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J.D.C., X.H., E.-J.K., S.P., Y.-T.L., M.L.O., and J.F. performed experiments; J.D.C., X.H., E.-J.K., S.P., Y.-T.L., J.F., K.U., S.-M.K., and Y.-M.G. analyzed data; J.D.C., X.H., E.-J.K., Y.-T.L., J.F., K.U., S.-M.K., D.P.J., and Y.-M.G. interpreted results of experiments; J.D.C., X.H., E.-J.K., S.P., Y.-T.L., K.U., and Y.-M.G. prepared figures; J.D.C., X.H., Y.-T.L., S.-M.K., D.P.J., and Y.-M.G. edited and revised manuscript; J.D.C., X.H., E.-J.K., S.P., Y.-T.L., M.L.O., J.F., K.U., S.-M.K., D.P.J., and Y.-M.G. approved final version of manuscript; S.-M.K., D.P.J., and Y.-M.G. conception and design of research; Y.-M.G. drafted manuscript.

We thank Drs. Sushma K. Cribbs (MD, Pulmonary Medicine, Emory University), Annette Esper (MD, Pulmonary Medicine, Emory University), and Shuzhao Li (PhD, Director of Immunometabolomics, Emory University) for providing comments about the manuscript.

No conflicts of interest, financial or otherwise, are declared by the author(s).

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Research Funding:

This study was supported by National Institute of Environmental Health Sciences Grants R01-ES-023485 (D. P. Jones and Y.-M. Go) and R21-ES-025632 (DPJ and Y.-M. Go), National Institutes of Health Grant S10-OD-018006 (D. P. Jones), National Institute of Allergy and Infectious Diseases Grants R01-AI-105170 (S.-M. Kang), R01-AI-093772 (S.-M. Kang), and R21-AI-119366 (S.-M. Kang), and Cystic Fibrosis Foundation CHANDL16F0 (JDC).

Keywords:

  • metabolic pathway analysis
  • mouse lung metabolome
  • pulmonary disease
  • targeted metabolic intervention

Metabolic pathways of lung inflammation revealed by high-resolution metabolomics (HRM) of H1N1 influenza virus infection in mice

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Journal Title:

AJP - Regulatory, Integrative and Comparative Physiology

Volume:

Volume 311, Number 5

Publisher:

, Pages R906-R916

Type of Work:

Article | Post-print: After Peer Review

Abstract:

© 2016 the American Physiological Society.Influenza is a significant health concern worldwide. Viral infection induces local and systemic activation of the immune system causing attendant changes in metabolism. High-resolution metabolomics (HRM) uses advanced mass spectrometry and computational methods to measure thousands of metabolites inclusive of most metabolic pathways. We used HRM to identify metabolic pathways and clusters of association related to inflammatory cytokines in lungs of mice with H1N1 influenza virus infection. Infected mice showed progressive weight loss, decreased lung function, and severe lung inflammation with elevated cytokines [interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ] and increased oxidative stress via cysteine oxidation. HRM showed prominent effects of influenza virus infection on tryptophan and other amino acids, and widespread effects on pathways including purines, pyrimidines, fatty acids, and glycerophospholipids. A metabolome-wide association study (MWAS) of the aforementioned inflammatory cytokines was used to determine the relationship of metabolic responses to inflammation during infection. This cytokine-MWAS (cMWAS) showed that metabolic associations consisted of distinct and shared clusters of 396 metabolites highly correlated with inflammatory cytokines. Strong negative associations of selected glycosphingolipid, linoleate, and tryptophan metabolites with IFN-γ contrasted strong positive associations of glycosphingolipid and bile acid metabolites with IL-1β, TNF-α, and IL-10. Anti-inflammatory cytokine IL-10 had strong positive associations with vitamin D, purine, and vitamin E metabolism. The detailed metabolic interactions with cytokines indicate that targeted metabolic interventions may be useful during life-threatening crises related to severe acute infection and inflammation.

Copyright information:

© 2016 the American Physiological Society.

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