Abstract
Growing evidences have associated Zika virus (ZIKV) infection with congenital malformations, including microcephaly. Nonetheless, signaling mechanisms that promote the disease outcome are far from being understood, affecting the development of suitable therapeutics. In this study, we applied shotgun mass spectrometry (MS)-based proteomics combined with cell biology approaches to characterize altered molecular pathways on human neuroprogenitor cells (NPC) and neurons derived from induced pluripotent stem cells infected by ZIKV-BR strain, obtained from the 2015 Brazilian outbreak. Furthermore, ZIKV-BR infected NPCs showed unique alteration of pathways involved in neurological diseases, cell death, survival and embryonic development compared to ZIKV-AF, showing a human adaptation of the Brazilian viral strain. Besides, infected neurons differentiated from NPC presented an impairment of neurogenesis and synaptogenesis processes. Taken together, these data explain that CNS developmental arrest observed in Congenital Zika Syndrome is beyond neuronal cell death.
Highlights
Zika Virus (ZIKV) is a flavivirus first isolated in non-human primate in 1947 in the ZIKA Forest in Uganda (Dick et al, 1952)
To identify altered molecular pathways affected in CNS cells upon Zika virus (ZIKV) infection, we generated human neural progenitor cells (NPCs) and neurons from iPSCs and infected these with ZIKVBR and the MR-766 strain (ZIKV-AF) (Figure 1)
NPCs were cultured as 3D-neurospheres (NS) and a comprehensive MSbased quantitative proteomics approach was applied after 96 h of ZIKV-AF, ZIKV-BR (1 MOI), or vehicle (MOCK) exposure (Figure 2A and Supplementary Figure S1A)
Summary
Zika Virus (ZIKV) is a flavivirus first isolated in non-human primate in 1947 in the ZIKA Forest in Uganda (Dick et al, 1952). From 1960’s until recent past, ZIKV infection were described to be either asymptomatic or associated with conjunctivitis, fever, maculopapular rash, and arthralgia (Duffy et al, 2009). ZIKV infection has been associated with a congenital syndrome in newborns called Congenital Zika Syndrome (CZS) (Cugola et al, 2016; Franca et al, 2016), which is characterized by a congenital malformation spectrum including microcephaly, intracranial. Zika Virus Impairs Human Synaptogenesis calcifications, eye abnormalities or other congenital central nervous system-related abnormalities (Franca et al, 2016; Kindhauser et al, 2016; Alvarado and Schwartz, 2017). Neural progenitor cells (NPC) seem to be the main affected population by ZIKV with consequent cell death (Cugola et al, 2016; Chavali et al, 2017), impairment of cell cycle progression (Tang et al, 2016), premature differentiation and defective cell division (Gabriel et al, 2017) leading to depletion of neural progenitors of the cortical layer
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