Alves-Leon Soniza Vieira, Ferreira Cristina Dos Santos, Herlinger Alice Laschuk, Fontes-Dantas Fabricia Lima, Rueda-Lopes Fernanda Cristina, Francisco Ronaldo da Silva, Gonçalves João Paulo da Costa, de Araújo Amanda Dutra, Rêgo Cláudia Cecília da Silva, Higa Luiza Mendonça, Gerber Alexandra Lehmkuhl, Guimarães Ana Paula de Campos, de Menezes Mariane Talon, de Paula Tôrres Marcelo Calado, Maia Richard Araújo, Nogueira Bruno Miceli Gonzalez, França Laise Carolina, da Silva Marcos Martins, Naurath Christian, Correia Aline Saraiva da Silva, Vasconcelos Claudia Cristina Ferreira, Tanuri Amilcar, Ferreira Orlando Costa, Cardoso Cynthia Chester, Aguiar Renato Santana, de Vasconcelos Ana Tereza Ribeiro
Translational Neuroscience Laboratory, Rio de Janeiro State Federal University, Rio de Janeiro, Brazil.
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.
Front Genet. 2021 Mar 17;12:639364. doi: 10.3389/fgene.2021.639364. eCollection 2021.
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.
基孔肯雅病毒（CHIKV）是一种再度出现的虫媒病毒，它所引发的疾病主要特征为发热、皮疹和严重的持续性多关节痛，不过不到1%的病例会出现严重的神经学表现，如中枢神经系统（CNS）的炎症性脱髓鞘疾病（IDD），像急性播散性脑脊髓炎（ADEM）和广泛横贯性脊髓炎。与宿主反应和疾病严重程度相关的遗传因素仍知之甚少。在本研究中，我们进行了全外显子组测序（WES），以确定与CHIKV感染后CNS IDD临床表型结果相关的人类白细胞抗原（HLA）等位基因、基因和细胞途径。该队列包括345名患者，其中160名被确诊感染CHIKV。有6例出现了类似CNS IDD的神经学表现。对12名患者进行了WES数据分析，包括患有CNS IDD的病例以及6名没有任何神经学表现的CHIKV患者。我们在所有分析的外显子组中鉴定出29个携带罕见、致病性或可能致病性变异的候选基因。还确定了HLA等位基因，并且出现CNS IDD的患者与多发性硬化症（MS）和视神经脊髓炎谱系障碍（NMOSD）等疾病有共同特征。当将这些基因纳入基因本体分析时，检索到了与CNS IDD综合征相关的途径，这表明CHIKV诱导的CNS结果可能与其他神经疾病共享遗传背景。据我们所知：本研究是对CHIKV感染中CNS表型遗传危险因素的首次全基因组研究。我们的数据表明，与脱髓鞘疾病相关的HLA - DRB1等位基因也可能使CHIKV感染患者出现CNS IDD结果的风险增加。
