Chaudhary Nidhi, Srivastava Shikha, Dave Upma, Ojha Amrita, Guchhait Prasenjit, Chandele Anmol, Patel Ashok Kumar
Kusuma School of Biological Sciences, Indian Institute of Technology New Delhi, India.
Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India; Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, FL, 33458, USA.
Virus Res. 2022 Feb;309:198668. doi: 10.1016/j.virusres.2021.198668. Epub 2021 Dec 29.
Dengue virus (DENV) is most prevalent arthropod-borne human pathogen belongs to Flaviviridae family causes thousands of deaths annually. HMGB1 is highly conserved, ubiquitously expressed, non-histone nuclear protein which plays important role in diseases like metabolic disorders, cancer, and viral infections. However, the importance of HMGB1 in DENV infection is understudied. In this study, we observed that DENV-2 induces cytoplasmic translocation and secretion of HMGB1. Interestingly, inhibition of HMGB1 secretion by ethyl pyruvate (EP) enhanced viral propagation while silencing of HMGB1 resulted in abrogated viral replication in DENV-2 infected A549 cells. RNA-Electrophoretic mobility shift assay and immunoprecipitation showed that HMGB1 interacts with 5'-3' UTRs of DENV-2 genome. This interaction further stimulates production of proinflammatory cytokines like TNF-α, IL-6 and IL-1β which have been implicated in pathogenesis of severe DENV disease. Together, our finding suggests that DENV-2 modulates HMGB1 translocation and HMGB1-DENV-2 UTRs RNA interaction further induces proinflammatory cytokines production in A549 cells. This study discloses HMGB1 as an important host factor contributing to disease pathogenesis and hence can be targeted as an alternative approach for antiviral development against DENV virus infection.
登革病毒（DENV）是最常见的节肢动物传播的人类病原体，属于黄病毒科，每年导致数千人死亡。高迁移率族蛋白B1（HMGB1）是一种高度保守、广泛表达的非组蛋白核蛋白，在代谢紊乱、癌症和病毒感染等疾病中发挥重要作用。然而，HMGB1在登革病毒感染中的重要性尚未得到充分研究。在本研究中，我们观察到DENV-2诱导HMGB1的细胞质转位和分泌。有趣的是，丙酮酸乙酯（EP）对HMGB1分泌的抑制增强了病毒的传播，而HMGB1的沉默导致DENV-2感染的A549细胞中病毒复制被消除。RNA电泳迁移率变动分析和免疫沉淀表明，HMGB1与DENV-2基因组的5'-3'非翻译区相互作用。这种相互作用进一步刺激了促炎细胞因子如肿瘤坏死因子-α、白细胞介素-6和白细胞介素-1β的产生，这些细胞因子与严重登革病毒疾病的发病机制有关。总之，我们的研究结果表明，DENV-2调节HMGB1的转位，并且HMGB1-DENV-2非翻译区RNA相互作用进一步诱导A549细胞中促炎细胞因子的产生。本研究揭示了HMGB1是导致疾病发病机制的重要宿主因子，因此可以作为针对登革病毒感染的抗病毒开发的替代方法的靶点。
