Mij
Senior Member (Voting Rights)
Significance
This study examines systemic metabolite changes occurring throughout acute and chronic viral infections. We identified an early, transient nutrient shift in chronic infection, characterized by an increase in medium- and long-chain fatty acids. Concomitantly, a stem-like CD8 T cell population, crucial for maintaining other T cells during chronic infection, was found to be highly lipid-avid and capable of using exogenous fatty acids to fuel mitochondrial metabolism. Administering fatty acids late in chronic infection, when endogenous lipid levels normalized, favored stem-like T cells over their effector-like progeny.
These findings highlight the potential role of fatty acids in fine-tuning Tex subsets and offer a valuable resource for studying other metabolic signatures during viral infections.
Abstract
Chronic infections induce CD8 T cell exhaustion, marked by impaired effector function. While intrinsic drivers are well studied, the role of the surrounding metabolic environment in shaping exhausted CD8 T cells (Tex) is less understood. Using untargeted metabolomics and the murine lymphocytic choriomeningitis virus infection model, we investigated systemic metabolite changes following acute vs. chronic viral infections. We identified distinct short-term and persistent metabolite shifts, with the most significant differences occurring transiently during the early phase of the sustained infection. This included nutrient changes that were partially associated with CD8 T cell–induced anorexia and lipolysis.
One remarkable observation was the elevation of medium- and long-chain fatty acids (FA) and acylcarnitines during the first week after chronic infection. Consistently, virus-specific CD8 T cells from chronic infection exhibited increased lipid accumulation and uptake compared to their counterparts from acute infection, particularly the stem-like Tex (TexSTEM), which generates TexINT that directly limit viral replication. Notably, only TexSTEM increased oxidative metabolism upon ex vivo FA exposure, while short-term administration of FA during late chronic infection exclusively increased TexSTEM and their mitochondrial potential. The last-mentioned treatment also led to reduced TexINT and enhanced PD-1 across all Tex subsets, which coincided with compromised viral control.
Our study offers a valuable resource for investigating the regulatory role of specific metabolites during acute and chronic viral infections and highlights the potential of FA to fine-tune Tex subsets during protracted infections.
LINK
This study examines systemic metabolite changes occurring throughout acute and chronic viral infections. We identified an early, transient nutrient shift in chronic infection, characterized by an increase in medium- and long-chain fatty acids. Concomitantly, a stem-like CD8 T cell population, crucial for maintaining other T cells during chronic infection, was found to be highly lipid-avid and capable of using exogenous fatty acids to fuel mitochondrial metabolism. Administering fatty acids late in chronic infection, when endogenous lipid levels normalized, favored stem-like T cells over their effector-like progeny.
These findings highlight the potential role of fatty acids in fine-tuning Tex subsets and offer a valuable resource for studying other metabolic signatures during viral infections.
Abstract
Chronic infections induce CD8 T cell exhaustion, marked by impaired effector function. While intrinsic drivers are well studied, the role of the surrounding metabolic environment in shaping exhausted CD8 T cells (Tex) is less understood. Using untargeted metabolomics and the murine lymphocytic choriomeningitis virus infection model, we investigated systemic metabolite changes following acute vs. chronic viral infections. We identified distinct short-term and persistent metabolite shifts, with the most significant differences occurring transiently during the early phase of the sustained infection. This included nutrient changes that were partially associated with CD8 T cell–induced anorexia and lipolysis.
One remarkable observation was the elevation of medium- and long-chain fatty acids (FA) and acylcarnitines during the first week after chronic infection. Consistently, virus-specific CD8 T cells from chronic infection exhibited increased lipid accumulation and uptake compared to their counterparts from acute infection, particularly the stem-like Tex (TexSTEM), which generates TexINT that directly limit viral replication. Notably, only TexSTEM increased oxidative metabolism upon ex vivo FA exposure, while short-term administration of FA during late chronic infection exclusively increased TexSTEM and their mitochondrial potential. The last-mentioned treatment also led to reduced TexINT and enhanced PD-1 across all Tex subsets, which coincided with compromised viral control.
Our study offers a valuable resource for investigating the regulatory role of specific metabolites during acute and chronic viral infections and highlights the potential of FA to fine-tune Tex subsets during protracted infections.
LINK