Pathogen-induced changes in host cell metabolism are known to be important for the immune response. In this study, we investigated how infection with the Lyme disease-causing bacterium Borrelia burgdorferi (Bb) affects host metabolic pathways and how these metabolic pathways may impact host defense. First, metabolome analysis was performed on human primary monocytes from healthy volunteers, stimulated for 24 h with Bb at low multiplicity of infection (MOI).
Pathway analysis indicated that glutathione (GSH) metabolism was the pathway most significantly affected by Bb Specifically, intracellular levels of GSH increased on average 10-fold in response to Bb exposure. Furthermore, these changes were found to be specific, as they were not seen during stimulation with other pathogens. Next, metabolome analysis was performed on serum samples from patients with early-onset Lyme disease in comparison with patients with other infections.
Supporting the in vitro analysis, we identified a cluster of GSH-related metabolites, the γ-glutamyl amino acids, specifically altered in patients with Lyme disease, and not in other infections. Lastly, we performed in vitro experiments to validate the role for GSH metabolism in host response against Bb. We found that the GSH pathway is essential for Bb-induced cytokine production and identified glutathionylation as a potential mediating mechanism.
Taken together, these data indicate a central role for the GSH pathway in the host response to Bb GSH metabolism and glutathionylation may therefore be important factors in the pathogenesis of Lyme disease and potentially other inflammatory diseases as well.
Kerstholt M1,2, Vrijmoeth H1,2, Lachmandas E1,2, Oosting M1,2, Lupse M3, Flonta M3, Dinarello CA4,2,5, Netea MG1,2,6, Joosten LAB4,2. Role of glutathione metabolism in host defense against Borrelia burgdorferi infection. Proc Natl Acad Sci U S A. 2018 Feb 14. pii: 201720833. doi: 10.1073/pnas.1720833115. [Epub ahead of print]