Transendothelial migration of the Lyme disease spirochete involves spirochete internalization as an intermediate step...

Area of Science:

• Microbiology
• Cell Biology
• Pathogenesis

Background:

• Lyme borreliosis, caused by Borrelia burgdorferi, is the most common tick-borne illness in the Northern Hemisphere.
• The hematogenous dissemination of B. burgdorferi is crucial for its pathogenesis but remains poorly understood.
• Understanding how B. burgdorferi traverses endothelial cells is key to explaining its systemic spread and diverse clinical manifestations.

Purpose of the Study:

• To investigate the molecular mechanisms of Borrelia burgdorferi transmigration across human microvascular endothelial cells.
• To determine the route of endothelial cell traversal utilized by B. burgdorferi.
• To identify host cell proteins involved in B. burgdorferi invasion and subsequent migration.

Main Methods:

• Utilized cultured primary and immortalized human microvascular endothelial cells.
• Observed B. burgdorferi transmigration using microscopy.
• Employed inhibitors to block endothelial junctions and common endocytic pathways.
• Investigated the roles of host proteins Cdc42 and Rac1 using specific inhibitors.

Main Results:

• Approximately 55% of wild-type B. burgdorferi successfully crossed the endothelial cell monolayer.
• Spirochetes utilized a transcellular route, entering through the cell body rather than at junctions.
• Inhibition of Cdc42 reduced B. burgdorferi internalization, while Rac1 inhibition impaired cellular egress.
• Cdc42 and Rac1 were identified as essential host proteins for B. burgdorferi transmigration.

Conclusions:

• Borrelia burgdorferi employs a transcellular pathway to disseminate through endothelial cells.
• Spirochete internalization via Cdc42 and subsequent egress mediated by Rac1 are critical steps in this process.
• This study identifies Cdc42 and Rac1 as the first host proteins implicated in B. burgdorferi transmigration across endothelial cells.