RelA alone appears essential for (p)ppGpp production when<i>Neisseria gonorrhoeae</i>encounters nutritional stress

Fisher, Scott D.; Reger, Andrew; Baum, Atalie; Hill, Stuart A.

doi:10.1016/j.femsle.2005.05.014

Cited by 13 publications

(13 citation statements)

References 22 publications

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“…In this study, we have identified a global regulatory system that plays a role in F. novicida virulence, where a relA mutant had reduced survival in macrophage-like cells, and was attenuated more than 100-fold in a BALB/c mouse model. We also confirmed that the reduced virulence observed was not a result of a growth defect, as has been described for other (p)ppGpp-deficient mutants (Fisher et al, 2005;Lemos et al, 2004;Okada et al, 2002). Uptake of F. novicida U112 DrelA : : cam into murine macrophages was similar to that of the wild-type and indicates that RelA is not involved in immune cell invasion.…”

Section: Discussionsupporting

confidence: 88%

“…The role of (p)ppGpp in Francisella appears to be complex, as disruption of the relA gene did not result in a reduced growth rate, a stationary phase defect or reduced biofilm formation, as reported in other bacteria (Fisher et al, 2005;Lemos et al, 2004;Okada et al, 2002). Many basic questions remain unanswered as to how (p)ppGpp exerts its effects, but it is thought that (p)ppGpp acts at the level of transcription, targeting RNA polymerase (Potrykus & Cashel, 2008).…”

Section: Discussionmentioning

confidence: 89%

“…The stringent response, induced by nutrient limitation, has been demonstrated in a range of bacteria, including Escherichia coli (Magnusson et al, 2005), N. gonorrhoeae (Fisher et al, 2005), Streptococcus suis (Li et al, 2009) and Borrelia burgdorferi (Bugrysheva et al, 2003b), and it appears that most bacteria require the stringent response for stationary phase survival (Mouery et al, 2006;Bugrysheva et al, 2003a). In addition, RelA has been shown to be involved in regulation of other diverse phenotypes, including biofilm formation by Streptococcus mutans (Lemos et al, 2004), osmotolerance of Listeria monocytogenes (Okada et al, 2002), stress response, vancomycin tolerance and virulence of Enterococcus faecalis (Abranches et al, 2009), and anaerobiosis in Mycobacterium tuberculosis (Sureka et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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RelA regulates virulence and intracellular survival of Francisella novicida

et al. 2009

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Analysis of the genome of Francisella tularensis has revealed few regulatory systems, and how the organism adapts to conditions in different niches is poorly understood. The stringent response is a global stress response mediated by (p)ppGpp. The enzyme RelA has been shown to be involved in generation of this signal molecule in a range of bacterial species. We investigated the effect of inactivation of the relA gene in Francisella by generating a mutant in Francisella novicida. Under amino acid starvation conditions, the relA mutant was defective for (p)ppGpp production. Characterization showed the mutant to grow similarly to the wild-type, except that it entered stationary phase later than wild-type cultures, resulting in higher cell yields. The relA mutant showed increased biofilm formation, which may be linked to the delay in entering stationary phase, which in turn would result in higher cell numbers present in the biofilm and reduced resistance to in vitro stress. The mutant was attenuated in the J774A macrophage cell line and was shown to be attenuated in the mouse model of tularaemia, but was able to induce a protective immune response. Therefore, (p)ppGpp appears to be an important intracellular signal, integral to the pathogenesis of F. novicida.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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RelA regulates virulence and intracellular survival of Francisella novicida

et al. 2009

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“…The relA-mediated SR to nutrient limitation has been shown to affect virulence and quorum-sensingrelated phenotypes in several gram-negative bacteria (14,16,17,23). PCR screening of the arrayed SCRI1043 mutant bank failed to identify any mutants carrying insertions in the relA gene.…”

