Rotavirus Replication in the Cholangiocyte Mediates the Temporal Dependence of Murine Biliary Atresia

Sujit K. Mohanty, Bryan Donnelly, Alexander Bondoc, Mubeen Jafri, Ashley Walther, Abigail Coots, Monica McNeal, David Witte, Gregory M. Tiao

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Biliary atresia (BA) is a neonatal disease that results in obliteration of the biliary tree. The murine model of BA, which mirrors the human disease, is based upon infection of newborn mice with rhesus rotavirus (RRV), leading to an obstructive cholangiopathy. The purpose of this study was to characterize the temporal relationship between viral infection and the induction of this model. BALB/c mice were infected with RRV on day of life (DOL) 0, 3, 5, and 7. Groups were characterized as early-infection (infection by DOL 3) or late-infection (infection after DOL 5). Early RRV infection induced symptoms in 95% of pups with a mortality rate of 80%. In contrast, late infection caused symptoms in only 50% of mice, and 100% of pups survived. The clinical findings correlated with histological analysis of extrahepatic biliary trees, cytokine expression, and viral titers. Primary murine cholangiocytes isolated, cultured, and infected with RRV yielded higher titers of infectious virus in those harvested from DOL 2 versus DOL 9 mice. Less interferon alpha and beta was produced in DOL 2 versus DOL 9 RRV infected primary cholangiocytes. Injection of BALB/c interferon alpha/beta receptor knockout (IFN-αβR-/-) pups at DOL 7 showed increased symptoms (79%) and mortality (46%) when compared to late infected wild type mice. In conclusion, the degree of injury sustained by relatively immature cholangiocytes due to more robust RRV replication correlated with more severe clinical manifestations of cholangiopathy and higher mortality. Interferon alpha production by cholangiocytes appears to play a regulatory role. These findings confirm a temporal dependence of RRV infection in murine BA and begin to define a pathophysiologic role of the maturing cholangiocyte.

Original languageEnglish (US)
Article numbere69069
JournalPLoS One
Volume8
Issue number7
DOIs
StatePublished - Jul 3 2013
Externally publishedYes

Fingerprint

Biliary Atresia
Rotavirus
abnormal development
Interferon-alpha
Interferon alpha-beta Receptor
Interferon-beta
mice
Viruses
infection
interferon-alpha
Infection
Cytokines
Rotavirus Infections
pups
signs and symptoms (animals and humans)
Biliary Tract
Infant, Newborn, Diseases
Mortality
interferon-beta
Virus Diseases

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mohanty, S. K., Donnelly, B., Bondoc, A., Jafri, M., Walther, A., Coots, A., ... Tiao, G. M. (2013). Rotavirus Replication in the Cholangiocyte Mediates the Temporal Dependence of Murine Biliary Atresia. PLoS One, 8(7), [e69069]. https://doi.org/10.1371/journal.pone.0069069

Rotavirus Replication in the Cholangiocyte Mediates the Temporal Dependence of Murine Biliary Atresia. / Mohanty, Sujit K.; Donnelly, Bryan; Bondoc, Alexander; Jafri, Mubeen; Walther, Ashley; Coots, Abigail; McNeal, Monica; Witte, David; Tiao, Gregory M.

In: PLoS One, Vol. 8, No. 7, e69069, 03.07.2013.

Research output: Contribution to journalArticle

Mohanty, SK, Donnelly, B, Bondoc, A, Jafri, M, Walther, A, Coots, A, McNeal, M, Witte, D & Tiao, GM 2013, 'Rotavirus Replication in the Cholangiocyte Mediates the Temporal Dependence of Murine Biliary Atresia', PLoS One, vol. 8, no. 7, e69069. https://doi.org/10.1371/journal.pone.0069069
Mohanty, Sujit K. ; Donnelly, Bryan ; Bondoc, Alexander ; Jafri, Mubeen ; Walther, Ashley ; Coots, Abigail ; McNeal, Monica ; Witte, David ; Tiao, Gregory M. / Rotavirus Replication in the Cholangiocyte Mediates the Temporal Dependence of Murine Biliary Atresia. In: PLoS One. 2013 ; Vol. 8, No. 7.
@article{3ab0d1849cee4f9fb077cb0e3bccfb54,
title = "Rotavirus Replication in the Cholangiocyte Mediates the Temporal Dependence of Murine Biliary Atresia",
abstract = "Biliary atresia (BA) is a neonatal disease that results in obliteration of the biliary tree. The murine model of BA, which mirrors the human disease, is based upon infection of newborn mice with rhesus rotavirus (RRV), leading to an obstructive cholangiopathy. The purpose of this study was to characterize the temporal relationship between viral infection and the induction of this model. BALB/c mice were infected with RRV on day of life (DOL) 0, 3, 5, and 7. Groups were characterized as early-infection (infection by DOL 3) or late-infection (infection after DOL 5). Early RRV infection induced symptoms in 95{\%} of pups with a mortality rate of 80{\%}. In contrast, late infection caused symptoms in only 50{\%} of mice, and 100{\%} of pups survived. The clinical findings correlated with histological analysis of extrahepatic biliary trees, cytokine expression, and viral titers. Primary murine cholangiocytes isolated, cultured, and infected with RRV yielded higher titers of infectious virus in those harvested from DOL 2 versus DOL 9 mice. Less interferon alpha and beta was produced in DOL 2 versus DOL 9 RRV infected primary cholangiocytes. Injection of BALB/c interferon alpha/beta receptor knockout (IFN-αβR-/-) pups at DOL 7 showed increased symptoms (79{\%}) and mortality (46{\%}) when compared to late infected wild type mice. In conclusion, the degree of injury sustained by relatively immature cholangiocytes due to more robust RRV replication correlated with more severe clinical manifestations of cholangiopathy and higher mortality. Interferon alpha production by cholangiocytes appears to play a regulatory role. These findings confirm a temporal dependence of RRV infection in murine BA and begin to define a pathophysiologic role of the maturing cholangiocyte.",
author = "Mohanty, {Sujit K.} and Bryan Donnelly and Alexander Bondoc and Mubeen Jafri and Ashley Walther and Abigail Coots and Monica McNeal and David Witte and Tiao, {Gregory M.}",
year = "2013",
month = "7",
day = "3",
doi = "10.1371/journal.pone.0069069",
language = "English (US)",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "7",

