Morin Attenuates Streptococcus suis Pathogenicity in Mice by Neutralizing Suilysin Activity
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Gen Li1, Gejin Lu1, Zhimin Qi1
1The First Hospital and Institute of Infection and Immunity, Jilin UniversityChangchun, China; Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin UniversityChangchun, China.
Abstract:
Streptococcus suis, a Gram-positive pathogen, is widely recognized as an important agent of swine infection, and it is also known to cause a variety of zoonoses, such as meningitis, polyarthritis and pneumonia. Suilysin (SLY), an extracellular pore-forming toxin that belongs to the cholesterol-dependent cytolysin family, is an essential virulence factor of S. suis capsular type 2 (SS2). Here, we found that morin hydrate (morin), a natural flavonoid that lacks anti-SS2 activity, inhibits the hemolytic activity of SLY, protects J774 cells from SS2-induced injury and protects mice from SS2 infection. Further, by molecular modeling and mutational analysis, we found that morin binds to the "stem" domain 2 in SLY and hinders its transformation from the monomer form to the oligomer form, which causes the loss of SLY activity. Our study demonstrates that morin hinders the cell lysis activity of SLY through a novel mechanism of interrupting the heptamer formation. These findings may lead to the development of promising therapeutic candidates for the treatment of SS2 infections.
Insights
Morin hydrate inhibits the pore-forming toxin suilysin (SLY) from Streptococcus suis, preventing cell damage and infection. This natural compound blocks SLY
Area of Science:
- Microbiology
- Toxicology
- Pharmacology
Background:
- Streptococcus suis (S. suis) is a significant swine pathogen causing zoonotic diseases.
- Suilysin (SLY), a cholesterol-dependent cytolysin, is a key virulence factor in S. suis capsular type 2 (SS2).
Purpose of the Study:
- To investigate the inhibitory effect of morin hydrate on SLY activity.
- To elucidate the mechanism by which morin hydrate affects SLY.
Main Methods:
- In vitro hemolytic activity assays.
- Cell protection assays using J774 macrophages.
- In vivo mouse infection models.
- Molecular modeling and mutational analysis of SLY.
Main Results:
- Morin hydrate inhibited SLY's hemolytic activity.
- Morin hydrate protected cells and mice from SS2 infection.
- Morin hydrate binds to SLY's stem domain, preventing monomer-to-oligomer transition and heptamer formation.
Conclusions:
- Morin hydrate effectively neutralizes SLY activity through a novel mechanism.
- Morin hydrate shows potential as a therapeutic agent against SS2 infections.