ZIKA virus elicits P53 activation and genotoxic stress in human neural progenitors similar to mutations involved in severe forms of genetic microcephaly and p53

Abstract

Epidemiological evidence from the current outbreak of Zika virus (ZIKV) and recent studies in animal models indicate a strong causal link between ZIKV and microcephaly. ZIKV infection induces cell-cycle arrest and apoptosis in proliferating neural progenitors. However, the mechanisms leading to these phenotypes are still largely obscure. In this report, we explored the possible similarities between transcriptional responses induced by ZIKV in human neural progenitors and those elicited by three different genetic mutations leading to severe forms of microcephaly in mice. We found that the strongest similarity between all these conditions is the activation of common P53 downstream genes. In agreement with these observations, we report that ZIKV infection increases total P53 levels and nuclear accumulation, as well as P53 Ser15 phosphorylation, correlated with genotoxic stress and apoptosis induction. Interestingly, increased P53 activation and apoptosis are induced not only in cells expressing high levels of viral antigens but also in cells showing low or undetectable levels of the same proteins. These results indicate that P53 activation is an early and specific event in ZIKV-infected cells, which could result from cell-autonomous and/or non-cell-autonomous mechanisms. Moreover, we highlight a small group of P53 effector proteins that could act as critical mediators, not only in ZIKV-induced microcephaly but also in many genetic microcephaly syndromes.

Immune Cell Dynamics in Rhesus Macaques Infected with a Brazilian Strain of Zika Virus

“…The expression of TACI and BCMA proteins, BAFF and APRIL receptors, have been demonstrated to be critical for the maintenance of ASC and antibody responses (44, 45). RNA-seq data from ZIKV infected neural progenitor cells showed downregulation of TNFRSF13C, another BAFF receptor (46). Considering that ZIKV loads can present a long duration in body fluids and antigen-specific ASCs are still found in low frequencies, it remains to be elucidated whether ZIKV infection also dampens the expression of BAFF receptors in B cells in vivo , impacting the titers of anti-ZIKV antibodies.…”

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

“…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.…”

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

“…Activation of p53 has also been reported after the infection of iPSC-derived human NPC with a ZIKV strain isolated from French Polynesia (PF13). The activation of p53 was not restricted to NPC expressing high levels of viral antigens (Ghouzzi et al, 2016), suggesting that this might be an early event or an indirect effect of ZIKV infection in neighboring cells. Other cell types, such as microglia, astrocytes, and endothelial cells, can also be infected Lum et al, 2017;Meertens et al, 2017), but it is unknown how the interplay among different cell types contribute to the outcome of microcephaly.…”

“…Studies using an Asian strain of ZIKV (FSS13025, isolated in Cambodia) or ZIKV isolated from recent outbreaks in Brazil (Cugola et al, 2016;Souza et al, 2016;Garcez et al, 2017;Sacramento et al, 2017), Puerto Rico (Hanners et al, 2016;Wells et al, 2016) and French Polynesia (Ghouzzi et al, 2016) have shown the ability of the virus to infect and induce apoptosis of human NPC.…”