A Single Genetic Code Change Makes African Salmonella More Deadly

A new study has identified a single genetic code change that allows Salmonella Typhimurium (ST313) to play a significant role in human bloodstream infections in sub-Saharan Africa.  The study was published in Proceedings of the National Academy of Sciences, 2018 (PNAS) [Role of a single noncoding nucleotide in the evolution of an epidemic African clade of Salmonella Disa L. Hammarlöf, Carsten Kröger, Siân V. Owen, Rocío Canals, Lizeth Lacharme-Lora, Nicolas Wenner, Anna E. Schager, Timothy J. Wells, Ian R. Henderson, Paul Wigley, Karsten Hokamp, Nicholas A. Feasey, Melita A. Gordon and Jay C. D. Hinton; PNAS 2018] 
Invasive non-typhoidal Salmonellosis (iNTS) is killing approximately 390,000 people annually in sub-Saharan Africa. iNTS is caused by Salmonella that enters the bloodstream and spreads through the body. The African iNST is caused by a variant of Salmonella Typhimurium (ST313) that is antibiotic resistant, and affect people with deficient immune system. This Salmonella strain seems to be very similar to the Salmonella Typhimurium that causes gastrointestinal illness.
The team of scientists, led by Professor Jay Hinton at the University of Liverpool, used advanced genetic techniques to switch various single-nucleotide polymorphism (SNPs) to find the one responsible for the difference in the Salmonella strain between the antibiotic-resistant strain that can enter the bloodstream, and the one causing gastroenteritis.
The team analyzed hundreds of Salmonella genomes and showed that the Salmonella Typhimurium ST313 is closely related to the ST19 strains that cause gastroenteritis. The core genome of the two strains share over 4,000 genes, varies by only ~1,000 SNPs. They hypothesized that one or more of these SNPs are accountable for the difference between the ST313 and ST19.  A single nucleotide difference that was unique to the African ST313, was identified as the cause of the virulence of the strain and its ability to grow in the bloodstream.
Using transcriptomics (a type of RNA analysis), the scientists identified SNPs that affected the level of expression of important Salmonella genes. After studying 1000 different SNPs, they found the single nucleotide difference that is unique to the African ST313 strain which causes high expression of a virulence factor called PgtE that prevents Salmonella being killed in the bloodstream.  The virulence factor PgtE is an outer membrane protease Salmonella that causes diseases ranging from gastroenteritis to severe enteric fever.
There are thousands of SNP differences between different types of Salmonella; therefore it is surprising that a change of just one letter in the DNA sequence will cause such a profound difference in the disease-causing ability of the organism. Until now it has been hard to connect an individual SNP to the bacterial ability to cause a disease.
The researchers used animal models (chicken) to infect with bacteria with altered SNP to show that by removing it the organism lost its ability to cause the disease.

Summary

The research team from the Universities of Birmingham and Liverpool has identified a single-nucleotide polymorphism (SNPs), which helps the African Salmonella to survive in the human bloodstream.  SNPs represent a change in a single DNA letter between the two Salmonella strains. It seems to be the first link between an individual SNP and a disease.
The single SNP responsible for high levels of expression of the PgtE in the outer membrane protease was linked to the virulence of African S. Typhimurium ST313. The study has implications for bacterial genome-wide association studies, which they claim should clearly include a focus on noncoding regions of the genome. The study findings also emphasize the value of identifying all gene promoters in bacterial pathogens, to allow nucleotide differences to be correlated with the process of transcriptional initiation.