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Article

Streptococcus pyogenes NAD+-Glycohydrolase Reduces Skeletal Muscle βNAD+ Levels Independently of Streptolysin O

1
Infectious Diseases Section, Veterans Affairs Medical Center, Boise, ID 83702, USA
2
Idaho Veterans Research and Education Foundation, Boise, ID 83702, USA
3
Department of Biomedical and Pharmaceutical Sciences, Idaho State University, Meridian, ID 83642, USA
4
Biomolecular Research Core, Boise State University, Boise, ID 83725, USA
5
Department of Medicine, University of Washington, Seattle, WA 98195, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Sabine Pellett, Shashi Sharma and Stephen A. Morse
Microorganisms 2022, 10(7), 1476; https://doi.org/10.3390/microorganisms10071476
Received: 30 June 2022 / Revised: 14 July 2022 / Accepted: 16 July 2022 / Published: 21 July 2022
(This article belongs to the Special Issue Gram Positive Toxins Producing Organisms)
Necrotizing soft tissue infections caused by Streptococcus pyogenes (group A streptococcus [GAS]) are characterized by rapid and extensive necrosis of fascia and muscle. Molecular epidemiological studies have demonstrated a positive correlation between GAS isolates that cause invasive infections and the production of S. pyogenes NAD+-glycohydrolase (SPN), an NADase secreted by GAS, but the effect of SPN on muscle cells has not been described. Thus, using standard βNAD+ and ATP quantification assays, we investigated the effects of SPN on cultured human skeletal muscle cell (SkMC) βNAD+ and ATP with and without streptolysin O (SLO)–a secreted cholesterol-dependent cytolysin known to act synergistically with SPN. We found that culture supernatants from GAS strains producing SLO and SPN depleted intracellular βNAD+ and ATP, while exotoxins from a GAS strain producing SLO and an enzymatically-inactive form of SPN had no effect on βNAD+ or ATP. Addition of purified, enzymatically-active SPN to NADase-negative culture supernatants or sterile media reconstituted βNAD+ depletion but had no effect ATP levels. Further, SPN-mediated βNAD+ depletion could be augmented by SLO or the homologous cholesterol-dependent cytolysin, perfringolysin O (PFO). Remarkably, SPN-mediated βNAD+ depletion was SkMC-specific, as purified SPN had minimal effect on epithelial cell βNAD+. Taken together, this study identifies a previously unrecognized role for SPN as a major disruptor of skeletal muscle βNAD+. Such activity could contribute to the rapid and widespread myonecrosis characteristic of severe GAS soft tissue infections. View Full-Text
Keywords: Streptococcus pyogenes; bacterial toxins; pathology; skeletal muscle Streptococcus pyogenes; bacterial toxins; pathology; skeletal muscle
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MDPI and ACS Style

McIndoo, E.R.; Price, E.; Lamb, C.L.; Dayton, C.S.; Bayer, C.R.; Stevens, D.L.; Bryant, A.E.; Hobdey, S.E. Streptococcus pyogenes NAD+-Glycohydrolase Reduces Skeletal Muscle βNAD+ Levels Independently of Streptolysin O. Microorganisms 2022, 10, 1476. https://doi.org/10.3390/microorganisms10071476

AMA Style

McIndoo ER, Price E, Lamb CL, Dayton CS, Bayer CR, Stevens DL, Bryant AE, Hobdey SE. Streptococcus pyogenes NAD+-Glycohydrolase Reduces Skeletal Muscle βNAD+ Levels Independently of Streptolysin O. Microorganisms. 2022; 10(7):1476. https://doi.org/10.3390/microorganisms10071476

Chicago/Turabian Style

McIndoo, Eric R., Emily Price, Cheri L. Lamb, Christopher S. Dayton, Clifford R. Bayer, Dennis L. Stevens, Amy E. Bryant, and Sarah E. Hobdey. 2022. "Streptococcus pyogenes NAD+-Glycohydrolase Reduces Skeletal Muscle βNAD+ Levels Independently of Streptolysin O" Microorganisms 10, no. 7: 1476. https://doi.org/10.3390/microorganisms10071476

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