Abstract
The ability of Staphylococcus aureus and other pathogens to consume glucose is critical during infection. However, glucose consumption increases the cellular demand for manganese sensitizing S. aureus to host-imposed manganese starvation. The current investigations were undertaken to elucidate how S. aureus copes with the need to consume glucose when metal-limited by the host. A critical component of host defense is production of the manganese binding protein calprotectin. S. aureus has two variants of phosphoglycerate mutase, one of which is manganese-dependent, GpmI, and another that is manganese-independent, GpmA. Leveraging the ability to impose metal starvation in culture utilizing calprotectin revealed that the loss of GpmA, but not GpmI, sensitized S. aureus to manganese starvation. Metabolite feeding experiments revealed that the growth defect of GpmA when manganese-starved was due to a defect in glycolysis and not gluconeogenesis. Loss of GpmA reduces the ability of S. aureus to cause invasive disease in wild type mice. However, GpmA was dispensable in calprotectin-deficient mice, which have defects in manganese sequestration, indicating that this isozyme contributes to the ability of S. aureus to overcome manganese limitation during infection. Cumulatively, these observations suggest that expressing a metal-independent variant enables S. aureus to consume glucose while mitigating the negative impact that glycolysis has on the cellular demand for manganese. S. aureus is not the only bacterium that expresses manganese-dependent and -independent variants of phosphoglycerate mutase. Similar results were also observed in culture with Salmonella enterica serovar Typhimurium mutants lacking the metal-independent isozyme. These similar observations in both Gram-positive and Gram-negative pathogens suggest that expression of metal-independent glycolytic isozymes is a common strategy employed by bacteria to survive in metal-limited environments, such as the host.
Highlights
The preferred carbon source for many pathogens is glucose and disruption of glycolysis reduces the ability of many invaders to cause infection [1,2,3,4,5,6,7,8,9,10]
Glycolysis can increase the need for manganese and sensitize invaders to the manganese-withholding defense of the host, known as nutritional immunity
These results suggest that using metal-independent isozymes to enable the consumption of sugars within the host or other metal-limited environments is a common strategy employed by diverse bacteria
Summary
The preferred carbon source for many pathogens is glucose and disruption of glycolysis reduces the ability of many invaders to cause infection [1,2,3,4,5,6,7,8,9,10]. Host defenses reduce the ability of pathogens to consume glycolytic substrates by limiting metal availability or via other mechanisms [18, 19]. The spread of antibiotic-resistant isolates has led the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) to call for the development of novel therapeutics to treat S. aureus and other pathogens [20, 21]. Understanding how pathogens generate energy and preserve the activity of critical metabolic pathways despite the concerted efforts of the immune system has the potential to identify new opportunities for therapeutic intervention
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
