1. The Transcriptional and Protein Profile From Human Infected Neuroprogenitor Cells Is Strongly Correlated to Zika Virus Microcephaly Cytokines Phenotype Evidencing a Persistent Inflammation in the CNS.
- Author
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Lima MC, de Mendonça LR, Rezende AM, Carrera RM, Aníbal-Silva CE, Demers M, D'Aiuto L, Wood J, Chowdari KV, Griffiths M, Lucena-Araujo AR, Barral-Netto M, Azevedo EAN, Alves RW, Farias PCS, Marques ETA, Castanha PMS, Donald CL, Kohl A, Nimgaonkar VL, and Franca RFO
- Subjects
- Brazil, Cambodia, Cells, Cultured, Central Nervous System pathology, Central Nervous System virology, Chemokine CXCL10 cerebrospinal fluid, Chemokine CXCL10 immunology, Chemokine CXCL9 cerebrospinal fluid, Chemokine CXCL9 immunology, Cytokines analysis, Female, Gene Expression Profiling, Humans, Infant, Inflammation immunology, Inflammation pathology, Interferon-alpha cerebrospinal fluid, Interferon-alpha immunology, Interferon-beta immunology, Male, Microcephaly pathology, Pregnancy, Pregnancy Complications, Infectious virology, Virus Replication immunology, Zika Virus Infection immunology, Central Nervous System immunology, Induced Pluripotent Stem Cells cytology, Microcephaly immunology, Neural Stem Cells cytology, Zika Virus immunology
- 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.
- Published
- 2019
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