RAGE and CCR7 mediate the transmigration of Zika-infected monocytes through the blood-brain barrier

Area of Science:

• Neuroscience
• Virology
• Immunology

Background:

• The "Trojan Horse" mechanism of Zika virus (ZIKV) neuroinvasion via the blood-brain barrier (BBB) is not fully understood.
• Monocyte migration to the brain is implicated in ZIKV pathogenesis, potentially involving pattern-recognition and chemokine receptors.

Purpose of the Study:

• To investigate the role of chemokine receptor 7 (CCR7) and receptor for advanced glycation end (RAGE) in ZIKV-infected monocyte migration across the BBB.
• To determine if high mobility group box protein 1 (HMGB1) contributes to endothelial cell permeability.

Main Methods:

• Infection of MonoMac-1 (MM-1) cells with ZIKV.
• Assessment of HMGB1 accumulation in the cellular milieu.
• Evaluation of endothelial cell junction marker dysregulation.
• Transmigration assays using CCR7 and RAGE antagonists (FPS-ZM1) under inflammatory conditions.

Main Results:

• ZIKV infection of MM-1 cells leads to HMGB1 release.
• HMGB1 dysregulates junction markers in human brain microvascular endothelial cells.
• Monocyte migration is dependent on chemokine ligand 19 (CCL19) for CCR7 and RAGE pathways, especially during inflammation.
• RAGE inhibition significantly reduced ZIKV-infected cell transmigration.

Conclusions:

• HMGB1 plays a role in ZIKV-induced BBB disruption.
• CCR7 and RAGE are critical for ZIKV-infected monocyte trafficking across the BBB.
• Targeting monocyte migration pathways may offer therapeutic strategies against ZIKV neuroinfection.