Pathogenic bacteria exploit transferrin receptor transcytosis to penetrate the blood-brain barrier

Area of Science:

• Neuroscience
• Immunology
• Microbiology

Background:

• The blood-brain barrier (BBB) protects the brain from pathogens but its breach by meningitis-causing bacteria is poorly understood.
• Meningitis remains a serious disease, necessitating research into bacterial invasion mechanisms.

Purpose of the Study:

• To elucidate the mechanisms by which major bacterial meningitis pathogens cross the human BBB.
• To detail the vesicle fusion and transferrin receptor (TfR) transcytosis pathway used by bacteria.

Main Methods:

• Utilized an in vitro human BBB model using brain microvascular endothelial cells (HBMECs).
• Employed a mouse model to study bacterial BBB penetration in vivo.
• Investigated molecular interactions including protein ubiquitination, complex formation, and vesicle fusion.

Main Results:

• Identified a common vesicle fusion mechanism exploited by *Streptococcus pneumoniae*, group B *Streptococcus*, and *Escherichia coli*.
• Demonstrated bacterial hijacking of TfR transcytosis for BBB crossing.
• Revealed that Toll-like receptor signaling on bacteria-containing vesicles (BCVs) triggers TRAF3 modification and a specific protein complex (RCC2, RalA, exocyst subcomplex I) formation.
• Showed SEC6 and SNAP23 mediate the tethering and fusion of BCVs with TfR vesicles.

Conclusions:

• Innate immunity activates specific TRAF3 modifications and HBMEC-specific protein complexes on BCVs.
• This process ensures precise recognition and fusion with TfR vesicles, facilitating bacterial penetration of the BBB.