Abstract
Zika virus (ZIKV) is an emerging mosquito-borne (Aedes genus) arbovirus of the Flaviviridae family. Although ZIKV has been predominately associated with a mild or asymptomatic dengue-like disease, its appearance in the Americas has been accompanied by a multi-fold increase in reported incidence of fetal microcephaly and brain malformations. The source and mode of vertical transmission from mother to fetus is presumptively transplacental, although a causal link explaining the interval delay between maternal symptoms and observed fetal malformations following infection has been missing. In this study, we show that primary human placental trophoblasts from non-exposed donors (n = 20) can be infected by primary passage ZIKV-FLR isolate, and uniquely allowed for ZIKV viral RNA replication when compared to dengue virus (DENV). Consistent with their being permissive for ZIKV infection, primary trophoblasts expressed multiple putative ZIKV cell entry receptors, and cellular function and differentiation were preserved. These findings suggest that ZIKV-FLR strain can replicate in human placental trophoblasts without host cell destruction, thereby serving as a likely permissive reservoir and portal of fetal transmission with risk of latent microcephaly and malformations.
Highlights
Until recently Zika viral illness was thought to be self-limiting and resembling that of dengue and chikungunya with clinical manifestations of fever, headache, arthralgia, myalgia and maculopapular rash
As recently described[18], Zika virus (ZIKV)-FLR was isolated by inoculating A. albopictus C6/36 mosquito cells with serum from a non-pregnant subject infected over a short interval stay in Barranquilla, Colombia
We compared the replication of our FLR clinical isolate of Zika virus to that of a dengue serotype 2 strain virus; dengue virus (DENV) serotype 2 grows at very high rates in human target cells, but has not been shown to cause fetal malformations after billions of human infections around the globe[21,22]
Summary
Until recently Zika viral illness was thought to be self-limiting and resembling that of dengue and chikungunya with clinical manifestations of fever, headache, arthralgia, myalgia and maculopapular rash. They observed that these historic and non-contemporaneous strains could infect placental trophoblast cell lines, but not primary human trophoblasts Of note, their measure of infectivity was the presence of the negative viral RNA strand at early times following infection (24 and 48 hours post infection), and all replication comparisons were relative to human brain microvascular endothelial cells[11]. Their measure of infectivity was the presence of the negative viral RNA strand at early times following infection (24 and 48 hours post infection), and all replication comparisons were relative to human brain microvascular endothelial cells[11] They further observed that conditioned media from human trophoblasts infected with these serially passaged ZIKV from the African (Ugandan) and Asian (Cambodian) outbreaks presumptively contained Type III interferon (IFNλ1), which potentially enables downstream expression of interferon stimulated genes that could restrict virus replication[11]. ZIKV has recently been observed to infect and to attenuate human neural progenitor cell (hNPC) growth and differentiation in vitro, and hNPC derived from induced pluripotent stem cells release ZIKV infectious particles[15]
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