Exome-Wide Search for Genes Associated With Central Nervous System Inflammatory Demyelinating Diseases Following CHIKV Infection: The Tip of the Iceberg

Soniza Vieira Alves-Leon; Cristina Dos Santos Ferreira; Alice Laschuk Herlinger; Fabricia Lima Fontes-Dantas; Fernanda Cristina Rueda-Lopes; Ronaldo da Silva Francisco Jr; João Paulo da Costa Gonçalves; Amanda Dutra de Araújo; Cláudia Cecília da Silva Rêgo; Luiza Mendonça Higa; Alexandra Lehmkuhl Gerber; Ana Paula de Campos Guimarães; Mariane Talon de Menezes; Marcelo Calado de Paula Tôrres; Richard Araújo Maia; Bruno Miceli Gonzalez Nogueira; Laise Carolina França; Marcos Martins da Silva; Christian Naurath; Aline Saraiva da Silva Correia; Claudia Cristina Ferreira Vasconcelos; Amilcar Tanuri; Orlando Costa Ferreira Jr; Cynthia Chester Cardoso; Renato Santana Aguiar; Ana Tereza Ribeiro de Vasconcelos

doi:10.3389/fgene.2021.639364

Exome-Wide Search for Genes Associated With Central Nervous System Inflammatory Demyelinating Diseases Following CHIKV Infection: The Tip of the Iceberg

Front Genet. 2021 Mar 17:12:639364. doi: 10.3389/fgene.2021.639364. eCollection 2021.

Authors

Soniza Vieira Alves-Leon^{1

2}, Cristina Dos Santos Ferreira³, Alice Laschuk Herlinger⁴, Fabricia Lima Fontes-Dantas¹, Fernanda Cristina Rueda-Lopes⁵, Ronaldo da Silva Francisco Jr³, João Paulo da Costa Gonçalves^{1

2}, Amanda Dutra de Araújo^{1

2}, Cláudia Cecília da Silva Rêgo^{1

2}, Luiza Mendonça Higa⁴, Alexandra Lehmkuhl Gerber³, Ana Paula de Campos Guimarães³, Mariane Talon de Menezes⁴, Marcelo Calado de Paula Tôrres⁴, Richard Araújo Maia⁴, Bruno Miceli Gonzalez Nogueira¹, Laise Carolina França¹, Marcos Martins da Silva⁶, Christian Naurath⁷, Aline Saraiva da Silva Correia⁷, Claudia Cristina Ferreira Vasconcelos⁸, Amilcar Tanuri⁴, Orlando Costa Ferreira Jr⁴, Cynthia Chester Cardoso⁴, Renato Santana Aguiar⁹, Ana Tereza Ribeiro de Vasconcelos³

Affiliations

¹ Translational Neuroscience Laboratory, Rio de Janeiro State Federal University, Rio de Janeiro, Brazil.
² Department of Neurology/Reference and Research Center for Multiple Sclerosis and Other Central Nervous System Idiopathic Demyelinating Inflammatory Diseases, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
³ Bioinformatics Laboratory, National Laboratory for Scientific Computing, Petrópolis, Brazil.
⁴ Molecular Virology Laboratory, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
⁵ Department of Radiology, Antônio Pedro University Hospital, Fluminense Federal University, Niterói, Brazil.
⁶ Department of Clinical Medicine, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
⁷ Federal Hospital Cardoso Fontes, Ministry of Health, Rio de Janeiro, Brazil.
⁸ Department of Neurology, University Hospital Gafrée e Guinle, Rio de Janeiro State Federal University, Rio de Janeiro, Brazil.
⁹ Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.

Abstract

Chikungunya virus (CHIKV) is a re-emergent arbovirus that causes a disease characterized primarily by fever, rash and severe persistent polyarthralgia, although <1% of cases develop severe neurological manifestations such as inflammatory demyelinating diseases (IDD) of the central nervous system (CNS) like acute disseminated encephalomyelitis (ADEM) and extensive transverse myelitis. Genetic factors associated with host response and disease severity are still poorly understood. In this study, we performed whole-exome sequencing (WES) to identify HLA alleles, genes and cellular pathways associated with CNS IDD clinical phenotype outcomes following CHIKV infection. The cohort includes 345 patients of which 160 were confirmed for CHIKV. Six cases presented neurological manifestation mimetizing CNS IDD. WES data analysis was performed for 12 patients, including the CNS IDD cases and 6 CHIKV patients without any neurological manifestation. We identified 29 candidate genes harboring rare, pathogenic, or probably pathogenic variants in all exomes analyzed. HLA alleles were also determined and patients who developed CNS IDD shared a common signature with diseases such as Multiple sclerosis (MS) and Neuromyelitis Optica Spectrum Disorders (NMOSD). When these genes were included in Gene Ontology analyses, pathways associated with CNS IDD syndromes were retrieved, suggesting that CHIKV-induced CNS outcomesmay share a genetic background with other neurological disorders. To our knowledge, this study was the first genome-wide investigation of genetic risk factors for CNS phenotypes in CHIKV infection. Our data suggest that HLA-DRB1 alleles associated with demyelinating diseases may also confer risk of CNS IDD outcomes in patients with CHIKV infection.

Keywords: HLA alleles; acute disseminated encephalomyelitis; chikungunya; inflammatory demyelinating diseases; myelitis; neurological manifestations in viral infection; pathogenic variants; whole exome sequence.

Copyright © 2021 Alves-Leon, Ferreira, Herlinger, Fontes-Dantas, Rueda-Lopes, Francisco, Gonçalves, de Araújo, Rêgo, Higa, Gerber, Guimarães, de Menezes, de Paula Tôrres, Maia, Nogueira, França, da Silva, Naurath, Correia, Vasconcelos, Tanuri, Ferreira, Cardoso, Aguiar and de Vasconcelos.