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Abstract
Zika Virus (ZIKV) is a flavivirus that has been implicated in causing brain deformations, birth defects, and microcephaly in fetuses, and associated with Guillain-Barre syndrome. Mechanisms responsible for transmission of ZIKV across the placenta to the fetus are incompletely understood. Herein, we define key events modulating infection in clinically relevant cells, including primary placental macrophages (human Hofbauer cells; HC), trophoblasts, and neuroblastoma cells. Consistent with previous findings, HC and trophoblasts are permissive to ZIKV infection. Decrease of interferon signaling by Jak ½ inhibition (using ruxolitinib) significantly increased ZIKV replication in HC, trophoblasts, and neuroblasts. Enhanced ZIKV production in ruxolitinib-treated HC was associated with increased expression of HLA-DR and DC-SIGN. Nucleoside analogs blocked ruxolitinib-mediated production of extracellular virus. Although low-level ZIKV infection occurred in untreated HC and trophoblasts, replicating virions were incapable of infecting naive Vero cells. These deficient virions from untreated HC have “thin-coats” suggesting an immature structure. Blocking Jak ½ signaling (with ruxolitinib) restored replication competence as virions produced under these conditions confer cytopathic effects to naive Vero cells. These data demonstrate that Jak-STAT signaling directly impacts the ability of primary placental cells to produce replication-competent virus and is a key determinant in the production of mature virions in clinically relevant cells, including HC and trophoblasts. Design of targeted agents to prevent ZIKV replication in the placenta should consider Jak ½ signaling, the impact of its block on ZIKV infection, and subsequent transmission to the fetus.
Highlights
The family Flaviviridae encompasses over 70 members, including West Nile Virus (WNV), Dengue Virus (DENV), Japanese Encephalitis Virus (JEV), Yellow Fever Virus (YFV), and Zika Virus (ZIKV) [1]
Virus was removed after 2 hours and cells were cultured in the presence or absence of ruxolitinib for 6 days prior to extracellular staining with flurochrome-conjugated mAb to DC-SIGN (Figure 2A), or HLA-DR (Figure 2B), and sub-gated on forward and side scatter plots and doublet discrimination
With the ZIKV epidemic reaching a pandemic in certain parts of South and Central America and the Caribbean, rapid understanding of how the virus replicates across relevant target cells, key events involved in transmission of the virus to the fetus, and potential immunological modulators that govern replication competence are important to determine, but poorly understood
Summary
The family Flaviviridae encompasses over 70 members, including West Nile Virus (WNV), Dengue Virus (DENV), Japanese Encephalitis Virus (JEV), Yellow Fever Virus (YFV), and Zika Virus (ZIKV) [1]. Associated brain abnormalities include microcephaly with reduced viability and cell growth in human neurospheres and brain organoids [5, 7] Together, these data underscore the fact that mother-to-child transmission (MTCT) of ZIKV represents a major health concern. The antiviral IFN response is a key modulator of innate immunity, orchestrating a first line of defense to facilitate paracrine and autocrine production of IFN-α/β and priming of interferon signaling genes (ISG). These genes crosstalk with bystander cells to promote expression of genes that perform antiviral functions. Since IFNs represent a key and early antiviral modulawww.PaiJournal.com tor in innate immunity triggered by viral infection, flaviviruses have evolved strategies to block early innate immune signaling in order to establish infection [1, 9, 14, 15]
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