Recent Zika Virus Isolates Induce Premature Differentiation of Neural Progenitors in Human Brain Organoids

Abstract

SUMMARYThe recent Zika virus (ZIKV) epidemic is associated with microcephaly in newborns. Although the connection between ZIKV and neurodevelopmental defects is widely recognized, the underlying mechanisms are poorly understood. Here we show that two recently isolated strains of ZIKV, an American strain from an infected fetal brain (FB-GWUH-2016) and a closely-related Asian strain (H/PF/2013), productively infect human iPSC-derived brain organoids. Both of these strains readily target to and replicate in proliferating ventricular zone (VZ) apical progenitors. The main phenotypic effect was premature differentiation of neural progenitors associated with centrosome perturbation, even during early stages of infection, leading to progenitor depletion, disruption of the VZ, impaired neurogenesis, and cortical thinning. The infection pattern and cellular outcome differ from those seen with the extensively passaged ZIKV strain MR766. The structural changes we see after infection with these more recently isolated viral strains closely resemble those seen in ZIKV-associated microcephaly.

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). …”

Genetics and mechanisms leading to human cortical malformations

“…More recently, the ZIKV strains isolated in the last outbreak (H/PF/2013 (ZIKV-AS) and FB-GWUH-2016 (ZIKV-AM)) were characterized by Gabriel and col. [311], showing that ZIKV targets and replicates in proliferating NPCs, leading to premature differentiation associated with centrosome perturbation, NPC depletion, disruption of the VZ, impaired neurogenesis and cortical thinning. Altogether, recent evidence linking microcephaly with ZIKV infection through targeted-NPCs and the huge amount of research dedicated to the study of the effects of this virus and mechanisms of action, not only contributed to the development of an effective antiviral vaccine that could prevent ZIKV effects, but also provided potential fundamental clues of cortical development impairment under other pathological conditions which lead to MCDs.…”

Replication of early and recent Zika virus isolates throughout mouse brain development

“…information about virus infection of target cells within the context of the developing tissue and organ, since some cell types are missing and there is little to no immune system or vascular representation. Furthermore, many organoid cultures used to understand ZIKV biology only develop neural identity, not tissue organization (17,18). Organoid cultures do not allow for the study of neuropathologies in the late developing brain, are difficult to consistently manufacture, and are characterized by immature neuronal connectivity; therefore, they are far more simplistic than the brain (19).…”