Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid in humans, shares very high homology with closely related serovar, S. Typhimurium. Yet, unlike S. Typhimurium, S. Typhi does not establish infection in mice. We show that intraperitoneal infection of mice with S. Typhi is associated with induction of antibacterial activities. Cell-free peritoneal fluids from S. Typhi but not S. Typhimurium-infected mice inhibited replication of Salmonella ex vivo. Administration of

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... ne protease inhibitor, phenylmethylsulfonly fluoride (PMSF), during S. Typhi infection reduced production of this activity. In vitro, generation of this antibacterial activity from peritoneal macrophages infected with S. Typhi was inhibited with PMSF, and its release was dependent on cell death. Peritoneal cells infected with S. Typhi in vivo or in vitro showed increased mRNA levels of ferroportin and lipocalin. Our findings implicate early induction of antibacterial molecules in the failure of S. Typhi to establish infection in mice.