TY - JOUR
T1 - Metal-independent variants of phosphoglycerate mutase promote resistance to nutritional immunity and retention of glycolysis during infection
AU - Radin, Jana N.
AU - Kelliher, Jessica L.
AU - Solórzano, Paola K.Párraga
AU - Grim, Kyle P.
AU - Ramezanifard, Rouhallah
AU - Slauch, James M.
AU - Kehl-Fie, Thomas E.
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (R01 AI 118880) and a Vallee Scholar Award from the Vallee Foundation to TEKF. Work in the laboratory of JMS is supported by the National Institutes of Health (R01 AI 123381). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the Vallee Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank the members of the Kehl-Fie lab for critical reading of the manuscript.
Publisher Copyright:
© 2019 Radin et al.
PY - 2019/7
Y1 - 2019/7
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.ppat.1007971
DO - 10.1371/journal.ppat.1007971
M3 - Article
C2 - 31344131
AN - SCOPUS:85071226140
SN - 1553-7366
VL - 15
JO - PLoS Pathogens
JF - PLoS Pathogens
IS - 7
M1 - e1007971
ER -