Response and Recovery in the Plasma Metabolome Tracks the Acute LCMV-Induced Immune Response

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Abstract
Lymphocytic choriomeningitis virus (LCMV) infection of mice is noncytopathic, producing well-characterized changes reflecting the host immune response. Untargeted metabolomics using mass spectrometry identified endogenous small molecule changes in blood from mice inoculated with LCMV, sampled at days 1, 3, 7, and 14 post infection. These time points correspond to well characterized events during acute LCMV infection and the immune response. Diverse pathways were altered, including TCA cycle intermediates, γ-glutamyl dipeptides, lysophosphatidyl cholines, and fatty acids. The kynurenine pathway was activated, surprising because it is stimulated by IFN-γ, which LCMV suppresses, thus, suggesting alternative activators. In contrast, biopterin/neopterin, another IFN-γ stimulated pathway, was not activated. Many metabolites followed “response and recovery” kinetics, decreasing after infection to a minimum at days 3−7, and returning to normal by day 14. The TCA pathway followed this pattern, including citrate, cis-aconitate and α-ketoglutarate, intriguing because succinate has been shown to mediate cellular immunity. This response and recovery dynamic tracks the immune response, including the rise and fall of natural killer cell populations, serum TNF receptor concentration, and viral clearance. Metabolomics can provide target pathways for molecular diagnostics or therapeutics of viral infection and immunity.