show Abstracthide AbstractSalmonella enterica is one of the most important foodborne pathogens that infect a variety of animals and birds. In humans, S. Typhimurium causes gastroenteritis, leading to vomiting, diarrhea, fever, and abdominal cramps. We mainly get infected with Salmonella by ingesting comminated poultry products. Therefore, developing an oral live attenuated vaccine for the poultry industry is our best bet against Salmonella infection. In this article, we investigated the potential of the next generation of Salmonella vaccines. We generated a library of potentially attenuated S. Typhimurium mutants and compared fitness to that of a commercial vaccine. We also investigated the invasion and survival potential of these mutants in chicken macrophages. Our data indicate that although these mutants had no significant growth defects, they were much sensitive to macrophage attack. Analyzing the transcriptome data from infected primary chicken macrophages, we concluded that these mutants elicit a robust immune response by activating several immunoregulatory pathways. Our data also indicates that by combining phoPQ deletion with an already existing cya-crp deletion in MeganVac1, a much stronger immune response can be generated. Overall design: Transcriptome profile of attenuated Salmonella infected primary macrophages