# Alcohol Promotes Hepatitis B Progression by Impairment of Innate Immunity in Liver Cells

> **NIH NIH P50** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $241,763

## Abstract

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.

## Key facts

- **NIH application ID:** 10797028
- **Project number:** 5P50AA030407-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** NATALIA ALEKSANDR OSNA
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $241,763
- **Award type:** 5
- **Project period:** 2023-02-28 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10797028

## Citation

> US National Institutes of Health, RePORTER application 10797028, Alcohol Promotes Hepatitis B Progression by Impairment of Innate Immunity in Liver Cells (5P50AA030407-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10797028. Licensed CC0.

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