A new look on invasive Salmonella strains
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.
