Abstract
Zika virus (ZIKV) invades and persists in the central nervous system (CNS), causing severe neurological diseases. However the virus journey, from the bloodstream to tissues through a mature endothelium, remains unclear. Here, we show that ZIKV-infected monocytes represent suitable carriers for viral dissemination to the CNS using human primary monocytes, cerebral organoids derived from embryonic stem cells, organotypic mouse cerebellar slices, a xenotypic human-zebrafish model, and human fetus brain samples. We find that ZIKV-exposed monocytes exhibit higher expression of adhesion molecules, and higher abilities to attach onto the vessel wall and transmigrate across endothelia. This phenotype is associated to enhanced monocyte-mediated ZIKV dissemination to neural cells. Together, our data show that ZIKV manipulates the monocyte adhesive properties and enhances monocyte transmigration and viral dissemination to neural cells. Monocyte transmigration may represent an important mechanism required for viral tissue invasion and persistence that could be specifically targeted for therapeutic intervention.
Highlights
Zika virus (ZIKV) invades and persists in the central nervous system (CNS), causing severe neurological diseases
We show that ZIKV-infected monocyte-derived cells are found in the CNS of a human fetus with microcephaly and we assessed monocyte-driven ZIKV dissemination and damage in ex vivo culture models, including human embryonic stem cell-derived cerebral organoids and organotypic mouse cerebellar slices
ZIKV-infected monocyte-derived cells found in a human fetus CNS
Summary
Zika virus (ZIKV) invades and persists in the central nervous system (CNS), causing severe neurological diseases. We find that ZIKVexposed monocytes exhibit higher expression of adhesion molecules, and higher abilities to attach onto the vessel wall and transmigrate across endothelia This phenotype is associated to enhanced monocyte-mediated ZIKV dissemination to neural cells. The wide dissemination of the virus within the body suggests that molecular and cellular mechanisms from the host are subverted to allow ZIKV virions to travel from their port of entry toward tissues This is important for the difficult-to-access brain sanctuary. We show that ZIKV-infected monocyte-derived cells are found in the CNS of a human fetus with microcephaly and we assessed monocyte-driven ZIKV dissemination and damage in ex vivo culture models, including human embryonic stem cell (hESC)-derived cerebral organoids and organotypic mouse cerebellar slices. We correlate the increased transmigration phenotype to higher dissemination rates to hESCderived cerebral organoids compared with cell-free virus infection
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