Document text
Principal Investigator: NATALIA ALEKSANDR OSNA
Organization: UNIVERSITY OF NEBRASKA MEDICAL CENTER
Fiscal Year: 2023
Award: $241,763
Funding agency: National Institute on Alcohol Abuse and Alcoholism
This project is a part of a P50 grant on exposome and alcohol. It is focused on understanding the innate
immunity mechanisms, by which environmental exposure to ethanol metabolites increases the levels of
hepatitis B viral (HBV) infection and promotes its persistence and liver injury. Despite a prophylactic vaccine
availability, the number of chronic HBV carriers is estimated to be as high as 250 million worldwide, with an
annual death rate of 800,000. The incidences of chronic HBV -infection, the viral load and the outcomes of
end-stage diseases are higher in hepatitis B patients abusing alcohol, but the mechanisms behind these
events are still unclear. Here, we will study how exposures to virus, alcohol and unsaturated fatty acids affect
interferon (IFN) response in hepatocytes. We will also study the protective effect of macrophages on the
activation of interferon-stimulated genes (ISGs) and the reduction of HBV levels in hepatocytes. One anti-viral
ISGs, APOBEC3G, is of special importance since it degrades HBV cccDNA. This macrophage-hepatocyte
communication is mediated via extracellular vesicles (EVs). However, the protective effects of EVs secreted
from macrophages may be ruined when cells are exposed to alcohol. High-fat diet further exacerbates hepatitis
B pathogenesis enhanced by alcohol. Our central hypothesis is: that exposure to ethanol metabolites impairs
interferon signaling in HBV-infected hepatocytes and virus-activated macrophages both directly, via limiting
anti-viral ISG induction, and indirectly, via disrupting the protective EV-mediated crosstalk between
macrophages and hepatocytes, thereby promoting intrahepatic viral spread and enhanced pathogenesis. The
suppressive effects of ethanol on innate immunity in HBV-expressing hepatocytes may be further enhanced by
cell exposure to unsaturated fatty acids. For this study, we proposed 3 Aims:
Aim 1: To study the regulation of HBV-infection in hepatocytes by the activation of ISGs via the RIG1-MAVS-
IRF3 or the cGAS-STING-IRF3 and the JAK-STAT1/2 pathways under exposure to ethanol metabolites and
unsaturated fatty acids.
Aim 2: In the settings of alcohol and unsaturated fatty acid exposures, to assess the EV-mediated crosstalk
between HBV-infected hepatocytes and macrophages, which regulates anti-viral protection by innate immunity.
Aim 3: To elucidate the contribution of ethanol and high-fat diet to HBV expression, ISG induction, and liver
steatosis/inflammation in transgenic HBV-replicating mice, and to study whether these exposures affect other
organs/tissues (lung, heart, spleen, pancreas, adipose tissue) in these mice.
The obtained information has the strong potential to be translated to clinical practice and interventions through
the development of biomarkers for innate immunity dysfunction and the identification of possible treatment
targets.
Terms: <APOBEC3G><APOCEC3G gene><Absolute ethanol><Acceleration><Adipose tissue><Affect><Alcohol Chemical Class><Alcohol Drinking><Alcohol abuse><Alcohol consumption><Alcoholic Liver Diseases><Alcohols><Animal Model><Animal Models and Related Studies><Antigens><Apolipoprotein B mRNA-Editing Enzyme, Catalytic Polypeptide-Like 3G><Attenuated><Body Tissues><CEM15><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell-Mediated Lympholytic Cells><Cells><Chronic Hepatitis B><Circulation><Clinical><Clinical Trials><Communication><Complex><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Death Rate><Development><Dysfunction><ETOH><Environmental Exposure><EtOH abuse><EtOH drinking><EtOH use><Ethanol><Ethyl Alcohol><Event><Exposure to><FLJ12740><Fats><Fatty Acids><Fatty Liver><Fatty Tissue><Fatty acid glycerol esters><Feedback><Functional disorder><Future><Genes><Goals><Grain Alcohol><Grant><Heart><Hepatic Cells><Hepatic Parenchymal Cell><Hepatitis B><Hepatocyte><High Fat Diet><IFN><IFN activation><IFN-regulatory factor 3><IRF-3 protein><IRF3><IRF3 gene><Immune><Immune Cell Activation><Immunes><Impairment><Incidence><Infection><Inflammation><Injury to Liver><Innate Immunity><Interferon Activation><Interferon Regulatory Factor 3><Interferons><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigators><Liver><Liver Cells><Liver Steatosis><Lung><Lung Respiratory System><MDS019><Macrophage><Malignant Neoplasms><Malignant Tumor><Mediating><Methylcarbinol><Mice><Mice Mammals><Modality><Monitor><Murine><Mus><Mφ><Native Immunity><Natural Immunity><Nebraska><Non-Specific Immunity><Nonspecific Immunity><Organ><Outcome><Pancreas><Pancreatic><Pathogenesis><Pathology><Pathway interactions><Patients><Phorbolin-Like Protein MDS019><Physiopathology><Preventative vaccine><Preventive vaccine><Prophylactic vaccine><Qualifying><RARRES3><RARRES3 gene><RIG1><Regulation><Research><Research Personnel><Researchers><Resistance><Resolution><STAT1><STAT1 gene><STAT91><Signal Transduction><Signal Transduction Systems><Signaling><Spleen><Spleen Reticuloendothelial System><Stimulator of Interferon Genes><TIG3><Tissues><Transgenic Organisms><Translating><Unsaturated Fatty Acids><Viral><Viral Burden><Viral Diseases><Viral Genes><Viral Hepatitis B><Viral Load><Viral Load result><Viral Markers><Viral Pathogenesis><Virus><Virus Diseases><Virus Replication><Work><access to vaccination><access to vaccines><adipose><alcohol abuser><alcohol co-abuse><alcohol effect><alcohol exposed><alcohol exposure><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol ingestion><alcohol intake><alcohol problem><alcohol product use><alcohol related liver disease><alcohol use><alcohol-associated liver disease><alcohol-induced hepatic dysfunction><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcohol-related liver disease><alcoholic beverage consumption><alcoholic drink intake><alcoholic liver injury><attenuate><attenuates><bK150C2.7><biological signal transduction><biomarker development><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><chronic HBV infection><chronic hepatitis B virus infection><clinical practice><cyclic GMP-AMP synthase/STING><dJ494G10.1><developmental><end stage disease><end stage liver disease><end stage liver failure><ethanol abuse><ethanol consumption><ethanol drinking><ethanol effect><ethanol exposed><ethanol exposure><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol ingestion><ethanol intake><ethanol liver disease><ethanol product use><ethanol use><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><experience><experiment><experimental research><experimental study><experiments><exposed to alcohol><exposed to ethanol><exposure to alcohol><exposure to ethanol><extracellular vesicles><gene induction><hazardous alcohol use><hepatic body system><hepatic damage><hepatic injury><hepatic organ system><hepatic steatosis><hepatosteatosis><immune activation><immunogen><induction of genes><interventional strategy><intrahepatic><killer T cell><liver damage><liver injury><malignancy><model of animal><mortality><neoplasm/cancer><pathophysiology><pathway><pre-clinical><preclinical><problem alcohol use><problem drinking><problematic alcohol consumption><problematic alcohol use><protective effect><pulmonary><resistant><resolutions><response><serum hepatitis><systemic inflammation><systemic inflammatory response><transgenic><vaccination access><vaccination availability><vaccine access><vaccine availability><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus pathogenesis><virus-induced disease><white adipose tissue><yellow adipose tissue>