1887

Abstract

The evolution of bacterial pathogens from commensal organisms involves virulence gene acquisition followed by pathoadaptation to the new host, including inactivation of antivirulence loci (AVL). AVL are core ancestral genes whose expression is incompatible with the pathogenic lifestyle. Previous studies identified (encoding lysine decarboxylase) as an AVL of spp. In this study, AVL of were identified by examining a phenotypic difference from its non-pathogenic ancestor, . Unlike most strains, spp. are nicotinic acid auxotrophs, the pathway for the synthesis of NAD being uniformly defective. In , this defect is due to alterations in the and/or genes encoding the enzyme complex that converts -aspartate to quinolinate, a precursor to NAD synthesis. Quinolinate was found to inhibit invasion and cell-to-cell spread of 5a and its ability to induce polymorphonuclear neutrophil transepithelial migration. Virulence of other species was also inhibited by quinolinate. Introduction of functional and genes from K-12 into 5a restored its ability to synthesize quinolinate but also resulted in strong attenuation of virulence in this strain. The results define and as AVL in and validate the concept of pathoadaptive evolution of bacteria from commensal ancestors by inactivation of AVL. They also suggest that studies focusing on this form of bacterial evolution can identify novel inhibitors of virulence in other bacterial pathogens.

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2007-07-01
2024-03-28
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