NAD-glycohydrolase depletes intracellular NAD+ and inhibits acidification of autophagosomes to enhance multiplication of group A Streptococcus in endothelial cells

Cheng Lu Hsieh, Hsuan Min Huang, Shu Ying Hsieh, Po Xing Zheng, Yee-Shin Lin, Chuan Chiang-Ni, Pei-Jane Tsai, Shu-Ying Wang, Ching-Chuan Liu, Jiunn Jong Wu

Research output: Contribution to journalArticle

Abstract

Group A Streptococcus (GAS) is a human pathogen causing a wide spectrum of diseases, from mild pharyngitis to life-threatening necrotizing fasciitis. GAS has been shown to evade host immune killing by invading host cells. However, how GAS resists intracellular killing by endothelial cells is still unclear. In this study, we found that strains NZ131 and A20 have higher activities of NADase and intracellular multiplication than strain SF370 in human endothelial cells (HMEC-1). Moreover, nga mutants of NZ131 (SW957 and SW976) were generated to demonstrate that NADase activity is required for the intracellular growth of GAS in endothelial cells. We also found that intracellular levels of NAD+ and the NAD+/NADH ratio of NZ131-infected HMEC-1 cells were both lower than in cells infected by the nga mutant. Although both NZ131 and its nga mutant were trapped by LC3-positive vacuoles, only nga mutant vacuoles were highly co-localized with acidified lysosomes. On the other hand, intracellular multiplication of the nga mutant was increased by bafilomycin A1 treatment. These results indicate that NADase causes intracellular NAD+ imbalance and impairs acidification of autophagosomes to escape autophagocytic killing and enhance multiplication of GAS in endothelial cells.

Original languageEnglish
Article number1733
JournalFrontiers in Microbiology
Volume9
Issue numberAUG
DOIs
Publication statusPublished - 2018 Aug 3

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NAD+ Nucleosidase
Streptococcus
NAD
Endothelial Cells
Vacuoles
Necrotizing Fasciitis
Pharyngitis
Lysosomes
Autophagosomes
Growth

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Microbiology (medical)

Cite this

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title = "NAD-glycohydrolase depletes intracellular NAD+ and inhibits acidification of autophagosomes to enhance multiplication of group A Streptococcus in endothelial cells",
abstract = "Group A Streptococcus (GAS) is a human pathogen causing a wide spectrum of diseases, from mild pharyngitis to life-threatening necrotizing fasciitis. GAS has been shown to evade host immune killing by invading host cells. However, how GAS resists intracellular killing by endothelial cells is still unclear. In this study, we found that strains NZ131 and A20 have higher activities of NADase and intracellular multiplication than strain SF370 in human endothelial cells (HMEC-1). Moreover, nga mutants of NZ131 (SW957 and SW976) were generated to demonstrate that NADase activity is required for the intracellular growth of GAS in endothelial cells. We also found that intracellular levels of NAD+ and the NAD+/NADH ratio of NZ131-infected HMEC-1 cells were both lower than in cells infected by the nga mutant. Although both NZ131 and its nga mutant were trapped by LC3-positive vacuoles, only nga mutant vacuoles were highly co-localized with acidified lysosomes. On the other hand, intracellular multiplication of the nga mutant was increased by bafilomycin A1 treatment. These results indicate that NADase causes intracellular NAD+ imbalance and impairs acidification of autophagosomes to escape autophagocytic killing and enhance multiplication of GAS in endothelial cells.",
author = "Hsieh, {Cheng Lu} and Huang, {Hsuan Min} and Hsieh, {Shu Ying} and Zheng, {Po Xing} and Yee-Shin Lin and Chuan Chiang-Ni and Pei-Jane Tsai and Shu-Ying Wang and Ching-Chuan Liu and Wu, {Jiunn Jong}",
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NAD-glycohydrolase depletes intracellular NAD+ and inhibits acidification of autophagosomes to enhance multiplication of group A Streptococcus in endothelial cells. / Hsieh, Cheng Lu; Huang, Hsuan Min; Hsieh, Shu Ying; Zheng, Po Xing; Lin, Yee-Shin; Chiang-Ni, Chuan; Tsai, Pei-Jane; Wang, Shu-Ying; Liu, Ching-Chuan; Wu, Jiunn Jong.

In: Frontiers in Microbiology, Vol. 9, No. AUG, 1733, 03.08.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - NAD-glycohydrolase depletes intracellular NAD+ and inhibits acidification of autophagosomes to enhance multiplication of group A Streptococcus in endothelial cells

AU - Hsieh, Cheng Lu

AU - Huang, Hsuan Min

AU - Hsieh, Shu Ying

AU - Zheng, Po Xing

AU - Lin, Yee-Shin

AU - Chiang-Ni, Chuan

AU - Tsai, Pei-Jane

AU - Wang, Shu-Ying

AU - Liu, Ching-Chuan

AU - Wu, Jiunn Jong

PY - 2018/8/3

Y1 - 2018/8/3

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AB - Group A Streptococcus (GAS) is a human pathogen causing a wide spectrum of diseases, from mild pharyngitis to life-threatening necrotizing fasciitis. GAS has been shown to evade host immune killing by invading host cells. However, how GAS resists intracellular killing by endothelial cells is still unclear. In this study, we found that strains NZ131 and A20 have higher activities of NADase and intracellular multiplication than strain SF370 in human endothelial cells (HMEC-1). Moreover, nga mutants of NZ131 (SW957 and SW976) were generated to demonstrate that NADase activity is required for the intracellular growth of GAS in endothelial cells. We also found that intracellular levels of NAD+ and the NAD+/NADH ratio of NZ131-infected HMEC-1 cells were both lower than in cells infected by the nga mutant. Although both NZ131 and its nga mutant were trapped by LC3-positive vacuoles, only nga mutant vacuoles were highly co-localized with acidified lysosomes. On the other hand, intracellular multiplication of the nga mutant was increased by bafilomycin A1 treatment. These results indicate that NADase causes intracellular NAD+ imbalance and impairs acidification of autophagosomes to escape autophagocytic killing and enhance multiplication of GAS in endothelial cells.

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