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.

Low-Level Aflatoxin B1 Promotes Influenza Infection and Modulates a Switch in Macrophage Polarization from M1 to M2

“…increased. These findings are consistent with the outcomes of viral infection [39][40][41], suggesting that AFB 1 exacerbated viral infection. In addition, levels of 20 and 40 µg/kg AFB 1 also increased lung injury and inflammatory cell infiltration in SIV-infected mice.…”

Novel endosomal NOX2 oxidase inhibitor ameliorates pandemic influenza A virus‐induced lung inflammation in mice

“…IAV cause severe respiratory tract infections, which are associated with lung inflammation, excessive ROS production from NOX2 oxidase and significant lung pathology . The spatial restrictions of ROS strongly suggest that their site of production governs their site of action.…”

Metabolic host response and therapeutic approaches to influenza infection

“…Thus, induction of mTORC1 signaling by the influenza virus leads to higher usage of essential amino acid storages for concurrent production of large amounts of viral and cellular proteins. Infection of influenza virus can also alter the cellular level and metabolism of purines and pyrimidines [8,98,100], and is associated with both increased activities of nucleotide catabolism core enzymes including adenosine deaminase (ADA) and xanthine oxidase (XO) and elevated levels of inosine, hypoxanthine, xanthine, and uric acid in serum and bronchoalveolar lavage fluid. Enhanced catabolic degradation of nucleotides and their metabolites can facilitate the production of superoxide and contribute to the pathogenesis of influenza infection [23].…”

“…Results of a published study showed that the replication of the influenza virus depends on host cellular metabolism such that metabolites including nucleic acids, proteins, glycoproteins, and lipids are crucially required for the life cycle of the influenza virus [7]. Recent research on a mouse model showed that influenza infection could affect more than 100 metabolite markers in serum, lung, and bronchoalveolar lavage fluid [8]. Acquiring the required materials from the host cell to self-replicate, the virus can disrupt biochemical processes such as glycolysis, fatty acid (FA) synthesis, and glutamine pathways [9].…”