Section: Resultsmentioning

confidence: 99%

RelA-Dependent (p)ppGpp Production Controls Exoenzyme Synthesis inErwinia carotovorasubsp.atroseptica

et al. 2007

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In this report, we investigate the link between nutrient limitation, RelA-mediated (p)ppGpp production, and virulence in the phytopathogen Erwinia carotovora subsp. atroseptica. A relA null mutant (JWC7) was constructed by allelic exchange, and we confirmed that, unlike the wild-type progenitor, this mutant did not produce elevated levels of (p)ppGpp upon nutrient downshift. However, (p)ppGpp production could be restored in strain JWC7 during nutrient limitation by supplying relA in trans. During growth on exoenzymeinducing minimal medium, the relA mutant showed a diminution in secreted pectate lyase and protease activities and a severe defect in motility. The relA mutant was also impaired in its ability to cause rot in potato tubers. In the presence of serine hydroxamate (a competitive inhibitor of seryl tRNA synthase and a potent inducer of the stringent response in wild-type E. carotovora subsp. atroseptica), exoenzyme production was essentially abolished in JWC7 but could be restored in the presence of plasmid-borne relA. The inhibition of exoenzyme production in JWC7 caused by serine hydroxamate could not be overcome by addition of the quorum-sensing signal molecule, N-3-oxohexanoyl-L-homoserine lactone. Quantitative reverse transcription-PCR analysis of selected RNA species confirmed that the effects of relA on secreted pectate lyase activity and motility could be attributed to a reduction in transcription of the corresponding genes. We conclude that nutrient limitation is a potent environmental cue that triggers (p)ppGpp-dependent exoenzyme production in E. carotovora subsp. atroseptica. Furthermore, our data suggest that nutrient limitation [or rather, (p)ppGpp accumulation] is a prerequisite for effective quorum-sensing-dependent activation of exoenzyme production.

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“…cluster next to the gammaproteobacterial branch (30). ppGpp production has been described for Neisseria gonorrhoeae (20). In contrast to E. coli, the gonococcal SpoT protein does not seem to contribute to ppGpp production, and a relA single mutant had a growth defect on rich solid medium.…”

Section: Discussionmentioning

confidence: 99%

Role of RelA and SpoT in Burkholderia pseudomallei Virulence and Immunity

et al. 2012

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bBurkholderia pseudomallei is a Gram-negative soil bacterium and the causative agent of melioidosis, a disease of humans and animals. It is also listed as a category B bioterrorism threat agent by the U.S. Centers for Disease Control and Prevention, and there is currently no melioidosis vaccine available. Small modified nucleotides such as the hyperphosphorylated guanosine molecules ppGpp and pppGpp play an important role as signaling molecules in prokaryotes. They mediate a global stress response under starvation conditions and have been implicated in the regulation of virulence and survival factors in many bacterial species. In this study, we created a relA spoT double mutant in B. pseudomallei strain K96243, which lacks (p)ppGpp-synthesizing enzymes, and investigated its phenotype in vitro and in vivo. The B. pseudomallei ⌬relA ⌬spoT mutant displayed a defect in stationary-phase survival and intracellular replication in murine macrophages. Moreover, the mutant was attenuated in the Galleria mellonella insect model and in both acute and chronic mouse models of melioidosis. Vaccination of mice with the ⌬relA ⌬spoT mutant resulted in partial protection against infection with wild-type B. pseudomallei. In summary, (p)ppGpp signaling appears to represent an essential component of the regulatory network governing virulence gene expression and stress adaptation in B. pseudomallei, and the ⌬relA ⌬spoT mutant may be a promising live-attenuated vaccine candidate.

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RelA alone appears essential for (p)ppGpp production whenNeisseria gonorrhoeaeencounters nutritional stress

Cited by 13 publications

References 22 publications

RelA regulates virulence and intracellular survival of Francisella novicida

RelA regulates virulence and intracellular survival of Francisella novicida

RelA-Dependent (p)ppGpp Production Controls Exoenzyme Synthesis inErwinia carotovorasubsp.atroseptica

Role of RelA and SpoT in Burkholderia pseudomallei Virulence and Immunity

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