The study by Miller, Kukral, and Mekalanos investigates the role of the phoP/phoQ two-component regulatory system in the virulence of *Salmonella typhimurium*. They found that mutations in the phoP locus significantly reduce the virulence of *S. typhimurium* in BALB/c mice and its survival in macrophages. The phoP locus contains two genes, phoP and phoQ, which are part of an operon. The gene products, PhoP and PhoQ, are similar to other bacterial two-component regulators that respond to environmental stimuli. Mutations in either phoP or phoQ result in a marked decrease in virulence, likely due to reduced expression of virulence factors or impaired survival in macrophages. The study also identified the pagC gene, which is regulated by PhoP and is involved in intracellular survival. Strains with phoP mutations showed partial protection when used as live vaccines against wild-type *S. typhimurium*. The authors propose a model where PhoQ functions as a membrane-associated protein kinase that phosphorylates PhoP, activating the expression of pag genes, including pagC, which encodes a protein that helps *S. typhimurium* resist toxic factors in the phagolysosome. This work provides insights into the molecular basis of *S. typhimurium* pathogenesis and suggests potential applications in vaccine development.The study by Miller, Kukral, and Mekalanos investigates the role of the phoP/phoQ two-component regulatory system in the virulence of *Salmonella typhimurium*. They found that mutations in the phoP locus significantly reduce the virulence of *S. typhimurium* in BALB/c mice and its survival in macrophages. The phoP locus contains two genes, phoP and phoQ, which are part of an operon. The gene products, PhoP and PhoQ, are similar to other bacterial two-component regulators that respond to environmental stimuli. Mutations in either phoP or phoQ result in a marked decrease in virulence, likely due to reduced expression of virulence factors or impaired survival in macrophages. The study also identified the pagC gene, which is regulated by PhoP and is involved in intracellular survival. Strains with phoP mutations showed partial protection when used as live vaccines against wild-type *S. typhimurium*. The authors propose a model where PhoQ functions as a membrane-associated protein kinase that phosphorylates PhoP, activating the expression of pag genes, including pagC, which encodes a protein that helps *S. typhimurium* resist toxic factors in the phagolysosome. This work provides insights into the molecular basis of *S. typhimurium* pathogenesis and suggests potential applications in vaccine development.