Role of a single noncoding nucleotide in the evolution of an epidemic African clade of Salmonella

Abstract

SignificanceInvasive nontyphoidal Salmonella disease is a major and previously neglected tropical disease responsible for an estimated ∼390,000 deaths per year in Africa, largely caused by a variant of Salmonella Typhimurium called ST313. Despite the availability of >100,000 Salmonella genomes, it has proven challenging to associate individual SNPs with pathogenic traits of this dangerous bacterium. Here, we used a transcriptomic strategy to identify a single-nucleotide change in a promoter region responsible for crucial phenotypic differences of African S. Typhimurium. Our findings show that a noncoding nucleotide of the bacterial genome can have a profound effect upon the pathogenesis of infectious disease.

AfricanSalmonellaTyphimurium sequence type 313 lineage 2 evades MAIT cell recognition by overexpressing RibB

“…In STM-D23580, ribB and its 5’ untranslated region (5’UTR) are transcribed as a single transcript that is initiated from a single gene promoter which we identified previously [43]. By analogy with the genetic mechanism identified for over-expression of the PgtE virulence factor in STM-D23580 [44] we searched for nucleotide polymorphisms that distinguished the ribB regions of the two strains. There were no differences between the promoter sequences of the ribB genes or the 5’ UTR of the strains STM-D23580 and STM-4/74.…”

“…Typhimurium sequence type 313, suggesting a multifactorial adaptation of this African lineage to a systemic lifestyle. These include interference with the complement cascade [44], interference with DC function [42], reduced inflammasome activation [54], dissemination through CD11b + migratory DC [55] among others.…”

“…While the precise molecular mechanism responsible for ribB overexpression remains to be established, a single noncoding nucleotide polymorphism in the promoter of the pgtE gene of the sequence type 313 lineage 2 strain STM-D23580 is known to be responsible for high expression of the outer membrane PgtE virulence factor, which promotes bacterial survival and dissemination during mammalian infection [44]. The lack of nucleotide differences between the promoter sequences of the ribB genes or the riboswitch of the two strains suggests that the high level of expression of ribB in STM-D23580 is caused by a novel and uncharacterised regulatory mechanism.…”

Conserved regulation of omptin proteases by the PhoPQ two-component regulatory system in Enterobacteriaceae

“…Omptin proteases have a wide variety of substrates that may contribute to in vivo fitness of the bacterium containing them, including HDPs like LL-37 or CRAMP (McPhee et al, 2014;Brannon et al, 2015), components of the complement cascade or the clotting cascade (Lathem et al, 2007;Riva et al, 2015), and non-physiological but cationic substrates like protamine (Johanna Haiko et al, 2009). Alterations in either the activity of omptins or in their transcriptional activity have been associated with changes in virulence, including in pandemic Y. pestis or in invasive Salmonella enterica (Hammarlöf et al, 2018) suggesting that omptin proteases are critical factors for interaction with and resistance to components of the host innate immune system and that understanding both the mechanism(s) by which they are regulated and the substrates with which each omptin interacts may shed light on their role in pathogenesis.…”

A window into lysogeny: Revealing temperate phage biology with transcriptomics

“…Prophage gene expression during lysogeny was investigated using data from three previous studies (Canals et al, 2019; Hammarlöf et al, 2018; Kröger et al, 2013). A description of the experimental conditions associated with the RNA-seq data used in this analysis is given in Supplementary Table 1.…”