Strain-Dependent Consequences of Zika Virus Infection and Differential Impact on Neural Development

Abstract

Maternal infection with Zika virus (ZIKV) during pregnancy can result in neonatal abnormalities, including neurological dysfunction and microcephaly. Experimental models of congenital Zika syndrome identified neural progenitor cells as a target of viral infection. Neural progenitor cells are responsible for populating the developing central nervous system with neurons and glia. Neural progenitor dysfunction can lead to severe birth defects, namely, lissencephaly, microcephaly, and cognitive deficits. For this study, the consequences of ZIKV infection in human pluripotent stem cell-derived neural progenitor (hNP) cells and neurons were evaluated. ZIKV isolates from Asian and African lineages displayed lineage-specific replication kinetics, cytopathic effects, and impacts on hNP function and neuronal differentiation. The currently circulating ZIKV isolates exhibit a unique profile of virulence, cytopathic effect, and impaired cellular functions that likely contribute to the pathological mechanism of congenital Zika syndrome. The authors found that infection with Asian-lineage ZIKV isolates impaired the proliferation and migration of hNP cells, and neuron maturation. In contrast, the African-lineage infections resulted in abrupt and extensive cell death. This work furthers the understanding of ZIKV-induced brain pathology.

Asian Zika Virus Isolate Significantly Changes the Transcriptional Profile and Alternative RNA Splicing Events in a Neuroblastoma Cell Line

“…Initial studies examining gene dysregulation following ZIKV infection were undertaken in human neural stem cells (hNSCs) [30,31], human neural progenitor cells (hNPs) [27,32], organotypic cultures [29,33], neurospheres [34], and cerebral organoids [35]. These studies used different ZIKV strains, multiplicities of infection, and lengths of infection, and thus the extent of ZIKV infection ranged from 2.5% to 90% [27,[29][30][31][32][33][34][35]. Consistent with earlier reports of ZIKV infection in SH-SY5Y cells [80,81], immunofluorescence analyses revealed that 40% of cells were infected (Figure 1a,b).…”

Patterns of Herpes Simplex Virus 1 Infection in Neural Progenitor Cells

“…A fundamental aspect of adult neurogenesis is the ability of NPCs to migrate great distances through the parenchyma to reach damaged areas of the brain (19). Neurotropic viruses, such as HIV, human cytomegalovirus (HCMV), and Zika virus (20)(21)(22)(23), are known to alter migration behavior of NPCs, but the effect of HSV-1 on NPC migration is unknown. To investigate the effect of HSV-1 on NPC migration and whether HSV-1-induced alteration of NPC migration can be prevented by antiviral treatment, NPCs were infected at MOIs of 0.1 to 0.001 in the presence of 5BVdU-IFN-␣.…”

Network of Interactions between ZIKA Virus Non-Structural Proteins and Human Host Proteins

“…In these cells, ZIKV infection is followed by apoptosis, corroborating the hypothesis of ZIKV as the etiological agent of these neurological disorders [4,5,[10][11][12]. Further, independent studies have shown that the microcephaly and neural development-associated phenotypes is not a distinct feature of the Asian lineage [12][13][14][15][16]. However, the precise molecular mechanism(s) underlying these ZIKV-related manifestations is not understood.…”