}

TY - JOUR

T1 - Rotavirus Replication in the Cholangiocyte Mediates the Temporal Dependence of Murine Biliary Atresia

AU - Mohanty, Sujit K.

AU - Donnelly, Bryan

AU - Bondoc, Alexander

AU - Jafri, Mubeen

AU - Walther, Ashley

AU - Coots, Abigail

AU - McNeal, Monica

AU - Witte, David

AU - Tiao, Gregory M.

PY - 2013/7/3

Y1 - 2013/7/3

N2 - Biliary atresia (BA) is a neonatal disease that results in obliteration of the biliary tree. The murine model of BA, which mirrors the human disease, is based upon infection of newborn mice with rhesus rotavirus (RRV), leading to an obstructive cholangiopathy. The purpose of this study was to characterize the temporal relationship between viral infection and the induction of this model. BALB/c mice were infected with RRV on day of life (DOL) 0, 3, 5, and 7. Groups were characterized as early-infection (infection by DOL 3) or late-infection (infection after DOL 5). Early RRV infection induced symptoms in 95% of pups with a mortality rate of 80%. In contrast, late infection caused symptoms in only 50% of mice, and 100% of pups survived. The clinical findings correlated with histological analysis of extrahepatic biliary trees, cytokine expression, and viral titers. Primary murine cholangiocytes isolated, cultured, and infected with RRV yielded higher titers of infectious virus in those harvested from DOL 2 versus DOL 9 mice. Less interferon alpha and beta was produced in DOL 2 versus DOL 9 RRV infected primary cholangiocytes. Injection of BALB/c interferon alpha/beta receptor knockout (IFN-αβR-/-) pups at DOL 7 showed increased symptoms (79%) and mortality (46%) when compared to late infected wild type mice. In conclusion, the degree of injury sustained by relatively immature cholangiocytes due to more robust RRV replication correlated with more severe clinical manifestations of cholangiopathy and higher mortality. Interferon alpha production by cholangiocytes appears to play a regulatory role. These findings confirm a temporal dependence of RRV infection in murine BA and begin to define a pathophysiologic role of the maturing cholangiocyte.

AB - Biliary atresia (BA) is a neonatal disease that results in obliteration of the biliary tree. The murine model of BA, which mirrors the human disease, is based upon infection of newborn mice with rhesus rotavirus (RRV), leading to an obstructive cholangiopathy. The purpose of this study was to characterize the temporal relationship between viral infection and the induction of this model. BALB/c mice were infected with RRV on day of life (DOL) 0, 3, 5, and 7. Groups were characterized as early-infection (infection by DOL 3) or late-infection (infection after DOL 5). Early RRV infection induced symptoms in 95% of pups with a mortality rate of 80%. In contrast, late infection caused symptoms in only 50% of mice, and 100% of pups survived. The clinical findings correlated with histological analysis of extrahepatic biliary trees, cytokine expression, and viral titers. Primary murine cholangiocytes isolated, cultured, and infected with RRV yielded higher titers of infectious virus in those harvested from DOL 2 versus DOL 9 mice. Less interferon alpha and beta was produced in DOL 2 versus DOL 9 RRV infected primary cholangiocytes. Injection of BALB/c interferon alpha/beta receptor knockout (IFN-αβR-/-) pups at DOL 7 showed increased symptoms (79%) and mortality (46%) when compared to late infected wild type mice. In conclusion, the degree of injury sustained by relatively immature cholangiocytes due to more robust RRV replication correlated with more severe clinical manifestations of cholangiopathy and higher mortality. Interferon alpha production by cholangiocytes appears to play a regulatory role. These findings confirm a temporal dependence of RRV infection in murine BA and begin to define a pathophysiologic role of the maturing cholangiocyte.

UR - http://www.scopus.com/inward/record.url?scp=84879777508&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879777508&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0069069

DO - 10.1371/journal.pone.0069069

M3 - Article

C2 - 23844248

AN - SCOPUS:84879777508

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 7

M1 - e69069

ER -