Abstract
ABSTRACTUnderstanding the environmental factors that affect the production of virulence factors has major implications in evolution and medicine. While spatial structure is important in virulence factor production, observations of this relationship have occurred in undisturbed or continuously disturbed environments. However, natural environments are subject to periodic fluctuations, including changes in physical forces, which could alter the spatial structure of bacterial populations and impact virulence factor production. Using Pseudomonas aeruginosa PA14, we periodically applied a physical force to biofilms and examined production of pyoverdine. Intermediate frequencies of disturbance reduced the amount of pyoverdine produced compared to undisturbed or frequently disturbed conditions. To explore the generality of this finding, we examined how an intermediate disturbance frequency affected pyoverdine production in 21 different strains of P. aeruginosa. Periodic disturbance increased, decreased, or did not change the amount of pyoverdine produced relative to undisturbed populations. Mathematical modeling predicts that interactions between pyoverdine synthesis rate and biofilm density determine the amount of pyoverdine synthesized. When the pyoverdine synthesis rates are high, depletion of the biofilm due to disturbance reduces the accumulation of pyoverdine. At intermediate synthesis rates, production of pyoverdine increases during disturbance as bacteria dispersed into the planktonic state enjoy increased growth and pyoverdine production rates. At low synthesis rates, disturbance does not alter the amount of pyoverdine produced since disturbance-driven access to nutrients does not augment pyoverdine synthesis. Our results suggest that environmental conditions shape robustness in the production of virulence factors and may lead to novel approaches to treat infections.IMPORTANCE Virulence factors are required to cause infections. Previous work has shown that the spatial organization of a population, such as a biofilm, can increase the production of some virulence factors, including pyoverdine, which is produced by Pseudomonas aeruginosa. Pyoverdine is essential for the infection process, and reducing its production can limit infections. We have discovered that periodically changing the spatial structure of a biofilm of P. aeruginosa strain PA14 using a physical force can reduce the production of pyoverdine. A mathematical model suggests that this is due to the disruption of spatial organization. Using additional strains of P. aeruginosa isolated from patients and the environment, we use experiments and modeling to show that this reduction in pyoverdine is due to interactions between biofilm density and the synthesis rate of pyoverdine. Our results identify conditions where pyoverdine production is reduced and may lead to novel ways to treat infections.
Highlights
Virulence factors enable bacteria to colonize hosts, cause disease, and interfere with immune systems [1]
We used experimentation and mathematical modeling to determine how disturbing the spatial structure of biofilms composed of Pseudomonas aeruginosa with periodically applied physical forces alters the production of pyoverdine
The density of bacteria in the biofilm and planktonic states can be measured using a crystal violet assay quantified at an optical density at 555 nm (OD555) [38] and OD600, respectively
Summary
Virulence factors enable bacteria to colonize hosts, cause disease, and interfere with immune systems [1]. Our understanding of how spatial structure influences virulence factor production is largely based upon studies that are performed in constantly disturbed (e.g., well-mixed tubes) or stationary conditions (e.g., agar plates) These conditions do not necessarily mimic natural environments where environmental conditions will fluctuate. If a periodic change in force is sufficiently strong, it can lead to change in the spatial structure of a bacterial population, which may impact virulence factor production. Discovering how periodic fluctuations in physical forces affect virulence factor production can help determine evolutionary constraints that shape virulence factor production and how the robustness of such systems change across growth environments. This may lead to strategies to attenuate virulence factor production. This augments growth, the production of pyoverdine, and the expression of additional virulence factors [31]
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