1887

Abstract

Intracellular pathogens such as serovar Typhimurium (. Typhimurium) manipulate their host cells through the interplay of various virulence factors. A multitude of such virulence factors are encoded on the genome of . Typhimurium and are usually organized in pathogenicity islands. The virulence-associated genomic stretch of has structural features of pathogenicity islands and is present exclusively in non-typhoidal serovars of . It encodes metabolic enzymes predicted to be involved in methylglyoxal metabolism. -encoded lactoylglutathione lyase significantly impacts the proliferation of intracellular . The deletion mutant of ) fails to grow in epithelial cells but hyper-replicates in macrophages. This difference in proliferation outcome was the consequence of failure to detoxify methylglyoxal by Δ, which was also reflected in the form of oxidative DNA damage and upregulation of in the mutant. Within macrophages, the toxicity of methylglyoxal adducts elicits the potassium efflux channel (KefB) in the mutant which subsequently modulates the acidification of mutant-containing vacuoles (MCVs). The perturbation in the pH of the MCV milieu and bacterial cytosol enhances the pathogenicity island 2 translocation in Δ, increasing its net growth within macrophages. In epithelial cells, however, the maturation of Δ-containing vacuoles were affected as these non-phagocytic cells maintain less acidic vacuoles compared to those in macrophages. Remarkably, ectopic expression of Toll-like receptors 2 and 4 on epithelial cells partially restored the survival of Δ. This study identified a novel metabolic enzyme in . Typhimurium whose activity during intracellular infection within a given host cell type differentially affected the virulence of the bacteria.

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2014-09-01
2019-11-17
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