title: Metabolic pathways of lung inflammation revealed by high-resolution metabolomics (HRM) of H1N1 influenza virus infection in mice.
abstract: 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.
authors: Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia; and.
authors: Joshua D
authors: JD
authors: Chandler
authors: Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia; and.
authors: Xin
authors: X
authors: Hu
authors: Georgia State University, Atlanta, Georgia.
authors: Eun-Ju
authors: EJ
authors: Ko
authors: Georgia State University, Atlanta, Georgia.
authors: Soojin
authors: S
authors: Park
authors: Georgia State University, Atlanta, Georgia.
authors: Young-Tae
authors: YT
authors: Lee
authors: Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia; and.
authors: Michael
authors: M
authors: Orr
authors: Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia; and.
authors: Jolyn
authors: J
authors: Fernandes
authors: Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia; and.
authors: Karan
authors: K
authors: Uppal
authors: Georgia State University, Atlanta, Georgia.
authors: Sang-Moo
authors: SM
authors: Kang
authors: Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia; and.
authors: Dean P
authors: DP
authors: Jones
authors: Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia; and ygo@emory.edu.
authors: Young-Mi
authors: 0000-0003-3353-0844
authors: YM
authors: Go
mesh_terms: D000818:Animals; D005260:Female; D057166:High-Throughput Screening Assays; D053118:Influenza A Virus, H1N1 Subtype; D008168:Lung / Q000276:immunology*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000276:immunology*; D055442:Metabolome / Q000276:immunology*; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000821:virology; D011024:Pneumonia, Viral / Q000276:immunology* / Q000821:virology
keywords: metabolic pathway analysis; mouse lung metabolome; pulmonary disease; targeted metabolic intervention