Metal-independent variants of phosphoglycerate mutase promote resistance to nutritional immunity and retention of glycolysis during infection. PLoS Pathog 2019 Jul;15(7):e1007971
Date
07/26/2019Pubmed ID
31344131Pubmed Central ID
PMC6684088DOI
10.1371/journal.ppat.1007971Scopus ID
2-s2.0-85071226140 (requires institutional sign-in at Scopus site) 23 CitationsAbstract
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.
Author List
Radin JN, Kelliher JL, Solórzano PKP, Grim KP, Ramezanifard R, Slauch JM, Kehl-Fie TEAuthor
Jessica L. Kelliher PhD Assistant Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBacterial Proteins
Genetic Variation
Glycolysis
Isoenzymes
Leukocyte L1 Antigen Complex
Manganese
Metals
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphoglycerate Mutase
Staphylococcal Infections
Staphylococcus aureus
Virulence
