Ramundo Mariana Severo, da Fonseca Guilherme Cordenonsi, Ten-Caten Felipe, Gerber Alexandra L, Guimarães Ana Paula, Manuli Erika Regina, Côrtes Marina Farrel, Pereira Geovana Maria, Brustolini Otavio, Cabral Milena Gomes, Dos Santos Lázari Carolina, Brasil Patrícia, da Silveira Bressan Clarisse, Nakaya Helder I, Paranhos-Baccalà Gláucia, Vasconcelos Ana Tereza R, Sabino Ester Cerdeira
Departamento de Clínica Médica, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
Laboratório de Imunologia, LIM-19, Instituto do Coração (INCOR), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil, 05403-900.
Sci Rep. 2025 Feb 25;15(1):6745. doi: 10.1038/s41598-025-86761-x.
Chikungunya virus (CHIKV) infection often results in a chronic joint condition known as Post-Chikungunya Chronic Inflammatory Joint Disease (pCHIKV-CIJD). This condition disrupts individuals' daily lives and contributes to increased healthcare expenditure. This study investigated the molecular mechanisms underlying pCHIKV-CIJD development by analyzing RNA transcripts, including small RNAs, of whole blood from CHIKV-infected patients. By comparing patients who evolved to pCHIKV-CIJD with those who did not, we identified molecular signatures associated with chronification in acute and post-acute disease phases. These molecules were primarily associated with an altered immune response regulation. Notably, LIFR, an immune receptor that enhanced IL-6 transcription, was down-regulated in the acute phase of pCHIKV-CIJD patients, while its inhibitor, hsa-miR-98-5p, was up-regulated in these individuals. Other downregulated genes include members of immune mechanisms whose impairment can lead to a reduction in the first line of antiviral response, thereby promoting virus persistence for a longer period in these patients. Additionally, pCHIKV-CIJD patients exhibited reduced transcript levels of MMP8, LFT, and DDIT4, genes already implicated in the pathological process of other types of inflammatory arthritis and seemingly relevant for pCHIKV-CIJD development. Overall, our findings provide insights into the early molecular mechanisms involved in the chronification and highlight potential targets for further investigation.
基孔肯雅病毒（CHIKV）感染常常导致一种被称为基孔肯雅热后慢性炎症性关节病（pCHIKV-CIJD）的慢性关节疾病。这种疾病扰乱了个体的日常生活，并导致医疗保健支出增加。本研究通过分析基孔肯雅病毒感染患者全血中的RNA转录本（包括小RNA），来探究pCHIKV-CIJD发病的分子机制。通过比较发展为pCHIKV-CIJD的患者和未发展为此病的患者，我们确定了在急性和急性后期疾病阶段与疾病慢性化相关的分子特征。这些分子主要与免疫反应调节的改变有关。值得注意的是，在pCHIKV-CIJD患者的急性期，增强白细胞介素-6转录的免疫受体LIFR下调，而其抑制剂hsa-miR-98-5p在这些个体中上调。其他下调的基因包括免疫机制的成员，其功能受损可导致抗病毒反应的第一道防线减弱，从而促使病毒在这些患者体内持续更长时间。此外，pCHIKV-CIJD患者的基质金属蛋白酶8（MMP8）、肝纤维化指标（LFT）和DNA损伤诱导转录本4（DDIT4）的转录水平降低，这些基因已被证明与其他类型炎性关节炎的病理过程有关，似乎也与pCHIKV-CIJD的发病相关。总体而言，我们的研究结果为疾病慢性化所涉及的早期分子机制提供了见解，并突出了进一步研究的潜在靶点。
