The Stringent Response Is Required for Helicobacter pylori Survival of Stationary Phase, Exposure to Acid, and Aerobic Shock

Abstract

The gastric pathogen Helicobacter pylori must adapt to fluctuating conditions in the harsh environment of the human stomach with the use of a minimal number of transcriptional regulators. We investigated whether H. pylori utilizes the stringent response, involving signaling through the alarmone (p)ppGpp, as a survival strategy during environmental stresses. We show that the H. pylori homologue of the bifunctional (p)ppGpp synthetase and hydrolase SpoT is responsible for all cellular (p)ppGpp production in response to starvation conditions. Furthermore, the H. pylori spoT gene complements the growth defect of Escherichia coli mutants lacking (p)ppGpp. An H. pylori spoT deletion mutant is impaired for stationary-phase survival and undergoes a premature transformation to a coccoid morphology. In addition, the spoT deletion mutant is unable to survive specific environmental stresses, including aerobic shock and acid exposure, which are likely to be encountered by this bacterium during infection and transmission.

ppGpp Conjures Bacterial Virulence

“…The activation and function of SpoT in H. pylori more closely resemble those of E. coli SpoT rather than those of RelA, as H. pylori spoT readily complements an E. coli relA spoT double mutant, more so than a single relA mutant (138). This attribute may explain the lack of stringent control in response to amino acid starvation previously reported; it also provides insight into the role of ppGpp in the response and adaptation to specific nutrient conditions.…”

“…To date, ppGpp accumulation by H. pylori has been observed directly only in response to nutrient starvation and stress conditions (212). Nevertheless, the stationary-phase survival and morphology defects exhibited by ⌬spoT (ppGpp 0 ) mutants (138) point to the importance of maintaining ppGpp levels during entry into stationary phase. At this transition, H. pylori also induces the expression of virulence factors such as flagellin and napA, encoding a homologue of Dps (DNA protection during starvation) that is thought to protect against oxidative stress damage (48).…”

“…An accumulation of ppGpp is induced during acid shock (212), and genetic studies indicated that SpoT function is required for the survival of acid exposure, stationary phase, and increased levels of oxygen (138). In addition to tolerance to low nutrient availability and high pH, the persistence of H. pylori during chronic infection of the gastric mucosa also depends on the avoidance of host innate immune components.…”

RelA regulates virulence and intracellular survival of Francisella novicida

“…In Legionella pneumophila, (p)ppGpp has been shown to trigger a cascade that leads to differentiation of replicating bacteria to a transmissible, non-replicating form, with the induction of virulence traits such as motility (Swanson & Hammer, 2000). Stress-induced (p)ppGpp production in Helicobacter pylori is required for survival during acid exposure and aerobic shock (Mouery et al, 2006;Wells & Gaynor, 2006), conditions typically encountered during the course of infection. In Francisella, intracellular replication and virulence are dependent on MglA and SspA, which regulates the FPI (Guina et al, 2007;Nano & Schmerk, 2007;Charity et al, 2007).…”

“…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).…”