V. Kulkarni has nothing to disclose.
Conflict of interest: M. Selva has nothing to disclose.
Conflict of interest: N. Pradhan has nothing to disclose.
Conflict of interest: S.V.B.Y. Shivakumar has nothing to disclose.
Conflict of interest: S. Natarajan has nothing to disclose.
Conflict of interest: R. Karunaianantham has nothing to disclose.
Conflict of interest: N. Gupte has nothing to disclose.
Conflict of interest: K. Thiruvengadam has nothing to disclose.
Conflict of interest: O. Fiehn has nothing to disclose.
Conflict of interest: R. Bharadwaj has nothing to disclose.
Conflict of interest: A. Kagal has nothing to disclose.
Conflict of interest: S. Gaikwad has nothing to disclose.
Conflict of interest: S. Sangle has nothing to disclose.
Conflict of interest: J.E. Golub has nothing to disclose.
Conflict of interest: B.B. Andrade has nothing to disclose.
Conflict of interest: V. Mave reports grants from NIH, during the conduct of the study.
Conflict of interest: A. Gupta reports grants from NIH, during the conduct of the study.
Conflict of interest: C. Padmapriyadarsini has nothing to disclose.
Support statement: The parent study CTRIUMPH and the data in this manuscript were collected as part of the Regional Prospective Observational Research for Tuberculosis (RePORT) India Consortium. This project has been funded in whole or in part with federal funds from the Government of India's (GOI) Department of Biotechnology (DBT), Indian Council of Medical Research (ICMR), the US National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Office of AIDS Research, and distributed in part by CRDF Global (USB1-31147-XX13 CRDF/NIH). Any mention of trade names, commercial projects, or organizations does not imply endorsement by any of the sponsoring organizations. Research reported in this publication was also supported by NIAID (UM1AI069465 and R01AI097494), NICHD (R00HD089753), the Gilead Foundation, the Ujala Foundation, and the Fogarty International Center BJGMC-JHU HIV-TB Program (D43TW009574). This work was further supported by the Johns Hopkins University School of Medicine funds and Columbia University Department of Epidemiology funds. BBA was supported by Intramural research program from FIOCRUZ and from the National Institutes of Health (U01AI115940) and NIH/CRDF RePORT International Supplemental Funds. A.N. Gupte was supported by NIH Research Training Grant # D43 TW009340 funded by the NIH Fogarty International Center. B.B. Andrade is a senior investigator from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil. Additional support was provided to O. Fiehn by NIH U24 DK097154 and to J.W. Newman by USDA Intramural Projects 2032-51530-022-00D and 2032-51530-025-00D. The USDA is an equal opportunity employer and provider. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received December 15, 2020.
- Accepted May 24, 2021.
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