Molecular signatures associated with ZIKV exposure in human cortical neural progenitors

Abstract

Zika virus (ZIKV) infection causes microcephaly and has been linked to other brain abnormalities. How ZIKV impairs brain development and function is unclear. Here we systematically profiled transcriptomes of human neural progenitor cells exposed to Asian ZIKV C , African ZIKV M , and dengue virus (DENV). In contrast to the robust global transcriptome changes induced by DENV, ZIKV has a more selective and larger impact on expression of genes involved in DNA replication and repair. While overall expression profiles are similar, ZIKV C , but not ZIKV M , induces upregulation of viral response genes and TP53. P53 inhibitors can block the apoptosis induced by both ZIKV C and ZIKV M in hNPCs, with higher potency against ZIKV C -induced apoptosis. Our analyses reveal virus-and strain-specific molecular signatures associated with ZIKV infection. These datasets will help to investigate ZIKV-host interactions and identify neurovirulence determinants of ZIKV.

Advances in Zika Virus Research: Stem Cell Models, Challenges, and Opportunities

“…The decision by the CDC was unprecedented at such an early stage of the epidemic and in the absence of confirmative clinical evidence from large cohorts, which only came several months later (de Araujo et al, 2016). Many independent studies around the same time showed similar results of ZIKV infection and its pathological impact using both human iPSC- and fetal brain tissue-derived neural progenitors in monolayer and 3D neurosphere cultures (Brault et al, 2016; Cugola et al, 2016; Garcez et al, 2016; Liang et al, 2016; Simonin et al, 2016; Zhang et al, 2016a). Initial studies used the prototype ZIKV strain MR766 of African origin and the basic findings have since been confirmed with recent clinic isolates, including the Cambodian strain FSS13025 of Asian origin (Zhang et al, 2016a), and strains isolated from Brazil (Cugola et al, 2016), Mexico (ZIKV MEX_I_7) (Barrows et al, 2016), and Puerto Rico (PRVABC59) (Xu et al, 2016), all of which are originally of Asian origin.…”

“…A potential DENV-ZIKV interaction is a concern because of the significant overlap between the major geographic areas affected by the two viruses. In vitro studies so far indicate that DENV differs from ZIKV in its inability to affect neural progenitor cells (Garcez et al, 2016; Zhang et al, 2016a) and there is no strong evidence of anti-dengue antibody enhancing ZIKV infection occurring in vivo. A recent study did show that anti-ZIKV antibodies may enhance DENV infection in mice, but the reverse did not occur in the same experimental setting (Stettler et al, 2016).…”

“…The capacity of different ZIKV strains to cause various human disorders is still not clear and remains an interesting question. In cellular models, some quantitative differences have been observed in terms of neural progenitor proliferation, cell death and gene expression (Cugola et al, 2016; Simonin et al, 2016; Zhang et al, 2016a). It should be pointed out that any strain-specific phenotypes in experimental models need to be considered in the context of passage histories of the strains.…”

“…Cell death, mainly through caspase-3 activation and apoptosis, has been frequently observed following ZIKV infection of neural progenitors in vitro, in animal models, and in clinical samples of ZIKV-infected fetuses (Cugola et al, 2016; Dang et al, 2016; Li et al, 2016a; Onorati et al, 2016; Qian et al, 2016; Shao et al, 2016; Tang et al, 2016; Wu et al, 2016; Yockey et al, 2016; Zhang et al, 2016a) (Figure 3). ZIKV infection increases total levels of tumor suppressor protein p53, its nuclear accumulation, and Ser15 phosphorylation (Ghouzzi et al, 2016) and p53 inhibitors block the apoptosis induced by ZIKV in human neural progenitors (Zhang et al, 2016a).…”

“…ZIKV infection increases total levels of tumor suppressor protein p53, its nuclear accumulation, and Ser15 phosphorylation (Ghouzzi et al, 2016) and p53 inhibitors block the apoptosis induced by ZIKV in human neural progenitors (Zhang et al, 2016a). Together these findings show that ZIKV interferes with key survival and homeostasis mechanisms, which helps explain the pleiotropic and destructive consequences of infection in cells and tissues.…”