Abstract
Zika virus (ZIKV) infection during pregnancy is associated with microcephaly, a congenital malformation resulting from neuroinflammation and direct effects of virus replication on the developing central nervous system (CNS). However, the exact changes in the affected CNS remain unknown. Here, we show by transcriptome analysis (at 48 h post-infection) and multiplex immune profiling that human induced-neuroprogenitor stem cells (hiNPCs) respond to ZIKV infection with a strong induction of type-I interferons (IFNs) and several type-I IFNs stimulated genes (ISGs), notably cytokines and the pro-apoptotic chemokines CXCL9 and CXCL10. By comparing the inflammatory profile induced by a ZIKV Brazilian strain with an ancestral strain isolated from Cambodia in 2010, we observed that the response magnitude differs among them. Compared to ZIKV/Cambodia, the experimental infection of hiNPCs with ZIKV/Brazil resulted in a diminished induction of ISGs and lower induction of several cytokines (IFN-α, IL-1α/β, IL-6, IL-8, and IL-15), consequently favoring virus replication. From ZIKV-confirmed infant microcephaly cases, we detected a similar profile characterized by the presence of IFN-α, CXCL10, and CXCL9 in cerebrospinal fluid (CSF) samples collected after birth, evidencing a sustained CNS inflammation. Altogether, our data suggest that the CNS may be directly affected due to an unbalanced and chronic local inflammatory response, elicited by ZIKV infection, which contributes to damage to the fetal brain.
Highlights
Congenital Zika Syndrome (CZS) comprise a wide spectrum of birth defects and symptoms observed in infants who have been exposed to Zika virus (ZIKV) during embryonic development [1]
Our findings suggest an important role of type-I interferon (IFN) response and chemokines CXCL10 and CXCL9 in the pathogenesis of microcephaly, which may represent a still unaddressed target with the potential to interrupt the destructive central nervous system (CNS) inflammation induced by ZIKV infection
Comparative analysis of the transcriptional signature of infected human induced-neuroprogenitor stem cells (hiNPCs) demonstrated that ZIKV/Cambodia infection resulted in a higher modulation of specific gene clusters, including several C-X-C motif chemokines and type-I IFN response genes (Figures 1C,D)
Summary
Congenital Zika Syndrome (CZS) comprise a wide spectrum of birth defects and symptoms observed in infants who have been exposed to Zika virus (ZIKV) during embryonic development [1]. Other minor abnormalities have been documented, the most dramatic symptoms are microcephaly, severe microcephaly, arthrogryposis, and ocular damage [2]. Associated with ZIKV infection in pregnancy was first reported in Brazil in 2015 during a large outbreak of this virus [5]. Initial associations between ZIKV infection and microcephaly development were based on the identification of viral RNA in fetal amniotic fluid [6] and in the brain tissue of fetuses and infants diagnosed with microcephaly [7, 8]. Several reports from independent groups confirmed the association between ZIKV infection during pregnancy and congenital abnormalities [9]
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