Abstract
BackgroundIn the intracellular pathogen Brucella spp., the activation of the stringent response, a global regulatory network providing rapid adaptation to growth-affecting stress conditions such as nutrient deficiency, is essential for replication in the host. A single, bi-functional enzyme Rsh catalyzes synthesis and hydrolysis of the alarmone (p)ppGpp, responsible for differential gene expression under stringent conditions.ResultscDNA microarray analysis allowed characterization of the transcriptional profiles of the B. suis 1330 wild-type and Δrsh mutant in a minimal medium, partially mimicking the nutrient-poor intramacrophagic environment. A total of 379 genes (11.6% of the genome) were differentially expressed in a rsh-dependent manner, of which 198 were up-, and 181 were down-regulated. The pleiotropic character of the response was confirmed, as the genes encoded an important number of transcriptional regulators, cell envelope proteins, stress factors, transport systems, and energy metabolism proteins. Virulence genes such as narG and sodC, respectively encoding respiratory nitrate reductase and superoxide dismutase, were under the positive control of (p)ppGpp, as well as expression of the cbb3-type cytochrome c oxidase, essential for chronic murine infection. Methionine was the only amino acid whose biosynthesis was absolutely dependent on stringent response in B. suis.ConclusionsThe study illustrated the complexity of the processes involved in adaptation to nutrient starvation, and contributed to a better understanding of the correlation between stringent response and Brucella virulence. Most interestingly, it clearly indicated (p)ppGpp-dependent cross-talk between at least three stress responses playing a central role in Brucella adaptation to the host: nutrient, oxidative, and low-oxygen stress.
Highlights
In the intracellular pathogen Brucella spp., the activation of the stringent response, a global regulatory network providing rapid adaptation to growth-affecting stress conditions such as nutrient deficiency, is essential for replication in the host
Expression of virB, the secretion system which plays a central role in Brucella virulence, is controlled by two transcriptional regulators which have been shown to be Rsh-dependent
Our novel data from the first stringent response transcriptome analysis of an α-proteobacterial pathogen confirm that expression of additional virulence genes is controlled by Rsh, as 14 other genes previously identified as essential for Brucella virulence are up-regulated by Rsh under nutrient starvation
Summary
In the intracellular pathogen Brucella spp., the activation of the stringent response, a global regulatory network providing rapid adaptation to growth-affecting stress conditions such as nutrient deficiency, is essential for replication in the host. The Gram negative bacterial pathogen Brucella is the causative agent of brucellosis, a major zoonotic disease causing abortion and sterility in animals and “Malta fever” in humans. The latter is characterized by an undulant adaptation to a variety of growth-affecting stress conditions [4]. RelA-SpoT homologues share both conserved (p)ppGpp synthase and hydrolase domains and were demonstrated to be bifunctional in Gram-positive bacteria and in α-Proteobacteria at the examples of Sinorhizobium meliloti and Rhizobium etli [10,13,14,15]
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