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Sequencing Study IDs Salmonella Strain Causing Serious Infections in Africa

NEW YORK (GenomeWeb News) – Using multi-locus and whole genome sequencing, an international research team has identified — and started characterizing — a new form of Salmonella enterica serotype Typhimurium associated with invasive infections in parts of sub-Saharan Africa.

In a paper appearing in the December issue of Genome Research, a Wellcome Trust Sanger Institute-led team used genomic analyses to identify a S. Typhimurium strain called ST313 from clinical samples in Malawi and Kenya. They found that the antibiotic-resistant strain, which appears to preferentially strike individuals with compromised immunity, malnutrition, or other underlying health conditions, is distinct from previously characterized S. Typhimurium.

"[ST313] seems to have evolved to acquire a unique armory that allows it to efficiently infect vulnerable children and adults in some African regions," co-lead author Robert Kingsley, an infectious disease researcher at the Sanger Institute, said in a statement. "The results highlight the power of in-depth genome sequence analysis to challenge basic medical assumptions and distinguish closely related pathogens."

In general, forms of non-typhoid-causing Salmonella mainly cause gastrointestinal problems such as food poisoning. But in the past decade or so, the researchers noted, non-typhoidal Salmonella — including S. Typhimurium — has been increasingly linked to invasive bacterial infections in parts of sub-Saharan Africa. Such infections often occur in conjunction with HIV in adults or with other health problems such as malaria, anemia, or malnutrition in children and can be life-threatening.

Using multi-locus sequence typing, the researchers compared S. Typhimurium isolated from 51 individuals with invasive S. Typhimurium infection in Malawi and Kenya, showing that all of the individuals tested in Malawi and 13 of the 20 individuals tested in Kenya were infected with an S. Typhimurium type dubbed STS313.

Based on comparisons with some 400 S. Typhimurium isolates in the global MLST database, the team found that STS313 is very rare in other parts of the world, with only two isolates turning up in the database from outside of sub-Saharan Africa: one in India and another in Scotland. Both the Indian and Scottish isolates came from cases involving invasive infections.

Next, the team used Sanger sequencing from shotgun libraries to get the whole genome sequence of a multi-drug resistant STS313 isolate called D23580.

When they compared the STS313 genome sequence with that of other sequenced S. Typhimurium isolates, the team detected a host of differences, including SNPs, insertions, deletions, and differences in the prophage-like regions and psuedogenes.

Overall, the researchers noted, the D23580 genome appears to have undergone genome reductions making it similar to another human pathogen, the typhoid fever-causing S. Typhi. For instance, they reported, the D23580 genome is roughly 15,000 bases smaller than the S. Typhimurium strain SL1344 and contains deletions affecting at least 20 genes.

"[T]his deadly strain has lost around one in 50 of the genes found in the 'typical' S. Typhimurium — a classic sign that it may be becoming more closely adapted to one host, in this case, humans," Kingsley said in a statement. "We also found similar patterns of genome degradation in ST313 compared [to] S. Typhi — a bacterium which is known to be well adapted to its human host."

The team also found four plasmids in D23580, including one containing a mobile element that they believe is contributing to the bug's antibiotic resistance.

"Our findings show that ST313 has acquired a block of genes that make it resistant to the common antibiotics," co-lead author Chisomo Msefula, a researcher with the Malawi-Liverpool-Wellcome Trust Clinical Research Programme, said in a statement. "The genes jumped into ST313 on a mobile genetic element called a transposon, bringing with it additional genes that make the strain more deadly."

The team also did additional experiments aimed at gaining a better understanding of how the pathogen emerged and became so prevalent in sub-Saharan Africa, including PCR analyses comparing 31 STS313 isolates collected in Malawi over a decade and re-sequencing studies of two STS313 isolates — a chloramphenicol sensitive isolate collected in Malawi in 1997 and a resistant strain collected in Kenya in 2003 — which were done using the Roche 454 GS-FLX platform.

Down the road, the team plans to do additional genomic studies to continue unraveling the pathogenesis and epidemiology of STS313.

"If we can understand what's special about the types of Typhimurium that emerge and susceptible populations, we might be able to predict in future where new pathogens will emerge," senior author Gordon Dougan, head of the Sanger Institute's microbial pathogenesis group, said in a statement. "We may also be able to design vaccines against those pathogens."