Deciphering the Role of Extracellular Vesicles Derived from ZIKV-Infected hcMEC/D3 Cells on the Blood-Brain Barrier System

Viruses. 2021 Nov 25;13(12):2363. doi: 10.3390/v13122363.


To date, no vaccines or antivirals are available against Zika virus (ZIKV). In addition, the mechanisms underlying ZIKV-associated pathogenesis of the central nervous system (CNS) are largely unexplored. Getting more insight into the cellular pathways that ZIKV recruits to facilitate infection of susceptible cells will be crucial for establishing an effective treatment strategy. In general, cells secrete a number of vesicles, known as extracellular vesicles (EVs), in response to viral infections. These EVs serve as intercellular communicators. Here, we investigated the role of EVs derived from ZIKV-infected human brain microvascular endothelial cells on the blood-brain barrier (BBB) system. We demonstrated that ZIKV-infected EVs (IEVs) can incorporate viral components, including ZIKV RNA, NS1, and E-protein, and further transfer them to several types of CNS cells. Using label-free impedance-based biosensing, we observed that ZIKV and IEVs can temporally disturb the monolayer integrity of BBB-mimicking cells, possibly by inducing structural rearrangements of the adherent protein VE-cadherin (immunofluorescence staining). Finally, differences in the lipidomic profile between EVs and their parental cells possibly suggest a preferential sorting mechanism of specific lipid species into the vesicles. To conclude, these data suggest that IEVs could be postulated as vehicles (Trojan horse) for ZIKV transmission via the BBB.

Keywords: Zika virus; blood–brain barrier; extracellular vesicles; lipidomics; monolayer integrity; viral transmission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / virology
  • Cells, Cultured
  • Central Nervous System / virology
  • Endothelial Cells / virology
  • Extracellular Vesicles / metabolism*
  • Extracellular Vesicles / virology
  • Humans
  • Lipidomics
  • RNA, Viral / metabolism
  • Viral Nonstructural Proteins / metabolism
  • Viral Proteins / genetics
  • Viral Proteins / metabolism
  • Zika Virus / physiology*
  • Zika Virus Infection / transmission*
  • Zika Virus Infection / virology


  • NS1 protein, zika virus
  • RNA, Viral
  • Viral Nonstructural Proteins
  • Viral Proteins