Bioinformatic analysis reveals the expression of unique transcriptomic signatures in Zika virus infected human neural stem cells

Abstract

BackgroundThe single-stranded RNA Flavivirus, Zika virus (ZIKV), has recently re-emerged and spread rapidly across the western hemisphere’s equatorial countries, primarily through Aedes mosquito transmission. While symptoms in adult infections appear to be self-limiting and mild, severe birth defects, such as microcephaly, have been linked to infection during early pregnancy. Recently, Tang et al. (Cell Stem Cell 2016, doi: 10.1016/j.stem.2016.02.016) demonstrated that ZIKV efficiently infects induced pluripotent stem cell (iPSC) derived human neural progenitor cells (hNPCs), resulting in cell cycle abnormalities and apoptosis. Consequently, hNPCs are a suggested ZIKV target.MethodsWe analyzed the transcriptomic sequencing (RNA-seq) data (GEO: GSE78711) of ZIKV (Strain: MR766) infected hNPCs. For comparison to the ZIKV-infected hNPCs, the expression data from hNPCs infected with human cytomegalovirus (CMV) (Strain: AD169) was used (GEO: GSE35295). Utilizing a combination of Gene Ontology, database of human diseases, and pathway analysis, we generated a putative systemic model of infection supported by known molecular pathways of other highly related viruses.ResultsWe analyzed RNA-sequencing data for transcript expression alterations in ZIKV-infected hNPCs, and then compared them to expression patterns of iPSC-derived hNPCs infected with CMV, a virus that can also induce severe congenital neurological defects in developing fetuses. We demonstrate for the first time that many of cellular pathways correlate with clinical pathologies following ZIKV infection such as microcephaly, congenital nervous system disorders and epilepsy. Furthermore, ZIKV activates several inflammatory signals within infected hNPCs that are implicated in innate and acquired immune responses, while CMV-infected hNPCs showed limited representation of these pathways. Moreover, several genes related to pathogen responses are significantly upregulated upon ZIKV infection, but not perturbed in CMV-infected hNPCs.ConclusionThe presented study is the first to report enrichment of numerous pro-inflammatory pathways in ZIKV-infected hNPCs, indicating that hNPCs are capable of signaling through canonical pro-inflammatory pathways following viral infection. By defining gene expression profiles, new factors in the pathogenesis of ZIKV were identified which could help develop new therapeutic strategies.

Zika virus infection and pregnancy: what we do and do not know

“…63 A study carried out using a bioinformatic approach showed that infection of human NPCs results in substantial changes in gene up-and down-regulation. 64 In this context, prominent features are represented by the hyper-expression of genes involved in the regulation of nucleic acid metabolism (hallmark of virus replication) and the down-regulation of genes involved in chromosome segregation and DNA replication and repair. 64 In addition, ZIKV infection of the above-mentioned cells results in the activation of several innate immunity pathways, that are different from those observed in other infections known to cause congenital fetal abnormalities, such as CMV.…”

“…64 In this context, prominent features are represented by the hyper-expression of genes involved in the regulation of nucleic acid metabolism (hallmark of virus replication) and the down-regulation of genes involved in chromosome segregation and DNA replication and repair. 64 In addition, ZIKV infection of the above-mentioned cells results in the activation of several innate immunity pathways, that are different from those observed in other infections known to cause congenital fetal abnormalities, such as CMV. 64 Experiments carried out in more complex systems, such as human cerebral organoids, are consistent with the above reported observations.…”

Zika Virus: What Have We Learnt Since the Start of the Recent Epidemic?

“…Thus, ZIKV-infected cells exhibit the characteristic ultrastructural alterations of flavivirusinfected cells (Dick, 1952;Offerdahl et al, 2017). In addition, ZIKV infection provokes changes in the pattern of cellular and viral RNA methylation and induces a major impact on the transcriptome of the host cell (Rolfe et al, 2016).…”

Zika Virus

“…Bunun nedeni, Zika virüs enfeksiyonun Dengue ateşi ve Chikungunya enfeksiyonlarına benzer bir tablo oluşturması olabilir (26)(27)(28)35,36) . (10,46) . (47,48) .…”

“…Virüsün enfektivitesi E proteininin N terminal glikolizasyonu ile arttırılabilmektedir. Mevcut çalışmalar N-linked glikolizasyondaki değişimlerin, Zika virüsünün transmisyonunda ve komplikasyon gelişimine neden olmasında belirgin bir rol oynayabileceği yönündedir (10)(11)(12)(13) . Zika virüsünün gebelikte geçirilen enfeksiyon ile ilişkili olarak bebekte mikrosefali oluşturmasında temel patolojik mekanizmanın sentrozomlardaki hasar olabileceği öne sürülmektedir (14) .…”