"Salmonella enterica serovar Typhimurium infects a wide range of animal hosts and normally causes a self-limiting gastroenteritis in humans. However, new variants of this serovar known as ST313 have emerged as important pathogens in sub-Saharan Africa, causing an invasive disease in susceptible HIV+ or malarial individuals. Genome sequencing showed that the ST313 isolate D23580 is closely related to other nontyphoidal Salmonella. For example, D23580 shares 94% of coding genes with the well-characterised European SL1344 strain (ST19), and the two strains can be distinguished by 1000 single nucleotide polymorphisms, five D23580-specific phages, and a set of specific pseudogenes. Pseudogenes represent genome degradation, and 60% of the features present in D23580 are conserved in the host-restricted S. enterica serovars Typhi and Paratyphi A that cause enteric fever in humans. It has been suggested that ST313 represents a “human-adapted” version of S. Typhimurium which has developed the ability to transmit directly between humans.DISTINCT, which stands for “Determining how Invasive S. Typhimurium INfects human Cells by Transposon-insertion sequencing”, aims to investigate the ""human-specificity"" of S. Typhimurium D23580. I will use an improved global Transposon mutagenesis (TraDIS) approach to identify Salmonella genes required for survival in human monocyte-derived macrophages, but not in murine primary macrophages. This will be the first time that comprehensive genome-wide analysis is used to understand how bacteria distinguish between different mammalian host cells. Overall, DISTINCT will provide novel findings about the dangerous Salmonella pathogen and specifically about the invasive ST313 isolates that are causing a major public health problem in sub-Saharan Africa. The identification of pathogenic features in this strain will bring us closer to new therapeutic targets to treat Salmonella infections and to protect future generations from invasive ST313."