“Black holes” and bacterial pathogenicity: A large genomic deletion that enhances the virulence of Shigella spp. and enteroinvasive Escherichia coli

Abstract

Plasmids, bacteriophages, and pathogenicity islands are genomic additions that contribute to the evolution of bacterial pathogens. For example, Shigella spp., the causative agents of bacillary dysentery, differ from the closely related commensal Escherichia coli in the presence of a plasmid in Shigella that encodes virulence functions. However, pathogenic bacteria also may lack properties that are characteristic of nonpathogens. Lysine decarboxylase (LDC) activity is present in Ϸ90% of E. coli strains but is uniformly absent in Shigella strains. When the gene for LDC, cadA, was introduced into Shigella flexneri 2a, virulence became attenuated, and enterotoxin activity was inhibited greatly. The enterotoxin inhibitor was identified as cadaverine, a product of the reaction catalyzed by LDC. Comparison of the S. flexneri 2a and laboratory E. coli K-12 genomes in the region of cadA revealed a large deletion in Shigella. Representative strains of Shigella spp. and enteroinvasive E. coli displayed similar deletions of cadA. Our results suggest that, as Shigella spp. evolved from E. coli to become pathogens, they not only acquired virulence genes on a plasmid but also shed genes via deletions. The formation of these ''black holes,'' deletions of genes that are detrimental to a pathogenic lifestyle, provides an evolutionary pathway that enables a pathogen to enhance virulence. Furthermore, the demonstration that cadaverine can inhibit enterotoxin activity may lead to more general models about toxin activity or entry into cells and suggests an avenue for antitoxin therapy. Thus, understanding the role of black holes in pathogen evolution may yield clues to new treatments of infectious diseases.

Inhibition of Shigella flexneri-induced transepithelial migration of polymorphonuclear leucocytes by cadaverine

“…Infection with Shigella initially causes diarrhoea followed by dysentery, an intense in¯am-matory response characterized by mucosal ulcerations and abscess formation. Our current ®ndings, coupled with our earlier report on the inhibition of S.¯exneri enterotoxins by cadaverine (Maurelli et al, 1998), suggest a signi®cant therapeutic potential for the use of cadaverine in the treatment of shigellosis. Animal studies to address this possible use of cadaverine are being planned.…”

“…The introduction of the cadA gene into S.¯exneri and the expression of LDC results in a striking inhibition of enterotoxin activity. This inhibition is caused by the production of cadaverine from the decarboxylation of lysine (Maurelli et al, 1998). In this report, we demonstrate that cadaverine also acts directly on intestinal epithelial cells and completely abolishes the transepithelial signalling of PMNs induced by virulent S.¯exneri in a pathogen-speci®c fashion.…”

Metabolic control through ornithine and uracil of epithelial cell invasion by Shigella flexneri

“…In these pathways, the genes codA, speF and cadA are present in E. coli but absent in S. flexneri. As has been suggested for cadA, the absence of these genes, which are marked with *, could be related to the pathoadaptative evolution which led from commensal E. coli to modern Shigella (Casalino et al, 2003;Maurelli et al, 1998), supporting the critical role of uracil, putrescine and cadaverine in virulence gene expression identified in this study. In addition, argF, which encodes one of the isozymes for ornithine carbamoyltransferase, is absent in S. flexneri and a transposable element IS1 alters the promoter region of the gene speB, responsible for the conversion of agmatine to putrescine.…”

Diarrheagenic Escherichia coli in sub-Saharan Africa: Status, Uncertainties and Necessities

“…They typically lack many E. coli metabolic genes and the loss of some of these loci is pathoadaptive [127,128].…”