Salmonellaexploits host- and bacterial-derived β-alanine for replication inside host macrophages

Salmonellais a major foodborne pathogen that can effectively replicate inside host macrophages to establish life-threatening systemic infections.Salmonellamust utilize diverse nutrients for growth in nutrient-poor macrophages, but which nutrients are required for intracellularSalmonellagrowth is largely unknown. Here, we found that either acquisition from the host or de novo synthesis of a nonprotein amino acid, β-alanine, is critical forSalmonellareplication inside macrophages. The concentration of β-alanine is decreased inSalmonella-infected macrophages, while the addition of exogenous β-alanine enhancesSalmonellareplication in macrophages, suggesting thatSalmonellacan uptake host-derived β-alanine for intracellular growth. Moreover, the expression ofpanD,the rate-limiting gene required for β-alanine synthesis inSalmonella,is upregulated whenSalmonellaenters macrophages. Mutation ofpanDimpairedSalmonellareplication in macrophages and colonization in the mouse liver and spleen, indicating that de novo synthesis of β-alanine is essential for intracellularSalmonellagrowth and systemic infection. Additionally, we revealed that β-alanine influencesSalmonellaintracellular replication andin vivovirulence by increasing expression of the zinc transporter genesznuABC,which in turn facilitates the uptake of the essential micronutrient zinc bySalmonella. Taken together, these findings highlight the important role of β-alanine in the intracellular replication and virulence ofSalmonella, andpanDis a promising target for controlling systemicSalmonellainfection.