Zika virus causes supernumerary foci with centriolar proteins and impaired spindle positioning

Abstract

Zika virus (ZIKV) causes congenital microcephaly. Although ZIKV can impair cell cycle progression and provoke apoptosis, which probably contributes to disease aetiology through depletion of neural progenitor cells, additional cellular mechanisms may be important. Here, we investigated whether ZIKV infection alters centrosome number and spindle positioning, because such defects are thought to be at the root of inherited primary autosomal recessive microcephaly (MCPH). In addition to HeLa cells, in which centrosome number and spindle positioning can be well monitored, we analysed retinal epithelial cells (RPE-1), as well as brain-derived microglial (CHME-5) and neural progenitor (ReN) cells, using immunofluorescence. We established that ZIKV infection leads to supernumerary foci containing centriolar proteins that in some cases drive multipolar spindle assembly, as well as spindle positioning defects in HeLa, RPE-1 and CHME-5 cells, but not in ReN cells. We uncovered similar phenotypes in HeLa cells upon infection with dengue virus (DENV-2), another flavivirus that does not target brain cells and does not cause microcephaly. We conclude that infection with Flaviviridae can increase centrosome numbers and impair spindle positioning, thus potentially contributing to microcephaly in the case of Zika.

Global Interactomics Uncovers Extensive Organellar Targeting by Zika Virus

“…ZIKV infection has been linked to significant defects in centrosome function (54,55). Consistent with these observations, our data reveal ZIKV polypeptide interactions with multiple centrosome and cilia regulatory proteins.…”

Molecular cloning and characterization of the genes encoding the proteins of Zika virus

“…Most interestingly, NS3 overexpression impaired the structure of centrosome. NS3 may contribute to the centrosome damage induced by ZIKV as reported recently (Gabriel et al, 2017; Wolf et al, 2017). …”

Pathophysiology and Mechanisms of Zika Virus Infection in the Nervous System

“…Subsequently, studies using more recent clinical isolates confirmed similar productive infection and death of NPCs in 2D cultures as well as premature differentiation, aberrant expression of centrosomal proteins, and disrupted centrosomal structure (Gabriel et al 2017). Disruption of the centrosome and spindle positioning was also observed in HeLa cells after ZIKV infection (Wolf et al 2017). Adherens junctions, a connective structure formed among NPCs, appear to be vulnerable to ZIKV infection, which leads to their degradation and reduced mouse NPC proliferation in an NS2A-dependent fashion (Yoon et al 2017).…”