# A chicken model to study hepatitis E virus pathogenesis

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2020 · $391,445

## Abstract

Project Summary: Hepatitis E virus (HEV) infects >20 million people worldwide annually leading to >44,000 deaths due
to HEV-related hepatobiliary diseases. A unique feature of HEV infection is fulminant hepatitis with high mortality of >25%
in pregnant women. Due to the lack of an animal model, the underlying mechanism in the pathogenesis of HEV-associated
fulminant hepatitis during pregnancy is unknown. The elevated levels of sex hormones such as progesterone and estrogen
during pregnancy are known to promote certain virus replications including HEV. Accumulating evidence indicate that
HEV replication is sex hormone-dependent, as HEV replication was significantly enhanced in the presence of sex hormones
or pregnancy sera in infected cells. The recent discovery of HEV from rabbits led to the development of a pregnancy model
for HEV, as fulminant hepatitis with high mortality was convincingly and independently reproduced in HEV-infected
pregnant rabbits. The long-term goal is to identify the host (hormonal and immunological) and viral factors contributing
to HEV-associated fulminant hepatic failure. In aim 1, we will determine the effect and mechanism of pregnancy-associated
sex hormones on HEV replication in human liver cells. We hypothesize that HEV infection inhibits the expression of
estrogen receptor ER-α and ER-β during pregnancy, which results in suppression of host innate immunity leading to
enhanced HEV replication. The effect of E1, E2 and P4, singly or in combination, on HEV replication in liver cells will be
determined, and the underlying mechanisms of sex hormones in regulating HEV replication through the expression of
estrogen receptor ER-α/ER-β, and progesterone receptor PGRMC1/PGRMC2 and their effect on cytokine expressions will
be delineated. In aim 2, we will elucidate the role and mechanism of pregnancy-associated sex hormones in the development
of fulminant hepatitis using a rabbit model. We hypothesize that changes of pregnancy-associated sex hormones suppress
host innate and cell-mediated immune responses leading to enhanced HEV replication and fulminant hepatitis. Pregnant
rabbits will be infected with HEV to identify the sex hormones and immunological correlates in the development of
fulminant hepatitis during pregnancy. The mechanisms of P4- and E1/E2-mediated fulminant hepatitis will be delineated
by quantifying mRNA and protein expression levels of ER-α/ER-β, PGRMC1/PGRMC2, and progesterone-induced
blocking factor in liver and placenta tissues, and their effect on cytokine expressions in infected rabbits. In aim 3, we will
define the viral genetic element(s) associated with fulminant hepatic failure. From case studies, 8 unique amino acid residues
within HEV ORF1 are associated with fulminant hepatic failure. We hypothesize that these mutations significantly enhance
HEV replication leading to higher viral loads and fulminant hepatic failure. We will first utilize HEV luciferase replicons
to determine the effect of the 8 ...

## Key facts

- **NIH application ID:** 9930017
- **Project number:** 5R01AI050611-15
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** XIANG-JIN MENG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,445
- **Award type:** 5
- **Project period:** 2002-06-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930017

## Citation

> US National Institutes of Health, RePORTER application 9930017, A chicken model to study hepatitis E virus pathogenesis (5R01AI050611-15). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/9930017. Licensed CC0.

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