Abstract
The bacterial stringent response is triggered by deficiencies of available nutrients and other environmental stresses. It is mediated by 5'-triphosphate-guanosine-3'-diphosphate and 5'-diphosphate-guanosine-3'-diphosphate (collectively (p)ppGpp) and generates global changes in gene expression and metabolism that enable bacteria to adapt to and survive these challenges. Borrelia burgdorferi encounters multiple stressors in its cycling between ticks and mammals that could trigger the stringent response. We have previously shown that the B. burgdorferi stringent response is mediated by a single enzyme, RelBbu, with both (p)ppGpp synthase and hydrolase activities, and that a B. burgdorferi 297 relBbu null deletion mutant was defective in adapting to stationary phase, incapable of down-regulating synthesis of rRNA and could not infect mice. We have now used this deletion mutant and microarray analysis to identify genes comprising the rel regulon in B. burgdorferi cultured at 34°C, and found that transcription of genes involved in glycerol metabolism is induced by rel Bbu. Culture of the wild type parental strain, the rel Bbu deletion mutant and its complemented derivative at 34°C and 25°C in media containing glucose or glycerol as principal carbon sources revealed a growth defect in the mutant, most evident at the lower temperature. Transcriptional analysis of the glp operon for glycerol uptake and metabolism in these three strains confirmed that rel Bbu was necessary and sufficient to increase transcription of this operon in the presence of glycerol at both temperatures. These results confirm and extend previous findings regarding the stringent response in B. burgdorferi. They also demonstrate that the stringent response regulates glycerol metabolism in this organism and is likely crucial for its optimal growth in ticks.
Highlights
Nutritional exigencies and other environmental challenges are met by bacteria through the use of global regulatory pathways [1,2,3,4]
The (p)ppGpp-mediated stringent response is a broadly conserved global regulatory response in bacteria that acts to preserve critical amounts of intracellular molecules in response to nutritional scarcity and/or other environmental stressors [1,2,3,5,48,50,55] such as those faced by B. burgdorferi in the distinctive vector and mammalian host environments it encounters in the course of its life cycle
We previously demonstrated that the B. burgdorferi stringent response could control growth, rRNA accumulation and virulence [38,47]
Summary
Nutritional exigencies and other environmental challenges are met by bacteria through the use of global regulatory pathways [1,2,3,4]. The comprehensive shifts in gene expression induced by these regulatory pathways at the transcriptional and post-transcriptional level permit the rapid and dramatic modulation of bacterial growth and metabolism needed to adapt to these challenges. One of these global regulatory responses, the stringent response, is conserved in virtually all bacteria. It was originally described in Escherichia coli in association with amino acid scarcity, but has subsequently been shown to be triggered by many other environmental stressors including insufficiencies of iron, glucose and fatty acids [1,2,3,4]. In E. coli, relA expression is regulated by the carbon storage regulator CsrA [19]
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