Systemic perturbations in amino acids/amino acid derivatives and tryptophan pathway metabolites associated with murine influenza A virus infection

Abstract

Background: Influenza A virus (IAV) is the only influenza virus causing flu pandemics (i.e., global epidemics of flu disease). Influenza (the flu) is a highly contagious disease that can be deadly, especially in high-risk groups. Worldwide, these annual epidemics are estimated to result in about 3 to 5 million cases of severe illness and in about 290,000 to 650,000 respiratory deaths. We intend to reveal the effect of IAV infection on the host's metabolism, immune response, and neurotoxicity by using a mouse IAV infection model.

Methods: 51 metabolites of murine blood plasma (33 amino acids/amino acid derivatives (AADs) and 18 metabolites of the tryptophan pathway) were analyzed by using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry with Electrospray Ionization at the acute (7 days post-infection (dpi)), resolution (14 dpi), and recovery (21 dpi) stages of the virus infection in comparison with controls.

Results: Among the 33 biogenic amino acids/AADs, the levels of five amino acids/AADs (1-methylhistidine, 5-oxoproline, α-aminobutyric acid, glutamine, and taurine) increased by 7 dpi, whereas the levels of ten amino acids/AADs (4-hydroxyproline, alanine, arginine, asparagine, cysteine, citrulline, glycine, methionine, proline, and tyrosine) decreased. By 14 dpi, the levels of one AAD (3-methylhistidine) increased, whereas the levels of five amino acids/AADs (α-aminobutyric acid, aminoadipic acid, methionine, threonine, valine) decreased. Among the 18 metabolites from the tryptophan pathway, the levels of kynurenine, quinolinic acid, hydroxykynurenine increased by 7 dpi, whereas the levels of indole-3-acetic acid and nicotinamide riboside decreased.

Conclusions: Our data may facilitate understanding the molecular mechanisms of host responses to IAV infection and provide a basis for discovering potential new mechanistic, diagnostic, and prognostic biomarkers and therapeutic targets for IAV infection.

Keywords: Amino acids; Immunometabolism; Infection; Influenza; Influenza A virus; Metabolites; Neurotoxicity; Tryptophan pathway.

Fig. 1

Heat map showing the profiles of 33 biogenic amino acids/AADs of control and IAV-infected mice. Each colored cell represents metabolite changes between the control and infection groups. The heat map was assembled by cluster analysis, and therefore, similar levels of metabolite changes are positioned at a short distance from each other, whereas different levels of metabolite changes are positioned at a long distance from each other. n = 5

Fig. 2

Metabolic pathway associations of significantly different biogenic amino acids/AADs at 7 dpi with IAV. Blue letters indicate a decrease in IAV infection, whereas red letters indicate an increase in IAV infection (p < 0.05)

Fig. 3

Heat map showing 18 metabolites of the tryptophan pathway during IAV infection. Each colored cell represents metabolite changes between the control and infection groups. The heat map was assembled by cluster analysis, and therefore, similar levels of metabolite changes are positioned at a short distance from each other, whereas different levels of metabolite changes are positioned at a long distance from each other. n = 5

Fig. 4

Metabolic pathway associations of significantly different metabolites of tryptophan pathway during IAV infection. Blue letters indicate a decrease in IAV infection, whereas red letters indicate an increase (p < 0.05) in IAV infection. IFN-γ Interferon-γ, IFN-α Interferon-α, TNF-α Tumor necrosis factor-α, TPH1/2 Tryptophan hydroxylase 1/2, DDC, 3,4-dihydroxyphenylalanine decarboxylase, MAO-A Monoamine oxidase A/B, IDO1/2 Indoleamine-2,3-dioxygenase 1/2, TDO2 Trypto-phan2,3-dioxygenase, KF Kynurenine formamidase, KAT Kynurenine aminotransferase, KMO Kynurenine 3-monooxygenase, KYNU Kynurenine hydrolase, HAAO 3-hydroxyanthranilic acid dioxygenase, QPRT Quinolinic acid phosphoribosyl transferase

Fig. 5

Metabolic correlation network diagram for metabolites analyzed during IAV infection. A Metabolic correlation network for biogenic amino acids/AADs analyzed during infection. B Metabolic correlation network for metabolites of the tryptophan pathway analyzed during infection. Each connected node represents structurally related metabolites, as determined by molecular networking. The metabolic data were imported into the Cytoscape software to form a differential metabolites network of interaction. The larger the area of the circle, the darker the color and the higher the degree values