Hyperglycemia potentiates increased Staphylococcus aureus virulence and resistance to growth inhibition by Pseudomonas aeruginosa

Abstract

ABSTRACT Diabetes is associated with several health consequences, including increased susceptibility to more frequent and severe infections. Bacterial infections associated with diabetes are typically polymicrobial, with Staphylococcus aureus and Pseudomonas aeruginosa frequently isolated from the same infection site. S. aureus and P. aeruginosa are frequently found in diabetic skin and soft tissue infections, in the lungs of people with cystic fibrosis, and in indwelling device infections. Numerous studies have investigated interactions between these two pathogens primarily using in vitro systems. These models have several limitations as they do not accurately reflect the complexities of an immune response nor the nutrient dynamics in a diabetic infection microenvironment. Here, we describe a novel murine indwelling device co-infection model that allows us to study the interactions between S. aureus and P. aeruginosa within the context of an immune response during both normal and diabetic infections. Our data shows that P. aeruginosa significantly inhibits S. aureus growth during co-infection in a normal mouse and that inhibition is not dependent on the P. aeruginosa PQS quorum sensing system. Conversely, in a diabetic co-infection, S. aureus overcomes inhibition by P. aeruginosa and this phenotype is reliant on S. aureus glycolysis. We also demonstrate that both organisms display increased virulence potential in a diabetic co-infection as we observe increased dissemination to peripheral tissues. This study revealed novel in vivo interactions between S. aureus and P. aeruginosa and advances our understanding of the complex interactions between microorganisms in polymicrobial infections in clinically relevant infection microenvironments. IMPORTANCE Individuals with diabetes are prone to more frequent and severe infections, with many of these infections being polymicrobial. Polymicrobial infections are frequently observed in skin infections and in individuals with cystic fibrosis, as well as in indwelling device infections. Two bacteria frequently co-isolated from infections are Staphylococcus aureus and Pseudomonas aeruginosa. Several studies have examined the interactions between these microorganisms. The majority of these studies use in vitro model systems that cannot accurately replicate the microenvironment of diabetic infections. We employed a novel murine indwelling device model to examine interactions between S. aureus and P. aeruginosa. Our data show that competition between these bacteria results in reduced growth in a normal infection. In a diabetic infection, we observe increased growth of both microbes and more severe infection as both bacteria invade surrounding tissues. Our results demonstrate that diabetes changes the interaction between bacteria resulting in poor infection outcomes.

Keywords

• diabetes
• indwelling medical devices
• glycolysis
• USA300
• dissemination