A new look on invasive Salmonella strains European researchers developed novel methodology to identify the pathogenic mechanism of an invasive Salmonella isolate. The deliverables of the study could be exploited to protect the population of Africa. Fundamental Research Health © CA-SSIS, Shutterstock Salmonella enterica serovar Typhimurium (S. Typhimurium) causes gastroenteritis in humans. However, the ST313 S. Typhimurium variants endemic in sub-Saharan Africa lead to invasive disease in susceptible HIV+, malarial and malnourished individuals. These isolates exhibit multiple-antibiotic resistance phenotype, necessitating the replacement of conventional therapies with alternative interventions. Recently, the genomic sequencing of a ST313 isolate (strain D23580) demonstrated a relatively high level of pseudogenes, many of which are found in the genomes of typhoidal Salmonellae. This finding suggests that the ST313 isolates have undergone adaptation to a unique niche in Africa. The primary objective of the EU-funded DISTINCT (Determining how invasive S. Typhimurium infects human cells by transposon-insertion sequencing) project was to identify the factors that have allowed S. Typhimurium ST313 isolates to cause invasive disease. Researchers employed transposon-insertion sequencing to identify bacterial genes responsible for survival inside monocyte-derived macrophages from human blood. They generated a series of transposon mutants in the S. Typhimurium ST313 strain D23580 and performed competitive fitness experiments under different infection-relevant conditions. The growth conditions reflected the intra-macrophage environment and conditions that supported S.Typhimurium pathogenicity. Scientists analysed transposon-insertion sequencing data by direct comparison with published Salmonella sequences and identified specific fitness features for D23580 in human cells. These ‘human-specific’ genes represent important targets for the development of novel therapeutics as well as for improved Salmonella vaccines. Given that antibiotic resistance has become a major public health threat worldwide, developing new targeted therapeutics requires an in-depth understanding of the mechanisms of pathogenesis. The DISTINCT mutagenesis approach has the potential to identify virulence-associated genes and pave the way towards novel antibacterial therapies. Keywords S. Typhimurium, ST313, DISTINCT, transposon-insertion sequencing, macrophage
