Abstract
Salmonella Typhimurium sequence type (ST) 313 causes invasive nontyphoidal Salmonella (iNTS) disease in sub-Saharan Africa, targeting susceptible HIV+, malarial, or malnourished individuals. An in-depth genomic comparison between the ST313 isolate D23580 and the well-characterized ST19 isolate 4/74 that causes gastroenteritis across the globe revealed extensive synteny. To understand how the 856 nucleotide variations generated phenotypic differences, we devised a large-scale experimental approach that involved the global gene expression analysis of strains D23580 and 4/74 grown in 16 infection-relevant growth conditions. Comparison of transcriptional patterns identified virulence and metabolic genes that were differentially expressed between D23580 versus 4/74, many of which were validated by proteomics. We also uncovered the S. Typhimurium D23580 and 4/74 genes that showed expression differences during infection of murine macrophages. Our comparative transcriptomic data are presented in a new enhanced version of the Salmonella expression compendium, SalComD23580: http://bioinf.gen.tcd.ie/cgi-bin/salcom_v2.pl. We discovered that the ablation of melibiose utilization was caused by three independent SNP mutations in D23580 that are shared across ST313 lineage 2, suggesting that the ability to catabolize this carbon source has been negatively selected during ST313 evolution. The data revealed a novel, to our knowledge, plasmid maintenance system involving a plasmid-encoded CysS cysteinyl-tRNA synthetase, highlighting the power of large-scale comparative multicondition analyses to pinpoint key phenotypic differences between bacterial pathovariants.
Highlights
Invasive nontyphoidal Salmonella is associated with a major and largely unreported tropical disease that is responsible for hundreds of thousands of deaths per year in Africa
The main causative agent is a pathovariant of Salmonella Typhimurium called ST313, which is closely related to the well-characterized ST19 sequence type of Salmonella that causes gastroenteritis globally
ST313 and ST19 vary by just 856 core genome singlenucleotide polymorphisms (SNPs)
Summary
Typhimurium) infects a wide range of animal hosts and generally causes self-limiting gastroenteritis in humans. Variants of this serovar, belonging to sequence type (ST) 313, are associated with invasive nontyphoidal Salmonella (iNTS) disease in susceptible HIV+, malaria-infected, or malnourished individuals in sub-Saharan Africa [1]. The multidrug resistance of ST313 isolates complicates patient treatment and accounts for the high case fatality rate (20.6%) of iNTS disease [3]. Two ST313 lineages have been associated with iNTS, and the clonal replacement of lineage 1 by lineage 2 is hypothesized to have been driven by the gain of chloramphenicol (Cm) resistance by lineage 2 [4]. Distinct ST313 isolates that do not belong to lineages 1 and 2 have been described in the United Kingdom [5] and in Brazil [6]
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