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Researchers Tackle Transcriptional Networks in Salmonella Strain

NEW YORK (GenomeWeb News) – A transcriptional study of a Salmonella enterica serovar implicated in a range of acute and chronic human infections is providing clues about how the bug sets up shop in its human host.

In a study set to appear online this week in the Proceedings of the National Academy of Sciences, an international team led by investigators at Trinity College Dublin's Smurfit Institute of Genetics describes how it brought together several sources of genomic data — including genome sequence data and information generated by standard RNA sequencing and a method called differential RNA-seq — to map transcriptional networks for a strain from the S. enterica serovar Typhimurium during the early stages of infection.

"It's [been] a decade since we discovered the Salmonella genes active during infection of mammalian cells," Trinity College Dublin microbial pathogenesis researcher Jay Hinton, the study's senior author, said in a statement. "Now we have found the switches that control these critical genes."

Though more than 2,300 S. enterica serovars found so far, S. Typhimurium has attracted particular attention, Hinton and his co-authors explained, not only because of its role in human infections — including an invasive form of Salmonella disease detected in parts of Africa — but also as a model for understanding the interplay between pathogens and their hosts.

Even so, they added, while previous studies have helped to identify some of the virulence factors and transcriptional shifts that occur in S. Typhimurium during infection, a complete picture of the networks governing such processes remains murky.

"It is clear that a precise choreography of gene expression is required for Salmonella infection, but basic genetic information such as the global locations of transcription start sites has been lacking," they wrote.

For their new analysis, the researchers started by sequencing the genome of the S. Typhimurium strain SL1344, identifying 4,742 predicted protein-coding genes. Of these, 4,530 were housed in the S. Typhimurium chromosome, while another 212 turned up on one of three plasmids.

A comparison between SL1344 gene sequences and those found in dozens of other enterobacteria, including additional S. Typhimurium strains, indicated that the newly sequenced strain contains 13 so-called Salmonella pathogenicity islands, as well as several prophages.

As part of its transcriptional analyses of S. Typhimurium's early stationary infection stage, meanwhile, the team did RNA-seq, differential RNA-seq, and flow cell reverse transcription sequencing experiments with Illumina and Roche 454 sequencing platforms.

Through these and other experiments, the researchers were able to define nearly 1,900 transcription start sites in the SL1344 genome. They also identified sense and antisense transcripts stemming from these sites and explored the interactions between Salmonella promoters, transcription factors, and RNA polymerase enzymes.

In addition, the investigators described a set of 140 small RNAs found in S. Typhimurium, including 60 sRNA not found previously. Using new and existing data, they showed that four-dozen of S. Typhimurium's sRNAs are Salmonella-specific, while six appear to be exclusive to that S. enterica serovar.

"The discovery of sRNAs that are expressed at early stationary phase will permit the characterization of the transcriptional network controlled by sRNAs in S. Typhimurium," the study's authors wrote, noting that the sRNA conservation patterns may also help in understanding how some transcription regulating features arose during evolution.

Moreover, they argued that similar studies exploring interactions between promoters, transcription factors, and other regulatory features under a range of infection-related circumstances could "herald a new era for research on the regulation of gene expression during infection by S. Tymphimurium."

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