Cross-kingdom metabolic manipulation promotes Salmonella replication inside macrophages

Abstract

Replication inside macrophages is crucial for systemic dissemination of Salmonella in hosts. In a Nature Communications article, Jiang et al. show that Salmonella stimulates glycolysis and represses serine synthesis in macrophages, leading to accumulation of host glycolytic intermediates that the bacteria use as carbon source and as cues for its replication.

Fig. 1. Salmonella manipulates macrophage metabolism, thus obtaining a carbon source and cues for intracellular replication.

a Following infection with Salmonella, macrophages increase the conversion of glucose (Glc) to lactate (Lac) through aerobic glycolysis. Additionally, the SopE2 effector, which is injected by Salmonella into the cytoplasm of host cells by the SPI-1 T3SS (T3SS-1), represses serine synthesis by inhibiting expression of PHGDH via the host cell Rho GTPase Cdc42. Increased aerobic glycolytic flux and reduction of serine synthesis prompt the accumulation of host 3-phosphoglycerate (3PG), Lac, and pyruvate (Pyr). b Within the Salmonella containing vacuole (SCV), bacterial replication is supported by the use of host 3PG as a carbon source, while host Lac and Pyr stimulate expression of SPI-2 genes (including those encoding T3SS-2 and effector proteins). In bacteria, the cAMP–CRP complex senses low levels of host Glc and activates the expression of PgtP (3PG transporter) through the VrpA transcriptional regulator. Furthermore, the two-component system CreB/C senses host Lac and Pyr and activates the expression of the VrpB transcriptional regulator, which in turn induces expression of the SsrA/B two-component system, the central positive regulator for SPI-2.