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Shared Molecular Signatures Across Zika Virus Infection and Multiple Sclerosis Highlight AP-1 Transcription Factor as a Potential Player in Post-ZIKV MS-Like Phenotypes

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Abstract

Zika virus (ZIKV) is an arbovirus of the Flaviviridae genus that has rapidly disseminated from across the Pacific to the Americas. Robust evidence has indicated a crucial role of ZIKV in congenital virus syndrome, including neonatal microcephaly. Moreover, emerging evidence suggests an association between ZIKV infection and the development of an extensive spectrum of central nervous system inflammatory demyelinating diseases (CNS IDD), such as multiple sclerosis–like clinical phenotypes. However, the underlying mechanisms of host-pathogen neuro-immune interactions remain to be elucidated. This study aimed to identify common transcriptional signatures between multiple sclerosis (MS) and ZIKV infection to generate molecular interaction networks, thereby leading to the identification of deregulated processes and pathways, which could give an insight of these underlying molecular mechanisms. Our investigation included publicly available transcriptomic data from MS patients in either relapse or remission (RR-MS) and datasets of subjects acutely infected by ZIKV for both immune peripheral cells and central nervous system cells. The protein-protein interaction (PPI) analysis showed upregulated AP-1 transcription factors (JUN and FOS) among the top hub and bottleneck genes in RR-MS and ZIKV data. Gene enrichment analysis retrieved a remarkable presence of ontologies and pathways linked to oxidative stress responses, immune cell function, inflammation, interleukin signaling, cell division, and transcriptional regulation commonly enriched in both scenarios. Considering the recent findings concerning AP-1 function in immunological tolerance breakdown, regulation of inflammation, and its function as an oxidative stress sensor, we postulate that the ZIKV trigger may contribute as a boost for the activation of such AP-1-regulated mechanisms that could favor the development of MS-like phenotypes following ZIKV infection in a genetically susceptible individual.

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Data Availability

The original RR-MS dataset used for the current study is available online at https://academic.oup.com/hmg/article/20/18/3606/556655 under the Supplementary information section. The original ZIKV dataset reported in this paper was deposited to the NCBI GEO and is available under access code GSE101878. The lists of differentially expressed genes used as input in the current study and all the outputs of the PPI analysis, gene enrichment, and Gene Ontology are available online in the supplementary file section or upon reasonable request to the corresponding authors. The studies with CNS cells and peripheral immune cells used for comparison in this study that were retrieved from the GEO database can be found upon the following accession numbers: GSE207347, GSE131605, GSE113636, GSE93385, GSE87750, GSE80434, GSE78711, GSE132228, GSE93870, and GSE198542. The DEG lists from Schultz et al. (2021) and Gueddes et al. (2021) were retrieved directly from supplementary material of the primary studies.

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Acknowledgements

We thank Kennedy Bonjour for assistance with the scientific illustration in Fig. 8.

Funding

This research was supported by FINEP (Grant No. 01.16.0078.00) and Rede Nacional de Especialistas em ZIKA e Doenças Correlatas (RENEZIKA) (CNPq Number 440779/2016-2), Coordination for the Improvement of Higher Education Personnel (CAPES Number 88887.130752/2016- 00), Department of Science and Technology (DECIT No. 14/2016), Brazilian National Council for Scientific and Technological Development, and Foundation for Rio de Janeiro State Research (FAPERJ). Author EVS is supported by CAPES 88882.456162/2019-01.

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Authors and Affiliations

  1. Laboratório de Neurociências Translacional, Instituto Biomédico, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, Brazil

    Elielson Veloso da Silva, Fabrícia Lima Fontes-Dantas, Amanda Dutra & Soniza Vieira Alves-Leon

  2. Programa de pós-graduação em Medicina (Neurologia/Neurociências), Universidade Federal Fluminense, Rio de Janeiro, Brazil

    Elielson Veloso da Silva & Osvaldo J. M. Nascimento

  3. Departamento de Farmacologia e Psicobiologia, Instituto de Biologia Roberto Alcântara Gomes, Universidade Estadual do Rio de Janeiro, Rio de Janeiro, Brazil

    Fabrícia Lima Fontes-Dantas

  4. Programa de Engenharia de Sistemas e Computação-COPPE, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Thiago Viana Dantas

  5. Hospital Universitário Clementino Fraga Filho, Centro de Referência em Doenças Inflamatórias Desmielinizantes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Soniza Vieira Alves-Leon

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  2. Fabrícia Lima Fontes-Dantas
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  3. Thiago Viana Dantas
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  4. Amanda Dutra
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  5. Osvaldo J. M. Nascimento
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  6. Soniza Vieira Alves-Leon
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Contributions

All authors contributed to the study conception and design. Data collection and analysis were carried out by Elielson V Silva, Fabrícia Lima Fontes-Dantas, Thiago Viana Dantas, and Amanda Dutra. The first draft of the manuscript was written by Elielson V Silva, Fabrícia Lima Fontes-Dantas, and Soniza Vieira Alves-Leon, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Soniza Vieira Alves-Leon.

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This study was conducted using open-source transcriptome data.

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da Silva, E.V., Fontes-Dantas, F.L., Dantas, T.V. et al. Shared Molecular Signatures Across Zika Virus Infection and Multiple Sclerosis Highlight AP-1 Transcription Factor as a Potential Player in Post-ZIKV MS-Like Phenotypes. Mol Neurobiol 60, 4184–4205 (2023). https://doi.org/10.1007/s12035-023-03305-y

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