Profiling whole-tissue metabolic reprogramming during cutaneous poxvirus infection and clearance

Abstract

Vaccinia virus (VACV) infection induces prominent changes in host cell metabolism. Little is known about the global metabolic reprogramming that takes place in whole tissue during viral infection. Here, we performed a longitudinal metabolomics study in VACV-infected mouse skin to investigate metabolic changes in the tissue during infection. We assessed metabolites in homogenized skin of the ear pinnae over time in the presence or absence of antigen-specific T cells using untargeted mass spectrometry. VACV infection induced several significant metabolic changes in the tissue, including in the levels of nucleic acid metabolites (reflecting the impact of viral replication on the skin metabolome). Furthermore, monocyte- and antiviral T cell-produced metabolites, such as itaconic acid and glutamine, were significantly increased following infection, highlighting the immune response’s contribution to the global skin metabolome. Additional RNA-Seq of infected skin tissue recapitulated metabolic changes identified by metabolomics analysis. Overall, our study reveals the metabolic balance of viral replication and the antiviral immune response in the skin, elucidating metabolic pathways that could contribute to cutaneous poxvirus control in vivo . IMPORTANCE Human poxvirus infections have caused significant public health burdens both historically and recently during the unprecedented global Mpox virus outbreak. Although vaccinia virus (VACV) infection of mice is a commonly used model to explore the anti-poxvirus immune response, little is known about the metabolic changes that occur in vivo during infection. We hypothesized that the metabolome of VACV-infected skin would reflect the increased energetic requirements of both virus-infected cells and immune cells recruited to sites of infection. Therefore, we profiled whole VACV-infected skin using untargeted mass spectrometry to define the metabolome during infection, complementing these experiments with flow cytometry and transcriptomics. We identified specific metabolites, including nucleotides, itaconic acid, and glutamine, that were differentially expressed during VACV infection. Together, this study offers insight into both virus-specific and immune-mediated metabolic pathways that could contribute to the clearance of cutaneous poxvirus infection.

T Cell Surveillance during Cutaneous Viral Infections

“…In recent years, studies have also highlighted the importance of cellular metabolism on effector T cell and T RM responses. VACV skin infection induces profound metabolic changes that reflect the contribution of both viral replication and recruited immune cells [59]. T cells have additional energy requirements during antiviral responses, drastically altering their cellular metabolism [60,61].…”