Xun Zhen, Yao Xiaobao, Zhu Chenggong, Ye Yuchen, Wu Songhang, Chen Tianbin, Zeng Yongbin, Lin Caorui, Yang Bin, Ou Qishui, Liu Can
Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Mater Today Bio. 2022 May 25;15:100302. doi: 10.1016/j.mtbio.2022.100302. eCollection 2022 Jun.
Currently, determining when to start antiviral therapy in patients with chronic HBV infection is a controversial issue. One crucial reason is that biomarkers for distinguishing the natural history of chronic HBV infection are unmet needs. In this study, we aimed to explore novel biomarkers and therapeutic targets for the diagnosis and treatment of chronic HBV infection by using tandem mass tag (TMT)-based quantitative proteomics approach. Here, we firstly revealed the serum proteomic characterization of the natural history of chronic HBV infection using multiplex TMT labeling coupled with liquid chromatography-mass spectrometry. Then, we verified the levels of differentially expressed proteins (DEPs) across a large number of clinical samples by enzyme-linked immunosorbent assay (ELISA). We found that DEPs over the different phases of chronic HBV infection were primarily involved in the biological process of leukocyte-mediated immunity. Patients with chronic hepatitis were characterized as having an up-regulated proteasome pathway, including upregulation of proteasome activator subunit 1 (PSME1) and proteasome subunit alpha type 7 (PSMA7) levels. In addition, immune tolerant phase patients were characterized by having the lowest ephrin-B2 (EFNB2) levels and highest heat responsive protein 12 (HRSP12) levels. Moreover, inactive HBV carrier state patients were characterized by having a down-regulated glycolysis/gluconeogenesis pathway, with especially low expression of related enzymes alpha-enolase (ENO1) and fructose-1,6-bisphosphatase 1 (FBP1). What's more, HBeAg-negative chronic hepatitis patients were characterized as having the highest interleukin 18 binding protein (IL-18BP) levels. Thus, our results provide several potential diagnostic biomarkers for distinguishing the natural history of chronic HBV infection, such as PSME1, PSMA7, EFNB2, ENO1, and IL-18BP, and also present potential therapeutic interventions for chronic hepatitis B patients, such as targeting the proteasome or glycolysis/gluconeogenesis pathways. Our findings shed new light on the development of novel diagnostic biomarkers and therapeutic targets for the diagnosis and treatment of chronic HBV infection.
目前，确定慢性乙型肝炎病毒（HBV）感染患者何时开始抗病毒治疗是一个存在争议的问题。一个关键原因是，用于区分慢性HBV感染自然史的生物标志物尚未得到满足。在本研究中，我们旨在通过基于串联质谱标签（TMT）的定量蛋白质组学方法，探索用于慢性HBV感染诊断和治疗的新型生物标志物和治疗靶点。在此，我们首先使用多重TMT标记结合液相色谱-质谱法揭示了慢性HBV感染自然史的血清蛋白质组特征。然后，我们通过酶联免疫吸附测定（ELISA）在大量临床样本中验证了差异表达蛋白（DEP）的水平。我们发现，慢性HBV感染不同阶段的DEP主要参与白细胞介导的免疫生物学过程。慢性肝炎患者的特征是蛋白酶体途径上调，包括蛋白酶体激活剂亚基1（PSME1）和蛋白酶体亚基α7型（PSMA7）水平升高。此外，免疫耐受期患者的特征是 Ephrin-B2（EFNB2）水平最低，热反应蛋白12（HRSP12）水平最高。此外，HBV携带者状态患者的特征是糖酵解/糖异生途径下调，相关酶α-烯醇化酶（ENO1）和果糖-1,6-二磷酸酶1（FBP1）的表达尤其低。此外，HBeAg阴性慢性肝炎患者的特征是白细胞介素18结合蛋白（IL-18BP）水平最高。因此，我们的结果提供了几种用于区分慢性HBV感染自然史的潜在诊断生物标志物，如PSME1、PSMA7、EFNB2、ENO1和IL-18BP，也为慢性乙型肝炎患者提供了潜在的治疗干预措施，如靶向蛋白酶体或糖酵解/糖异生途径。我们的研究结果为慢性HBV感染的诊断和治疗中新型诊断生物标志物和治疗靶点的开发提供了新的思路。
