Multi-omics analysis of glycolytic reprogramming and ROS dynamics in host-specific responses to Salmonella Typhi infection in mice

Abstract

Introduction

Salmonella Typhi (S. Typhi), a Gram-negative, serves as the etiological agent of typhoid fever. In contrast to other Salmonella serovars, S. Typhi exclusively infects humans. However, the molecular interactions it engages in with the host immune system remain inadequately characterized. This study adopts a multi-omics strategy to elucidate the immune and metabolic dynamics within the murine spleen during S. Typhi infection.

Objectives

To identify and analyze transcriptomic, proteomic, and metabolomic alterations in the spleens of mice infected with S. Typhi. By comparing these host responses with those elicited by Salmonella Typhimurium (S. Typhimurium), a closely related serovar possessing a broad host range, the study seeks to uncover the unique metabolic reprogramming and immune-modulatory mechanisms specific to S. Typhi infection.

Methods

A multi-omics strategy was adopted, integrating transcriptomic, proteomic, and metabolomic data obtained from the spleen tissues of S. Typhi-infected mice. S. Typhimurium was utilized as a comparative control to distinguish host-specific responses. Additionally, the dynamics of reactive oxygen species (ROS), which play pivotal roles in mediating immune responses during infection, were examined.

Results

Integration of multi-omics datasets demonstrated distinct metabolic and immunological responses orchestrated by S. Typhi infection. Host metabolism was reprogrammed by S. Typhi through the upregulation of glycolysis and the facilitation of glucose-to-pyruvate conversion, while concurrently suppressing the tricarboxylic acid cycle (TCA cycle). These changes culminated in increased lactate accumulation, and augmented ROS production, all of which were associated with intensified immune activation.

Conclusion

S. Typhi infection induces metabolic reprogramming in the host, characterized by a redirected glycolytic flux and altered pyruvate metabolism. This metabolic shift enhances ROS production and modulates the immune response. These findings yield novel insights into host-specific strategies employed by S. Typhi and highlight the significance of metabolic remodeling in immune defense, thereby presenting potential therapeutic targets for combating typhoid fever.