Zika virus infection induces mitosis abnormalities and apoptotic cell death of human neural progenitor cells

CAPES (Zika FastTrack), FINEP, FAPERJ and FAPESB. Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / São Rafael Hospital. Center for Biotechnology and Cell Therapy. Salvador, BA, Brasil São Rafael Hospital. Center for Biotechnology and Cell Therapy. Salvador, BA, Brasil Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil Federal University of Bahia. Laboratory of Virology, Salvador, BA, Brasil Federal University of Bahia. Laboratory of Virology, Salvador, BA, Brasil Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Federal University of Bahia. Department of Pathology. Salvador, BA, Brasil Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil São Rafael Hospital. Center for Biotechnology and Cell Therapy. Salvador, BA, Brasil Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / São Rafael Hospital. Center for Biotechnology and Cell Therapy. Salvador, BA, Brasil Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / São Rafael Hospital. Center for Biotechnology and Cell Therapy. Salvador, BA, Brasil Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / São Rafael Hospital. Center for Biotechnology and Cell Therapy. Salvador, BA, Brasil Hospital Couto Maia. Salvador, BA, Brasil Federal University of Rio de Janeiro. Institute of Biophysics Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil São Rafael Hospital. Center for Biotechnology and Cell Therapy. Salvador, BA, Brasil Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / São Rafael Hospital. Center for Biotechnology and Cell Therapy. Salvador, BA, Brasil Zika virus (ZIKV) infection has been associated with severe complications both in the developing and adult nervous system. To investigate the deleterious effects of ZIKV infection, we used human neural progenitor cells (NPC), derived from induced pluripotent stem cells (iPSC). We found that NPC are highly susceptible to ZIKV and the infection results in cell death. ZIKV infection led to a marked reduction in cell proliferation, ultrastructural alterations and induction of autophagy. Induction of apoptosis of Sox2(+) cells was demonstrated by activation of caspases 3/7, 8 and 9, and by ultrastructural and flow cytometry analyses. ZIKV-induced death of Sox2(+) cells was prevented by incubation with the pan-caspase inhibitor, Z-VAD-FMK. By confocal microscopy analysis we found an increased number of cells with supernumerary centrosomes. Live imaging showed a significant increase in mitosis abnormalities, including multipolar spindle, chromosome laggards, micronuclei and death of progeny after cell division. FISH analysis for chromosomes 12 and 17 showed increased frequency of aneuploidy, such as monosomy, trisomy and polyploidy. Our study reinforces the link between ZIKV and abnormalities in the developing human brain, including microcephaly.