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

Lima, M. C. et al. (2019) 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. Frontiers in Immunology, 10, 1928. (doi: 10.3389/fimmu.2019.01928) (PMID:31474994) (PMCID:PMC6707094)

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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.

Item Type:Articles
Additional Information:The research leading to these results received funding from the Fundação de Amparo à Ciência e Tecnologia de Pernambuco/FACEPE, grant agreement nos. APQ-0055.2.11/16 and APQ-0044.2.11/16, and Conselho Nacional de Desenvolvimento Científico e Tecnológico/CNPq grant agreement 439975/2016-6 under RF coordination and responsibility. VN received grant support from the Stanley Medical Research Institute (07R-1712), National Institutes of Health (MH63480 and D43 TW009114) and Cura Zika—University of Pittsburgh.
Keywords:Immunology, Zika virus, central nervous system, inflammation, type-I interferon, interferonopathy, microcephaly, Zika congenital syndrome and cytokines.
Glasgow Author(s) Enlighten ID:Donald, Dr Claire and Kohl, Professor Alain
Authors: Lima, M. C., Mendonça, L. R. d., Rezende, A. M., Carrera, R. M., Aníbal-Silva, C. E., Demers, M., D'Aiuto, L., Wood, J., Chowdari, K. V., Griffiths, M., Lucena-Araujo, A. R., Barral-Netto, M., Azevedo, E. A. N., Alves, R. W., Farias, P. C. S., Marques, E. T. A., Castanha, P. M. S., Donald, C. L., Kohl, A., Nimgaonkar, V. L., and Franca, R. F. O.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Frontiers in Immunology
Publisher:Frontiers Media
ISSN (Online):1664-3224
Copyright Holders:Copyright © 2019 Lima, Mendonça, Rezende, Carrera, Aníbal-Silva, Demers, D’Aiuto, Wood, Chowdari, Griffiths, Lucena-Araujo, Barral-Netto, Azevedo, Alves, Farias, Marques, Castanha, Donald, Kohl, Nimgaonkar and Franca
First Published:First published in Frontiers in Immunology 10: 1928
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656551Arbovirus interactions with arthropod hostsAlain KohlMedical Research Council (MRC)MC_UU_12014/8MVLS III - CENTRE FOR VIRUS RESEARCH
172580The emergence of Zika virus in Brazil: investigating prevalence and host responses to design preventive strategiesAlain KohlMedical Research Council (MRC)MR/N017552/1III-MRC-GU Centre for Virus Research