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,Bruno Miceli Gonzalez Nogueira,Aline Saraiva Da Silva Correia,Cláudia Cecília Da Silva Rêgo,Alice Laschuk Herlinger,Marcos Martins Da Silva,Fernanda Cristina Rueda-Lopes,Laise Carolina França,Cristina Dos Santos Ferreira,Mariane Talon De Menezes,Alexandra Lehmkuhl Gerber,Ana Tereza Ribeiro De Vasconcelos,Marcelo Calado De Paula Tôrres,Cynthia Chester Cardoso,Ronaldo Da Silva Francisco,Renato Santana Aguiar,João Paulo Da Costa Gonçalves,Christian Naurath,Amanda Dutra De Araújo,Amílcar Tanuri ,Ana Paula Guimarães ,Richard Araujo Maia ,Fabrícia Lima Fontes-Dantas ,Orlando C Ferreira ,Cláudia Cristina Ferreira Vasconcelos ,Luiza M Higa

doi:10.3389/fgene.2021.639364

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.

Highlights

Chikungunya fever is typically described as a mild disease in which clinical symptoms are mainly related to articular pain and general malaise (Burt et al, 2017)
All patients with central nervous system (CNS) inflammatory demyelinating diseases (IDD) phenotype underwent imaging which showed the extent of the inflammatory lesion (Figure 1, Supplementary Figures 3–8)
It is believed that infections can trigger such demyelinating lesions by the activation of autoreactive T cells, with primary events taking place outside the CNS further initiating pathogenic T cell reactivation within the CNS, or by molecular mimicry and developing an autoantibody response (Salvetti et al, 2009; Delogu et al, 2011; Anaya et al, 2016; Burnard et al, 2017)

Summary

Introduction

Chikungunya fever is typically described as a mild disease in which clinical symptoms are mainly related to articular pain and general malaise (Burt et al, 2017). CHIKV infection is considered endemic in the Southeast Region of Brazil, with 1,159.4 cases/100,000 inhabitants having been registered in 2019 (BRASIL, 2020). Involvement of central and peripheral nervous systems has been reported in 0.3 to 1% (Cerny et al, 2017; Anand et al, 2019), which are considered atypical manifestations of CHIKV. The central nervous system (CNS) manifestations during CHIKV infections seem not to be different from other viruses like the Zika virus (Alves-Leon et al, 2019). White and gray matter are frequently affected in CNS cases and clinical findings sometimes mimic inflammatory demyelinating diseases (IDD) of the brain and spinal cord, mainly with clinical phenotypes of acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), longitudinal extensive myelitis, multifocal myelitis, optic neuritis, and neuromyelitis optic spectrum disorders (NMOSD) (Mehta et al, 2018)

Methods

Results

Conclusion