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Ethanol suppresses HBV peptide-MHC Class I presentation on hepatocytes

乙醇抑制 HBV 肽-MHC I 类在肝细胞上的呈递

基本信息

批准号：
10457273
负责人：
Murali Ganesan
金额：
$ 13.67万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-10-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457273
关键词：
Acetaldehyde Affect Alcohol abuse Alcohol consumption Alcoholic Liver Diseases Alcohols Antigen Presentation Antigens Cell membrane Cell surface Cells Chronic Chronic Hepatitis Chronic Hepatitis B Cirrhosis Clinical Clinical Research Complex Cytosol Cytotoxic T-Lymphocytes Data Defect Endoplasmic Reticulum Ethanol Ethanol Metabolism Event Fibrosis General Population Golgi Apparatus HLA-A2 Antigen HepG2 Hepatic Hepatitis B Hepatitis B Infection Hepatitis B Virus Hepatocyte High Prevalence Human Immune Immune Targeting Immune response Immune system Impairment In Vitro Incidence Interferon Type II Interferons Lead Liver Major Histocompatibility Complex Masks Mediating Modality Mus Outcome Patients Peptides Persons Primary carcinoma of the liver cells Process Role Scheme Severities Site Surface TAP1 gene TAP2 gene Techniques Testing Viral Viral Antigens Virus Virus Diseases Virus Replication Work adaptive immune response alcohol abuser alcohol effect antigen processing antigenic peptide transporter base chronic liver disease cytotoxic CD8 T cells epidemiology study innovation insight multicatalytic endopeptidase complex novel particle peptide I prevent problem drinker protein transport reconstitution tapasin therapeutic development therapy development trafficking virus core

项目摘要

ABSTRACT Hepatitis B virus (HBV) infection is one of the leading causes of hepatic decompensation and hepatocellular carcinoma worldwide; approximately 400 million people are infected with HBV. Due to the high prevalence of alcohol consumption in the general population, a significant portion of chronic HBV patients are also chronic alcohol abusers. Alcohol intake prolongs HBV persistence leading to establishment of chronic hepatitis. The mechanisms of rapid HBV infection progression and severe outcomes in alcohol-consuming patients are not clear. The virus is not cytopathogenic, and effective clearance requires the induction of an adaptive immune response, mainly via virus-specific CD8+ cytotoxic T lymphocytes (CTLs), which recognize viral peptide-major histocompatibility complex (MHC) class I on infected hepatocytes. While many studies have focused on alcohol-induced impairments of the immune response, information on how alcohol masks the presentation of HBV peptide-MHC class I complex on infected hepatocyte surfaces for escaping recognition by CTLs is missing. Therefore, the main focus of this study is to understand the effects of ethanol metabolism on the expression of the HBV peptide-MHC class I complex on HBV-infected hepatocytes. The presentation of this complex on cell membranes requires antigen processing by proteasomes in the cytosol, loading of peptides into MHC class I, assembly of peptide-loading complex with transporters for antigen presentation (TAP), its stabilization by tapasin in endoplasmic reticulum, and trafficking of this complex via trans-Golgi to the hepatocyte surface. Almost all of these steps are interferon-gamma dependent. Recently, we have found that the ethanol metabolite, acetaldehyde (Ach), suppresses HBV core peptide 18-27 presentation on HBV+ hepatocytes, which is accompanied by dysregulation of proteasome function, reduction in TAP1/tapasin expression and Golgi fragmentation, all of which work in combination to impair HBV-MHC class I complex presentation on infected hepatocytes. Based on these preliminary data, we put forth the hypothesis that ethanol metabolism decreases the display of HBV peptide-MHC class I complex on the hepatocyte surface by impairing viral peptide cleavage by the proteasome and by disrupting peptide-MHC class I trafficking to the cell surface. We will utilize a variety of state-of-the art and innovative techniques to test our novel hypothesis. The three specific aims of the proposed study are to: 1) Examine the effects of ethanol metabolism and HBV on antigenic peptide processing for MHC class I-restricted antigen presentation on hepatocytes; 2) Determine how ethanol metabolism affects the trafficking of peptide loading complex for expressing HBV peptide-MHC class I on hepatocytes; 3) Validate the results of specific aims 1-2 using chimeric mice double-reconstituted with human hepatocytes and a human immune system. Completion of the proposed studies will help in the development of treatment modalities for preventing the persistence of hepatitis B in alcohol abusing patients.

摘要