# Genetic basis of virus induced Biliary Atresia

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $445,832

## Abstract

Project Summary/Abstract
Biliary atresia is the most common cause of pediatric end stage liver disease and the number
one indication for pediatric liver transplantation. Because pathogenic viruses have been found in
the liver of afflicted children, a proposed etiology for biliary atresia is a perinatal viral infection
triggering immune mediated destruction of the biliary epithelium. The murine model of biliary
atresia supports a viral pathogenesis as newborn mice infected with rhesus rotavirus (RRV)
develop inflammation within the portal tract and extrahepatic bile duct obstruction. RRV targets
the cholangiocyte for infection and in addition to direct cholangiocyte injury also induces Natural
Killer cell mediated injury to the biliary epithelium.
We have previously shown that the amino acid, arginine (R) within the sequence “SRL” (amino
acids 445-447) on the RRV VP4 protein is required for viral binding and entry into biliary epithelial
cells. We developed a reverse genetics system to create a mutant of RRV (RRVVP4-R446G), which
had a single amino acid change in VP4 protein compared to wild type RRV. In vitro, the mutant
virus had reduced binding and infectivity in cholangiocytes. In vivo, it produced less symptoms
and mortality in neonatal mice, resulting in an attenuated form of biliary atresia. We will use this
mutant strain along with additional VP4 mutants to determine how RRV binds to, enters, traffics
through the cell, and ultimately activates the cholangiocyte's innate immune response. We will
also ascertain these VP4 mutants' ability to infect and activate plasmacytoid dendritic cells leading
to Natural Killer cell activation. These complimentary approaches will generate new insight in viral
induced biliary atresia.

## Key facts

- **NIH application ID:** 10328541
- **Project number:** 5R01DK091566-09
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** GREGORY M TIAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $445,832
- **Award type:** 5
- **Project period:** 2011-04-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328541

## Citation

> US National Institutes of Health, RePORTER application 10328541, Genetic basis of virus induced Biliary Atresia (5R01DK091566-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10328541. Licensed CC0.

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