Genome-wide Fitness Analysis of Reveals Mutants Are Attenuated Due to Iron Restriction

is a globally disseminated pathogen that is the cause of over 100 million infections per year. The resulting diseases are dependent upon host susceptibility and the infecting serovar. As serovar Typhimurium induces a typhoid-like disease in mice, this model has been used extensively to illuminate various aspects of infection and host responses. Due to the severity of infection in this model, researchers often use strains of mice resistant to infection or attenuated . Despite decades of research, many aspects of infection and fundamental biology remain poorly understood. Here, we use a transposon insertion sequencing technique to interrogate the essential genomes of widely used isogenic wild-type and attenuated . Typhimurium strains. We reveal differential essential pathways between strains and provide a direct link between iron starvation, DNA synthesis, and bacterial membrane integrity.IMPORTANCE is an important clinical pathogen that causes a high number of deaths and is increasingly resistant to antibiotics. Importantly, is used widely as a model to understand host responses to infection. Understanding how Salmonella survives is important for the design of new vaccines to combat this pathogen. Live attenuated vaccines have been used clinically for decades. A widely used mutation, , is thought to attenuate by restricting the ability of the bacterium to access particular amino acids. Here we show that this mutation limits the ability of to acquire iron. These observations have implications for the interpretation of many previous studies and for the use of in vaccine development.