A two-component regulatory system (phoP/phoQ) controls Salmonella typhimurium virulence. The study shows that mutations in the phoP locus significantly reduce the virulence of S. typhimurium in BALB/c mice and its survival in macrophages. The phoP and phoQ genes are part of an operon and are highly similar to other bacterial two-component regulators. Mutations in phoP or phoQ lead to reduced virulence and decreased survival in macrophages. Strains with mutations in phoP or phoQ provide partial protection against subsequent challenge with wild-type S. typhimurium. The phoP locus is required for the expression of the phoN gene and at least three other loci, including pagC, which is likely involved in intracellular survival. The phoP and phoQ proteins are part of a two-component regulatory system, with PhoQ acting as a membrane-associated protein kinase that phosphorylates PhoP in response to environmental signals. Phosphorylated PhoP activates promoters for genes involved in virulence, including pagC, which encodes a protein involved in resistance to defensins and other host factors in the phagolysosome. The study also shows that phoP mutants can be used as live vaccines, providing partial protection against wild-type S. typhimurium. The findings suggest that the phoP regulon is essential for Salmonella pathogenesis and may lead to the development of safe, attenuated Salmonella strains for use as vaccines.A two-component regulatory system (phoP/phoQ) controls Salmonella typhimurium virulence. The study shows that mutations in the phoP locus significantly reduce the virulence of S. typhimurium in BALB/c mice and its survival in macrophages. The phoP and phoQ genes are part of an operon and are highly similar to other bacterial two-component regulators. Mutations in phoP or phoQ lead to reduced virulence and decreased survival in macrophages. Strains with mutations in phoP or phoQ provide partial protection against subsequent challenge with wild-type S. typhimurium. The phoP locus is required for the expression of the phoN gene and at least three other loci, including pagC, which is likely involved in intracellular survival. The phoP and phoQ proteins are part of a two-component regulatory system, with PhoQ acting as a membrane-associated protein kinase that phosphorylates PhoP in response to environmental signals. Phosphorylated PhoP activates promoters for genes involved in virulence, including pagC, which encodes a protein involved in resistance to defensins and other host factors in the phagolysosome. The study also shows that phoP mutants can be used as live vaccines, providing partial protection against wild-type S. typhimurium. The findings suggest that the phoP regulon is essential for Salmonella pathogenesis and may lead to the development of safe, attenuated Salmonella strains for use as vaccines.