Abstract
The aquatic bacterium and human intestinal pathogen, Vibrio cholerae, senses and responds to a variety of environment-specific cues to regulate biofilm formation. Specifically, the polyamines norspermidine and spermidine enhance and repress V. cholerae biofilm formation, respectively. These effects are relevant for understanding V. cholerae pathogenicity and are mediated through the periplasmic binding protein NspS and the transmembrane bis-(3'-5') cyclic diguanosine monophosphate (c-di-GMP) phosphodiesterase MbaA. However, the levels of spermidine required to inhibit biofilm formation through this pathway are unlikely to be encountered by V. cholerae in aquatic reservoirs or within the human host during infection. We therefore hypothesized that other polyamines in the gastrointestinal tract may control V. cholerae biofilm formation at physiological levels. The tetramine spermine has been reported to be present at nearly 50 μm concentrations in the intestinal lumen. Here, we report that spermine acts as an exogenous cue that inhibits V. cholerae biofilm formation through the NspS-MbaA signaling system. We found that this effect probably occurs through a direct interaction of spermine with NspS, as purified NspS protein could bind spermine in vitro Spermine also inhibited biofilm formation by altering the transcription of the vps genes involved in biofilm matrix production. Global c-di-GMP levels were unaffected by spermine supplementation, suggesting that biofilm formation may be regulated by variations in local rather than global c-di-GMP pools. Finally, we propose a model illustrating how the NspS-MbaA signaling system may communicate exogenous polyamine content to the cell to control biofilm formation in the aquatic environment and within the human intestine.
Highlights
Vibrio cholerae is an aquatic organism that can be highly motile by use of a single polar flagellum in the planktonic state or sessile through production of biofilms, aggregates of bacteria often found attached to surfaces [1]
In V. cholerae, high levels of c-di-GMP result in increased biofilm formation, whereas low levels lead to enhanced motility and virulence factor production [2]. cdi-GMP primarily influences V. cholerae biofilm formation through activation of the transcriptional regulator VpsT, which enhances vps gene transcription in its c-di-GMP– bound form [16]
We have previously shown that norspermidine enhances V. cholerae biofilm formation through the NspS–MbaA signaling system, whereas spermidine reverses this process [20, 28]
Summary
The aquatic bacterium and human intestinal pathogen, Vibrio cholerae, senses and responds to a variety of environment-specific cues to regulate biofilm formation. We have previously identified a two-protein signaling system controlling V. cholerae biofilm formation, probably through modulation of c-di-GMP levels [20] This system is composed of the transmembrane PDE, MbaA, and the periplasmic solutebinding protein, NspS. Polyamines are short hydrocarbon chains with two or more amine groups that are positively charged at physiological pH These molecules are ubiquitous in living organisms and have been shown to control a variety of cellular functions, including biofilm formation, toxin activity, oxidative and acid stress tolerance, protein synthesis, and DNA replication in bacteria [22, 23]. Spermidine is produced by the human host and resident bacteria of the intestine, where V. cholerae is thought to favor the planktonic lifestyle; the concentration of spermidine required to inhibit biofilm formation through the NspS—MbaA pathway far exceeds reported levels of this polyamine in the intestines (24 –26). We use these findings to suggest potential roles of this pathway in the V. cholerae life cycle
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