871: Primary Placental Trophoblasts from Primate Species are Permissive for Zika Virus (ZIKV) Replication

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We and others have recently shown that human placental trophoblasts are infected by ZIKV, and function as a viral reservoir. However, it is unknown if the capacity for productive infection is unique to humans or true of other primate species. This is important given the need for relevant clinical models, as well as furthering our understanding of congenital viral-host interactions. Our study aims were to look for common patterns of infectivity and gene expression in primate trophoblasts (e.g., marmoset, baboon and human) employing whole transcriptome RNA Sequencing (RNA Seq). A primary Brazilian ZIKV isolate from the current pandemic (ZIKV/H.sapiens/Brazil/SPH2015) was employed. Trophoblasts were isolated from non-infected, uncomplicated term marmoset and baboon pregnancies (n=5) following Cesarean delivery, and compared to n=25 human primary trophoblasts infected with recent other ZIKV strains. Trophoblasts were FACS analyzed for purity, and infected with 0.25ml of 1x105 pfu/ml of ZIKV or mock. Infectivity was analyzed by ZIKV-specific qRT-PCR, IHC & single molecule RNA FISH. RNA-Seq was carried out on the Illumina HiSeq platform with 150nt paired-end settings and analyzed by HTseq/edgrR; significance was determined after controlling for multiple comparisons. We observed log replication of ZIKV in pure isolate populations of marmoset and baboon primary trophoblasts; imaging confirmed intracytoplasmic replication (Fig. 1A,1B). >30 million reads/sample were generated, with 60% (+/-2%) mapped to the primate species-specific genome. For example, whole transcriptome gene expression patterns in the marmoset showed significant up-regulation (q<1x10-6) of interferon-associated pathways, with differential expression most prominent on days 4-7 following infection (dpi; Fig. 1C). This study demonstrates for the first time that placental trophoblasts from multiple primate species are permissive for ZIKV replication and likely serve as portals for infection. As ZIKV was first isolated from rhesus macaques in the Ugandan Zika forest in 1947 and human transcriptional pathways modify interferon responses, our findings suggest that ZIKV may share opportunistic pathogenesis in the primate placenta. We speculate that these studies are of likely significant mechanistic interest to ZIKV perinatal pathogenesis.