Zika virus infection dysregulates human neural stem cell growth and inhibits differentiation into neuroprogenitor cells

Abstract

The current outbreak of Zika virus-associated diseases in South America and its threat to spread to other parts of the world has emerged as a global health emergency. A strong link between Zika virus and microcephaly exists, and the potential mechanisms associated with microcephaly are under intense investigation. In this study, we evaluated the effect of Zika virus infection of Asian and African lineages (PRVABC59 and MR766) in human neural stem cells (hNSCs). These two Zika virus strains displayed distinct infection pattern and growth rates in hNSCs. Zika virus MR766 strain increased serine 139 phosphorylation of histone H2AX (γH2AX), a known early cellular response proteins to DNA damage. On the other hand, PRVABC59 strain upregulated serine 15 phosphorylation of p53, p21 and PUMA expression. MR766-infected cells displayed poly (ADP-ribose) polymerase (PARP) and caspase-3 cleavage. Interestingly, infection of hNSCs by both strains of Zika virus for 24 h, followed by incubation in astrocyte differentiation medium, induced rounding and cell death. However, astrocytes generated from hNSCs by incubation in differentiation medium when infected with Zika virus displayed minimal cytopathic effect at an early time point. Infected hNSCs incubated in astrocyte differentiating medium displayed PARP cleavage within 24–36 h. Together, these results showed that two distinct strains of Zika virus potentiate hNSC growth inhibition by different mechanisms, but both viruses strongly induce death in early differentiating neuroprogenitor cells even at a very low multiplicity of infection. Our observations demonstrate further mechanistic insights for impaired neuronal homeostasis during active Zika virus infection.

Zika Virus Infection Induces DNA Damage Response in Human Neural Progenitors That Enhances Viral Replication

“…This event leads to the recruitment of numerous DNA repair proteins, such as the p53-binding protein 1 (53BP1) (21,22). Recently, it was demonstrated that ZIKV infection leads to increased ␥H2A.X signals (7,23,24); however, neither direct evidence of DNA breaks during ZIKV infection, nor the consequences of this damage on cell cycle progression or viral replication have been shown.…”

Comparative analysis of sfRNA in the genome of pre-epidemic and epidemic Zika viruses for host interacting proteins potentially related to the recent epidemic

“…Other host proteins interacting with ZIKV sfRNA which has role embryonic development are SCML2, TBX2, PROX1, RTF1, ELAVL1, ATF6, SETDB2, PUM3 and ZBTB16. Further, ZIKV affect the differentiation, proliferation and death of neuronal cells (20)(21)(22)(23)(24). This study, provided indication proteins has role in the ZIKV pathogenesis in neuronal differentiation; proliferation and death are TCF4, TCF3, POU6F2, TCF12, FOXO3, REB3L2 and MEF2D.…”

p53‐Dependent pathway and the opening of mPTP mediate the apoptosis of co‐cultured Sertoli‐germ cells induced by microcystin‐LR

“…Furthermore, PFT‐α, the inhibitor of p53 , can significantly inhibit the expression of p53 and PUMA, and antagonize the apoptosis of co‐cultured Sertoli‐germ cells induced by MC‐LR. Studies have found that the DNA damage, the upregulation of phosphorylated p53 , and the content of PUMA were observed in human neural stem cells of Zika virus‐infected patients . The study on the role of SiO 2 in lung fibroblasts revealed that SiO 2 can induce pulmonary fibrosis, which is mediated by an increased expression of p53 and PUMA in cells.…”

“…Furthermore, PFT-α, the inhibitor of p53, can significantly inhibit the expression patients. 39 The study on the role of SiO 2 in lung fibroblasts revealed that SiO 2 can induce pulmonary fibrosis, which is mediated by an increased expression of p53 and PUMA in cells. However, the activation and migration of SiO 2 -induced fibroblasts were antagonized after silencing p53 with p53 siRNA.…”