Abstract
ABSTRACTZika virus (ZIKV) is a mosquito-borne Flavivirus that has emerged as the cause of encephalitis and fetal microencephaly in the Americas. ZIKV uniquely persists in human bodily fluids for up to 6 months, is sexually transmitted, and traverses the placenta and the blood-brain barrier (BBB) to damage neurons. Cells that support persistent ZIKV replication and mechanisms by which ZIKV establishes persistence remain enigmatic but central to ZIKV entry into protected neuronal compartments. The endothelial cell (EC) lining of capillaries normally constrains transplacental transmission and forms the BBB, which selectively restricts access of blood constituents to neurons. We found that ZIKV (strain PRVABC59) persistently infects and continuously replicates in primary human brain microvascular ECs (hBMECs), without cytopathology, for >9 days and following hBMEC passage. ZIKV did not permeabilize hBMECs but was released basolaterally from polarized hBMECs, suggesting a direct mechanism for ZIKV to cross the BBB. ZIKV-infected hBMECs were rapidly resistant to alpha interferon (IFN-α) and transiently induced, but failed to secrete, IFN-β and IFN-λ. Global transcriptome analysis determined that ZIKV constitutively induced IFN regulatory factor 7 (IRF7), IRF9, and IFN-stimulated genes (ISGs) 1 to 9 days postinfection, despite persistently replicating in hBMECs. ZIKV constitutively induced ISG15, HERC5, and USP18, which are linked to hepatitis C virus (HCV) persistence and IFN regulation, chemokine CCL5, which is associated with immunopathogenesis, as well as cell survival factors. Our results reveal that hBMECs act as a reservoir of persistent ZIKV replication, suggest routes for ZIKV to cross hBMECs into neuronal compartments, and define novel mechanisms of ZIKV persistence that can be targeted to restrict ZIKV spread.
Highlights
Zika virus (ZIKV) is a mosquito-borne Flavivirus that has emerged as the cause of encephalitis and fetal microencephaly in the Americas
We found that ZIKV persistently infects brain endothelial cells that normally protect neurons from viral exposure. human brain microvascular ECs (hBMECs) are not damaged by ZIKV infection and, analogous to persistent hepatitis C virus (HCV) infection, ZIKV constitutively induces and evades antiviral IFN-stimulated genes (ISGs) and IFN responses to continuously replicate in hBMECs
ECs present in placental, fetal, and brain capillaries are infected in ZIKV patients [6, 12, 15], and ZIKV transmission to fetal neurons requires the virus to cross placental and brain EC barriers. hBMECs form a protective blood-brain barrier that restricts viral access to neuronal compartments [18], and mechanisms by which ZIKV bypasses the BBB remain to be defined
Summary
Zika virus (ZIKV) is a mosquito-borne Flavivirus that has emerged as the cause of encephalitis and fetal microencephaly in the Americas. ZIKV uniquely persists in human bodily fluids for up to 6 months, is sexually transmitted, and traverses the placenta and the blood-brain barrier (BBB) to damage neurons. ZIKV crosses placental and blood-brain barrier (BBB) ECs, cells which normally prevent mixing of maternal and fetal blood and restrict access to adult and fetal neuronal compartments [17, 18]. ZIKV does not establish HCV-like permanence, ZIKV persistence is unique to mosquito-borne FVs and likely to be a key to the ability of ZIKV to be sexually transmitted and enter neuronal compartments
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