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Mechanism of gene regulation by a Staphylococcus aureus toxin

ABSTRACT: Virulence of many bacterial pathogens, including the important human pathogen Staphylococcus aureus, depends on the secretion of frequently high amounts of toxins. Toxin production involves the need for the bacteria to make physiological adjustments for energy conservation. While toxins are primarily known to be targets of gene regulation, such changes may be accomplished by regulatory functions of the toxins themselves. However, mechanisms by which toxins regulate gene expression have remained poorly understood. We show here that the phenol-soluble modulin toxins have gene regulatory functions, which in particular include regulation of their own export by direct interference with a GntR-type repressor protein. This capacity was most pronounced in PSMs with low cytolytic capacity, demonstrating functional specification among closely related members of that toxin family. Our study presents a paradigmatic example of how bacterial toxins may regulate gene expression to adapt to the physiological needs in situations of enhanced toxin production.

ORGANISM(S): Rickettsia rickettsii Staphylococcus epidermidis RP62A Staphylococcus epidermidis ATCC 12228 Coxiella burnetii RSA 493 Granulibacter bethesdensis Coxiella burnetii Chlamydia muridarum Chlamydia trachomatis D/UW-3/CX Staphylococcus haemolyticus JCSC1435 Borreliella burgdorferi B31 Staphylococcus aureus Chlamydia pneumoniae AR39 Staphylococcus aureus subsp. aureus MW2 Chlamydia caviae GPIC

PROVIDER: GSE72878 | GEO | 2016/12/19

SECONDARY ACCESSION(S): PRJNA295238

REPOSITORIES: GEO

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Project description:Shiga toxins (Stxs) are bacterial cytotoxins produced by the enteric pathogens Shigella dysenteriae serotype 1 and some serotypes of Escherichia coli that cause bacillary dysentery and hemorrhagic colitis, respectively. To date, approaches to studying the capacity of Stxs to alter gene expression in intoxicated cells have been limited to individual genes. However, it is known that many of the signaling pathways activated by Stxs regulate the expression of multiple genes in mammalian cells. To expand the scope of analysis of gene expression and to better understand the underlying mechanisms for the various effects of Stxs on cell functions, we carried out comparative microarray analyses to characterize the global transcriptional response of human macrophage-like THP-1 cells to Shiga toxin type 1 (Stx1) and LPS. Data were analyzed using a rigorous combinatorial approach with three separate statistical algorithms. Thirty-six genes met the criteria of up-regulated expression in response to Stx1 treatment with 14 genes uniquely up-regulated by Stx1. Microarray data were validated by real time RT-PCR for genes encoding Egr-1 (transcriptional regulator), COX-2 (inflammation), and DUSP1, 5 and 10 (regulation of MAPK signaling). Stx1-mediated signaling through ERK1/2 and Egr-1 appears to be involved in the increased expression of the proinflammatory mediator TNF-Î±. Activation of COX-2 expression is associated with the increased production of proinflammatory and vasoactive eicosanoids. However, the capacity of Stx1 to increase the expression of genes encoding phosphatases suggests that mechanisms to dampen the macrophage proinflammatory response may be built into host response to the toxins. Three separate experiments were performed for each of three treatment types: 3 untreated controls, 3 Stx-1 treated cell (400 ng/ml for 6h), 3 LPS-stimulated cells (200 ng/ml for 6h). Total RNA was isolated, processexc, and hybridized to a total of 9 Affymetrix human HG U133 arrays.

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Mechanism of gene regulation by a Staphylococcus aureus toxin

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