Ravi Varsha, Imran Md, Khare Kriti, Mishra Pallavi, Mohite Ramakant, Khan Md Abuzar, Swaminathan Aparna, Yadav Aanchal, Sinha Sristi, Shukla Richa, Chattopadhyay Partha, Soni Jyoti, Maurya Ranjeet, Sethi Tavpritesh, Tarai Bansidhar, Budhiraja Sandeep, Pandey Rajesh
INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) Laboratory, Division of Immunology and Infectious Disease Biology, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), North Campus, Near Jubilee Hall, Mall Road, New Delhi, Delhi, 110017, India.
Indraprastha Institute of Information Technology, New Delhi, Delhi, 110020, India.
Sci Rep. 2025 May 28;15(1):18724. doi: 10.1038/s41598-025-00462-z.
Transmission of the dengue virus (DENV) places a huge burden on public health in several endemic regions. Like other RNA viruses, mutations in the DENV genome greatly governs its virulence, transmissibility, and interaction with the host immune system. Present study focuses on integrated analysis of mutation and clinical data accompanied at the onset of dengue fever. The findings from the associated clinical data with the variants of the DENV are critical for early detection of the disease and understanding the disease progression. RNA was isolated from the 1310 serum samples collected from the NS1-antigen positive dengue patients. Serotyping reveals that DENV-2 was predominant in circulation. The genome of 1305 DENV-2 was sequenced using Oxford Nanopore Technology and Illumina platforms. A total of 1023 DENV-2 demonstrated > 50% genome coverage. Mutation analysis across the 1023 DENV-2 genomes yielded a total of 2667 mutations including 627 non-synonymous and 2040 synonymous mutations. We observed a notable over-representation of synonymous mutations in prM and ancC genes while a higher occurrence of non-synonymous mutations was found in ancC, prM, and M proteins. Comparison of mutation frequency between mild and severe demonstrates higher mutation frequency in severe phenotype. Moreover, we observed a total of 56 significant mutations including 23 in severe, 17 in moderate and 16 in mild. The E-protein having non-synonymous mutations were docked with DC-SIGN with lower binding energy (ΔG = - 11.9 kcal/mol) for severe as compared to mild (ΔG = - 13.5 kcal/mol), suggesting lesser affinity of E-protein and DC-SIGN in case of severe as compared to the mild. We have identified the core set of high frequency mutations significantly associated with distinct dengue disease severity viz., mild, moderate and severe. Furthermore, in-silico protein modelling and docking studies demonstrate the potential functional role of the non-synonymous mutations identified across E-protein in severe dengue.
登革病毒（DENV）的传播给多个流行地区的公共卫生带来了巨大负担。与其他RNA病毒一样，DENV基因组中的突变极大地决定了其毒力、传播能力以及与宿主免疫系统的相互作用。本研究重点关注登革热发病时伴随的突变与临床数据的综合分析。DENV变体相关临床数据的研究结果对于疾病的早期检测和了解疾病进展至关重要。从1310份NS1抗原阳性登革热患者的血清样本中分离出RNA。血清分型显示，DENV-2在流行中占主导地位。使用牛津纳米孔技术和Illumina平台对1305个DENV-2的基因组进行了测序。共有1023个DENV-2的基因组覆盖率>50%。对1023个DENV-2基因组进行的突变分析共产生了2667个突变，其中包括627个非同义突变和2040个同义突变。我们观察到prM和ancC基因中同义突变明显过度，而在ancC、prM和M蛋白中发现非同义突变的发生率更高。轻度和重度患者之间的突变频率比较表明，严重表型中的突变频率更高。此外，我们总共观察到56个显著突变，其中严重患者中有23个，中度患者中有17个，轻度患者中有16个。与轻度患者（ΔG = -13.5 kcal/mol）相比，具有非同义突变的E蛋白与DC-SIGN对接时，严重患者的结合能较低（ΔG = -11.9 kcal/mol），这表明严重患者中E蛋白与DC-SIGN的亲和力低于轻度患者。我们已经确定了与不同登革热疾病严重程度（即轻度、中度和重度）显著相关的高频突变核心集。此外，计算机模拟蛋白质建模和对接研究证明了在严重登革热中E蛋白上鉴定出的非同义突变的潜在功能作用。
