ICMR Consultant and Scientist G, National Institute of Virology, Pune, India.
J Viral Hepat. 2018 Dec;25(12):1617-1623. doi: 10.1111/jvh.12980. Epub 2018 Sep 19.
Hepatitis E infection caused by hepatitis E virus (HEV), a major public health concern in developing countries, is responsible for sporadic and epidemic acute viral hepatitis in adults. Pathogenesis of hepatitis E infection is poorly understood. Toll-like receptors (TLRs) are the key players of innate immunity recognize pathogen-associated molecular patterns (PAMPs). Previously, we found higher TLR4 expression (at protein and gene level) with impaired cytokine response upon stimulus of PBMCs with LPS in HEV-infected patients. In view of the earlier observations of the association of polymorphisms in TLR4 genes (A299G, C399T) with liver diseases, we investigated TLR4 polymorphisms in HEV-infected patients. We observed the significant association of TLR4-399CC and CT alleles with hepatitis E (both subclinical and acute patients). Carrier frequency of TLR4-399 CT was lower in patients' categories in comparison with the controls. Higher frequency of allele TLR4-399C significantly correlated with disease progression. Acute hepatitis E patients showed the higher frequency of CG and TA haplotypes, while the rare haplotype (TG) was more frequent in controls. The other single nucleotide polymorphism (SNP) at TLR4-299 (A>G) did not show any difference. We report here for the first time the association of TLR4 polymorphism with hepatitis E and suggest that TLR 4 hyporesponsiveness during HEV infection might be related to its polymorphism.
戊型肝炎感染由戊型肝炎病毒(HEV)引起,是发展中国家主要的公共卫生关注问题,可导致成人散发性和流行性急性病毒性肝炎。戊型肝炎感染的发病机制尚未完全清楚。Toll 样受体(TLR)是先天免疫的关键参与者,可识别病原体相关分子模式(PAMPs)。此前,我们发现戊型肝炎感染患者的外周血单核细胞(PBMCs)受到脂多糖(LPS)刺激时,TLR4 表达(在蛋白和基因水平上)更高,细胞因子反应受损。鉴于 TLR4 基因(A299G、C399T)多态性与肝脏疾病的关联较早被观察到,我们研究了戊型肝炎感染患者的 TLR4 多态性。我们观察到 TLR4-399CC 和 CT 等位基因与戊型肝炎(包括亚临床和急性患者)显著相关。与对照组相比,TLR4-399 CT 携带者频率在患者各分类中较低。等位基因 TLR4-399C 的更高频率与疾病进展显著相关。急性戊型肝炎患者显示出 CG 和 TA 单倍型的更高频率,而罕见的单倍型(TG)在对照组中更为频繁。TLR4-299(A>G)的另一个单核苷酸多态性(SNP)没有显示出任何差异。我们首次报道了 TLR4 多态性与戊型肝炎的关联,并提出 TLR4 在 HEV 感染期间的低反应性可能与其多态性有关。