Structural basis underlying the synergism of NADase and SLO during group A Streptococcus infection

Wei-Jiun Tsai; Yi-Hsin Lai; Yong-An Shi; Michal Hammel; Anthony P Duff; Andrew E Whitten; Karyn L Wilde; Chun-Ming Wu; Robert Knott; U-Ser Jeng; Chia-Yu Kang; Chih-Yu Hsu; Jian-Li Wu; Pei-Jane Tsai; Chuan Chiang-Ni; Jiunn-Jong Wu; Yee-Shin Lin; Ching-Chuan Liu; Toshiya Senda; Shuying Wang

doi:10.1038/s42003-023-04502-0

Structural basis underlying the synergism of NADase and SLO during group A Streptococcus infection

Commun Biol. 2023 Jan 31;6(1):124. doi: 10.1038/s42003-023-04502-0.

Authors

Wei-Jiun Tsai¹, Yi-Hsin Lai^#¹, Yong-An Shi^#², Michal Hammel³, Anthony P Duff⁴, Andrew E Whitten⁴, Karyn L Wilde⁴, Chun-Ming Wu⁵, Robert Knott⁴, U-Ser Jeng^{5

6}, Chia-Yu Kang⁷, Chih-Yu Hsu⁸, Jian-Li Wu⁹, Pei-Jane Tsai^{1

8

10}, Chuan Chiang-Ni^{2

11

12

13}, Jiunn-Jong Wu^{14

15}, Yee-Shin Lin^{7

10}, Ching-Chuan Liu⁷, Toshiya Senda¹⁶, Shuying Wang^{17

18

19

20}

Affiliations

¹ Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
² Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
³ Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
⁴ Australian Nuclear Science and Technology Organisation, Lucas Heights, NSW, Australia.
⁵ National Synchrotron Radiation Research Center, Hsinchu Science Park, Hsinchu, Taiwan.
⁶ Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
⁷ Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁸ Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Medical College, Tainan, Taiwan.
⁹ Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
¹⁰ Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.
¹¹ Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
¹² Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan.
¹³ Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan.
¹⁴ Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.
¹⁵ Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
¹⁶ Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki, Japan.
¹⁷ Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. sswang23@mail.ncku.edu.tw.
¹⁸ Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. sswang23@mail.ncku.edu.tw.
¹⁹ Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan. sswang23@mail.ncku.edu.tw.
²⁰ Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan. sswang23@mail.ncku.edu.tw.

^# Contributed equally.

Abstract

Group A Streptococcus (GAS) is a strict human pathogen possessing a unique pathogenic trait that utilizes the cooperative activity of NAD⁺-glycohydrolase (NADase) and Streptolysin O (SLO) to enhance its virulence. How NADase interacts with SLO to synergistically promote GAS cytotoxicity and intracellular survival is a long-standing question. Here, the structure and dynamic nature of the NADase/SLO complex are elucidated by X-ray crystallography and small-angle scattering, illustrating atomic details of the complex interface and functionally relevant conformations. Structure-guided studies reveal a salt-bridge interaction between NADase and SLO is important to cytotoxicity and resistance to phagocytic killing during GAS infection. Furthermore, the biological significance of the NADase/SLO complex in GAS virulence is demonstrated in a murine infection model. Overall, this work delivers the structure-functional relationship of the NADase/SLO complex and pinpoints the key interacting residues that are central to the coordinated actions of NADase and SLO in the pathogenesis of GAS infection.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bacterial Proteins
Humans
Mice
NAD+ Nucleosidase
Streptococcus*
Streptolysins*

Substances

streptolysin O
Streptolysins
Bacterial Proteins
NAD+ Nucleosidase

Grants and funding

P30 GM124169/GM/NIGMS NIH HHS/United States