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

Immunobiology. 2019 Nov;224(6):792-803. doi: 10.1016/j.imbio.2019.08.007. Epub 2019 Aug 25.


Details of the "Trojan Horse" mechanism by which Zika virus (ZIKV) crosses the blood-brain barrier (BBB) remain unclear. However, the migration of ZIKV-infected monocytes to the brain is thought to be dependent on both pattern-recognition and chemokine receptors. In this study, we investigated whether the migration of ZIKV-infected MonoMac-1 (MM-1) cells through the BBB is dependent on chemokine receptor 7 (CCR7) and receptor for advanced glycation end (RAGE); we also determined whether high mobility group box protein 1 (HMGB1) could facilitate the permeabilization of endothelial cells. We demonstrated that ZIKV infects MM-1 cells, leading to milieu accumulation of HMGB1. Our results suggest that HMGB1 is involved in the dysregulation of primary human brain microvascular endothelial cell junction markers. Our results also indicate that the migration of ZIKV-infected monocytes is dependent on chemokine ligand 19 (CCL19), the natural ligand of CCR7, in conditions recapitulating inflammation. RAGE-dependent migration of ZIKV-infected cells declined during transmigration assays in the presence of RAGE receptor antagonist FPS-ZM1. Understanding the molecular role of monocyte trafficking during ZIKV infections could facilitate the development of new therapeutic strategies to prevent the deleterious consequences of ZIKV neuroinfection.

Keywords: Blood-brain barrier; CCR7; HMGB1; Monocytes; RAGE; Zika virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / physiology*
  • Blood-Brain Barrier / physiology*
  • Cell Line
  • Cell Movement
  • Chemokine CCL19 / physiology*
  • Chlorocebus aethiops
  • Endothelial Cells / physiology
  • HMGB1 Protein / physiology*
  • Humans
  • Mitogen-Activated Protein Kinases / physiology*
  • Monocytes / physiology*
  • Monocytes / virology
  • Receptors, CCR7 / physiology*
  • Zika Virus
  • Zika Virus Infection*


  • Antigens, Neoplasm
  • CCL19 protein, human
  • CCR7 protein, human
  • Chemokine CCL19
  • HMGB1 Protein
  • HMGB1 protein, human
  • Receptors, CCR7
  • MOK protein, human
  • Mitogen-Activated Protein Kinases