Metabolic changes induced by T cell-mediated cutaneous vaccinia virus clearance

Abstract

Abstract Viral infections induce prominent alterations to the host metabolism. Vaccinia virus (VACV) has been used as a live vaccine preventing smallpox and monkeypox. However, much remains unknown about the metabolic regulations of the adaptive immune response mounted to VACV infection in the skin. To survey the metabolic changes during VACV clearance, we performed a longitudinal metabolomics study based on our cutaneous VACV infection murine model. We adoptively transferred OT-I CD8 +T cells into Rag−/−mice, then infected one ear with VACV expressing SIINFEKL and VACV lacking SIINFEKL in the contralateral ear. Ears were harvested on 0,5,6,7,8,10 days post infection (dpi), which were homogenized and methanol extracted prior to untargeted mass spectrometry analyses. Metabolomics profiling revealed that VACV infection induced significant metabolic changes over time in the ear tissue. Interestingly, the metabolic profile after viral clearance was still distinct from uninfected control group. The levels of phenylalanine (adj. p=0.032), oleic acid (adj. p=0.011), S-lactoylglutathione (adj. p=0.022), and hypoxanthine (adj. p=0.039) were significantly altered between samples undergoing T cells-mediated killing and those without. Furthermore, glutamic acid level was significantly different (adj. p=0.036) between groups with and without T cells, suggesting T cell utilization during VACV clearance. Overall, our results indicated that VACV infection caused significant and persistent metabolic perturbation in the skin tissue environment. Antiviral T cells that mediate VACV clearance may require specific metabolites or metabolic pathways to regulate cytotoxic functions.