Department of Biochemistry and Medical Biotechnology, Calcutta School of Tropical Medicine, 108, C. R. Avenue, Kolkata, West Bengal, 700073, India.
Department of Microbiology, Virus Unit, Calcutta School of Tropical Medicine, 108, C. R. Avenue, Kolkata, West Bengal, 700073, India.
Eur J Clin Microbiol Infect Dis. 2021 Jul;40(7):1369-1381. doi: 10.1007/s10096-020-04125-x. Epub 2021 Jan 25.
Dengue (DENV) and chikungunya (CHIKV) viral infections trigger high patient morbidity and mortality. Mono-/co-infection of these viruses activates innate immune response, triggering Toll-like receptor (TLR) pathways. The present study investigated the differential role of TLR3, 7 and 8 single-nucleotide polymorphisms (SNPs) between mono- and co-infected Eastern Indian patients. Interaction of TLR polymorphic variants with signal peptidase complex (SPC18) was explored which might affect immune signalling against DENV/CHIKV infections. Out of 550 febrile symptomatic patients, 128 DENV-CHIKV co-infected samples were genotyped for eight SNPs of TLR3 (rs3775290-chr4:186083063), TLR7 (rs179008-chrX:12885540, rs5741880-chrX:12869297, rs179010-chrX:12884766, rs3853839-chrX:12889539) and TLR8 (rs5744080-chrX:12919685, rs3764879-chrX:12906578, rs3764880-chrX:12906707) by PCR-RFLP along with 157 healthy individuals. Statistical analysis established genotypic association of TLR SNPs with DENV-CHIKV co-infection, and difference between mono- and co-infected patients and their role in determining high viral load (HVL) during competitive viral replication among co-infected patients. In silico protein-protein docking evaluated interactive effect of TLR variants with SPC18. The findings revealed patients with CC genotypes of TLR7 and 8 SNPs were significantly susceptible towards co-infection, whereas specific genotypes of TLR7 and 8 imparted protection against co-infection. Differential analysis between mono-/co-infected patients revealed distinct genotypic distribution of TLR3, 7 and 8 SNPs. Co-infected patients with TT-rs179010 exhibited DENV-HVL, whereas CHIKV-HVL was detected among patients with other genotypes. Molecular docking of TLR7-rs179008 Q variant and TLR8-rs3764880 V variant with SPC18 generated better free binding energy. This study underlined the importance of TLR7 and 8 SNPs towards mono-/co-infection of DENV/CHIKV, with certain genotypes associated with co-infection susceptibility. Moreover, it suggested a probable role of specific genotypes of TLR7 and 8 polymorphisms imparting high dengue/chikungunya viral load among co-infected patients.
登革热（DENV）和基孔肯雅热（CHIKV）病毒感染会导致患者发病率和死亡率高。这些病毒的单/混合感染会激活先天免疫反应，触发 Toll 样受体（TLR）途径。本研究调查了 TLR3、7 和 8 单核苷酸多态性（SNP）在东印度单感染和混合感染患者之间的差异作用。还探索了 TLR 多态性变体与信号肽酶复合物（SPC18）的相互作用，这可能会影响针对 DENV/CHIKV 感染的免疫信号。在 550 名发热症状患者中，对 128 例 DENV-CHIKV 混合感染样本进行了 8 个 TLR3（rs3775290-chr4：186083063）、TLR7（rs179008-chrX：12885540、rs5741880-chrX：12869297、rs179010-chrX：12884766、rs3853839-chrX：12889539）和 TLR8（rs5744080-chrX：12919685、rs3764879-chrX：12906578、rs3764880-chrX：12906707）SNP 的 PCR-RFLP 基因型分析，并与 157 名健康个体进行了比较。统计分析确定了 TLR SNP 与 DENV-CHIKV 混合感染的遗传相关性，以及单感染和混合感染患者之间的差异及其在决定混合感染患者竞争病毒复制期间高病毒载量（HVL）中的作用。计算机模拟蛋白-蛋白对接评估了 TLR 变体与 SPC18 的相互作用效果。研究结果表明，TLR7 和 8 SNP 的 CC 基因型患者对混合感染明显易感，而 TLR7 和 8 的特定基因型对混合感染具有保护作用。单感染和混合感染患者之间的差异分析揭示了 TLR3、7 和 8 SNP 的不同基因型分布。携带 TT-rs179010 的混合感染患者表现出 DENV-HVL，而其他基因型的混合感染患者则检测到 CHIKV-HVL。TLR7-rs179008 Q 变体和 TLR8-rs3764880 V 变体与 SPC18 的分子对接产生了更好的自由结合能。本研究强调了 TLR7 和 8 SNP 对 DENV/CHIKV 单/混合感染的重要性，某些基因型与混合感染易感性有关。此外，它还表明 TLR7 和 8 多态性的某些特定基因型可能会导致混合感染患者的登革热/基孔肯雅热病毒载量升高。
