The type 3 secretion effector IpgD promotes S. flexneri dissemination.

Area of Science:

• Microbiology
• Cell Biology
• Infectious Diseases

Background:

• Shigella flexneri causes significant global mortality and morbidity from bacillary dysentery.
• Pathogenic Shigella invades epithelial cells and spreads via cell-to-cell transmission, a process involving actin-based motility and membrane protrusion formation.
• The type 3 secretion system (T3SS) is crucial for Shigella dissemination, but its mechanisms remain unclear.

Purpose of the Study:

• To elucidate the role of the T3SS effector IpgD in Shigella flexneri cell-to-cell spread.
• To investigate how IpgD influences the formation and resolution of membrane structures during bacterial dissemination.
• To determine the in vivo significance of IpgD in Shigella pathogenesis.

Main Methods:

• Investigated the function of IpgD in mediating the resolution of membrane protrusions into double-membrane vacuoles (DMVs).
• Assessed the enzymatic activity of IpgD as a phosphatidylinositol 4-phosphatase and its effect on PtdIns(4,5)P2 levels.
• Utilized an infant rabbit model of shigellosis to evaluate the in vivo role of IpgD in dissemination and disease severity.

Main Results:

• Demonstrated that IpgD facilitates the resolution of membrane protrusions into DMVs, a key step in Shigella cell-to-cell spread.
• Showed that IpgD's phosphatase activity lowers PtdIns(4,5)P2 levels in protrusions, inhibiting actin polymerization that hinders DMV formation.
• Confirmed that IpgD is essential for efficient in vivo dissemination and contributes to the severity of dysentery in a rabbit model.

Conclusions:

• IpgD is a critical T3SS effector that promotes Shigella dissemination by regulating membrane dynamics and actin polymerization.
• Targeting IpgD function could be a strategy to combat Shigella infections.
• This study clarifies a key mechanism of Shigella pathogenesis and its contribution to disease severity.