A New Piece of the Shigella Pathogenicity Puzzle: Spermidine Accumulationby Silencing of the speG Gene

Abstract

The genome of Shigella, a gram negative bacterium which is the causative agent of bacillary dysentery, shares strong homologies with that of its commensal ancestor, Escherichia coli. The acquisition, by lateral gene transfer, of a large plasmid carrying virulence determinants has been a crucial event in the evolution towards the pathogenic lifestyle and has been paralleled by the occurrence of mutations affecting genes, which negatively interfere with the expression of virulence factors. In this context, we have analysed to what extent the presence of the plasmid-encoded virF gene, the major activator of the Shigella regulon for invasive phenotype, has modified the transcriptional profile of E. coli. Combining results from transcriptome assays and comparative genome analyses we show that in E. coli VirF, besides being able to up-regulate several chromosomal genes, which potentially influence bacterial fitness within the host, also activates genes which have been lost by Shigella. We have focused our attention on the speG gene, which encodes spermidine acetyltransferase, an enzyme catalysing the conversion of spermidine into the physiologically inert acetylspermidine, since recent evidence stresses the involvement of polyamines in microbial pathogenesis. Through identification of diverse mutations, which prevent expression of a functional SpeG protein, we show that the speG gene has been silenced by convergent evolution and that its inactivation causes the marked increase of intracellular spermidine in all Shigella spp. This enhances the survival of Shigella under oxidative stress and allows it to better face the adverse conditions it encounters inside macrophage. This is supported by the outcome of infection assays performed in mouse peritoneal macrophages and of a competitive-infection assay on J774 macrophage cell culture. Our observations fully support the pathoadaptive nature of speG inactivation in Shigella and reveal that the accumulation of spermidine is a key determinant in the pathogenicity strategy adopted by this microrganism.

Antivirulence Genes: Insights into Pathogen Evolution through Gene Loss

“…In a mouse macrophage model, wild-type Shigella is able to outcompete the same Shigella strain expressing the active speG gene from E. coli (4). Taken together, these data suggest that the accumulation of spermidine may be critical for Shigella intracellular survival in vivo, and loss of a functional speG gene was crucial for Shigella pathoadaptation to its new host niche.…”

“…No new publications have addressed ompT, so we will not discuss that particular AVG further. Since the last review, several additional AVGs have been identified in Shigella, including nadA/nadB and speG (4,42) (Fig. 1).…”

“…speG is inactivated in all Shigella lineages through a startling number of missense mutations, IS insertions, and complete deletions of speG (4). Unlike loss of the lysine decarboxylase system, loss of speG was not designed to prevent the synthesis of an inhibitory end product.…”

Effects of Norspermidine and Spermidine on Biofilm Formation by Potentially Pathogenic Escherichia coli and Salmonella enterica Wild-Type Strains

“…They are present in all living cells. In bacteria, polyamines are involved in a variety of functions, including intercellular signaling, stress resistance, and RNA and protein synthesis, as well as motility and virulence (5)(6)(7)(8)(9)(10)(11)(12)(13). Some polyamines have also been shown to play an essential role in biofilm formation, i.e., putrescine in Yersinia pestis (14) and Escherichia coli (15), spermidine in Bacillus subtilis (16), and norspermidine in Vibrio cholerae (17).…”

The Polyamine N -Acetyltransferase-Like Enzyme PmvE Plays a Role in the Virulence of Enterococcus faecalis

“…In addition, PmvE shows 26.3% identity and 50.4% similarity with SpeG (N 1 -spermidine/spermine acetyltransferase) from E. coli (Fig. 1B and C) (24). N-Acetyltransferases (NAT) are a large superfamily of enzymes that mostly catalyze the transfer of an acyl group to a substrate and are implicated in a variety of functions.…”