Cross-kingdom metabolic manipulation promotes Salmonella replication inside macrophages

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.

cells, known as the Warburg effect, which transforms most of the incoming glucose to lactate, even under oxygen-rich conditions 9 . It has been proposed that the Warburg effect provides specific nutrients for the multiplication of intracellular bacteria and cancer cells 9 . Indeed, Jiang et al. report that genetic or biochemical inhibition of macrophage glycolysis reduces intracellular replication of Salmonella 8 .
Interestingly, the authors also reveal that Salmonella-infected macrophages exhibit reduced serine synthesis and diminished activity of downstream metabolic pathways (glycine and glutathione synthesis) 8 . They show that the GEF SopE2 effector and its host target, Rho GTPase Cdc42, inhibit macrophage serine synthesis via downregulation of the phgdh gene, encoding a key enzyme in the pathway. Consistently, Jiang et al. report that SopE2 is necessary for effective systemic infection of mice by Salmonella, and that both SopE2 and Cdc42 are important for intracellular replication of the bacteria 8 .
The precise mechanisms by which Salmonella induces metabolic reprogramming in macrophages, particularly the link between SopE2-Cdc42 and phgdh expression, remain yet to be determined. It will also be interesting to understand the potential effects of such metabolic reprogramming on macrophage antimicrobial responses.
Host metabolites act as nutrients and as signals for the pathogen Jiang et al. show that the Salmonella-induced effects on macrophage metabolism lead to accumulation of host glycolytic intermediates including 3-phosphoglycerate (3PG), a serine synthesis precursor, which Salmonella uses as carbon source for replication inside macrophages and during infection of mice 8 .
In addition, the low levels of glucose present in infected macrophages induce upregulation of the bacterial 3PG transporter PgtP, through a regulatory cascade involving the cAMP-CRP complex and a previously uncharacterized transcriptional regulator, VrpA 8 . Thus, the alterations in macrophage metabolism not only provide Salmonella with a carbon source (3PG) but also with a cue (low glucose) that triggers the uptake of 3PG for intracellular replication.
The authors show that increased glycolysis within macrophages leads to accumulation of pyruvate and lactate, which also promote intracellular replication of Salmonella by stimulating SPI-2 gene expression 8 . The mechanism for this upregulation of SPI-2 is mediated by the two-component system CreB/C (known to be activated by pyruvate, lactate, and other short-chain carbon sources 10 ), together with a previously uncharacterized regulator (VrpB) and the SsrA/B two-component system (a known positive regulator of SPI-2 1 ) 8 .
Jiang et al. also report succinate accumulation within infected macrophages 8 . Interestingly, a recent study has shown that increased succinate levels in Salmonella-infected macrophages induce expression of SPI-2 genes and of genes associated with antimicrobial resistance 11 . We wonder whether succinate might activate SPI-2 expression through the CreB/C-VrpB regulatory cascade described by Jiang et al 8 . Interestingly, it is known that Salmonella utilizes microbiota-derived succinate and host-derived lactate as carbon sources to efficiently colonize the gut 12,13 .
All these findings suggest that Salmonella, and probably other bacteria, reprogram their own metabolism and regulatory mechanisms to take the best advantage of metabolites present in different niches of their hosts, using them as nutrients and/ or cues.

Concluding remarks
The study by Jiang et al 8 . reveals novel mechanisms mediating Salmonella pathogenesis and illustrates some remarkable strategies developed by bacteria to adapt and survive in their hosts (Fig. 1). Other intracellular pathogenic bacteria such as Brucella abortus, Chlamydia pneumoniae, Chlamydia trachomatis, Legionella pneumophila, and Mycobacterium tuberculosis are also known to shift their host cells towards a Warburg-like metabolism (aerobic glycolysis) 9 . This metabolic reprogramming of host cells seems to be pathogen-specific 9 , but the mechanisms behind it are still poorly understood. We expect that future research in this area will provide new strategies to develop anti-infective therapies.