Dataset Information

Rotavirus Reassortant-Induced Murine Model of Liver Fibrosis Parallels Human Biliary Atresia.

ABSTRACT: BACKGROUND AND AIMS:Biliary atresia (BA) is a devastating neonatal cholangiopathy that progresses to fibrosis and end-stage liver disease by 2 years of age. Portoenterostomy may reestablish biliary drainage, but, despite drainage, virtually all afflicted patients develop fibrosis and progress to end-stage liver disease requiring liver transplantation for survival. APPROACH AND RESULTS:In the murine model of BA, rhesus rotavirus (RRV) infection of newborn pups results in a cholangiopathy paralleling human BA and has been used to study mechanistic aspects of the disease. Unfortunately, nearly all RRV-infected pups succumb by day of life 14. Thus, in this study we generated an RRV-TUCH rotavirus reassortant (designated as TR(VP2,VP4) ) that when injected into newborn mice causes an obstructive jaundice phenotype with lower mortality rates. Of the mice that survived, 63% developed Ishak stage 3-5 fibrosis with histopathological signs of inflammation/fibrosis and bile duct obstruction. CONCLUSIONS:This model of rotavirus-induced neonatal fibrosis will provide an opportunity to study disease pathogenesis and has potential to be used in preclinical studies with an objective to identify therapeutic targets that may alter the course of BA.

SUBMITTER: Mohanty SK

PROVIDER: S-EPMC7384231 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Rotavirus Reassortant-Induced Murine Model of Liver Fibrosis Parallels Human Biliary Atresia.

Mohanty Sujit K SK Mohanty Sujit K SK Lobeck Inna I Donnelly Bryan B Dupree Phylicia P Walther Ashley A Mowery Sarah S Coots Abigail A Bondoc Alexander A Sheridan Rachel M RM Poling Holly M HM Temple Haley H McNeal Monica M Sestak Karol K Bansal Ruchi R Tiao Greg G

Hepatology (Baltimore, Md.) 20200211 4

<h4>Background and aims</h4>Biliary atresia (BA) is a devastating neonatal cholangiopathy that progresses to fibrosis and end-stage liver disease by 2 years of age. Portoenterostomy may reestablish biliary drainage, but, despite drainage, virtually all afflicted patients develop fibrosis and progress to end-stage liver disease requiring liver transplantation for survival.<h4>Approach and results</h4>In the murine model of BA, rhesus rotavirus (RRV) infection of newborn pups results in a cholangi ...[more]

PMID: 31442322

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Project description:Biliary atresia (BA) is a neonatal liver disease characterized by progressive fibroinflammatory obliteration of both intrahepatic and extrahepatic bile ducts. The etiologies of BA remain largely unknown, but rotavirus infection has been implicated at least for a subset of patients, and this causal relation has been well demonstrated in mouse models. In this study, we aim to further consolidate this evidence in human biliary organoids. We obtained seven batches of human biliary organoids cultured from fetal liver, adult liver, and bile duct tissues. We found that these organoids are highly susceptible and support the full life cycle of rotavirus infection in three-dimensional culture. The robust infection triggers active virus-host interactions, including interferon-based host defense mechanisms and injury responses. We have observed direct cytopathogenesis in organoids upon rotavirus infection, which may partially recapitulate the development of BA. Importantly, we have demonstrated the efficacy of mycophenolic acid and interferon alpha but not ribavirin in inhibiting rotavirus in biliary organoids. Furthermore, neutralizing antibody targeting rotavirus VP7 protein effectively inhibits infection in organoids. Thus, we have substantiated the causal evidence of rotavirus inducing BA in humans and provided potential strategies to combat the disease.IMPORTANCE There is substantial evidence indicating the possible involvement of rotavirus in biliary atresia (BA) development, at least in a subset of patients, but concrete proof remains lacking. In a mouse model, it has been well demonstrated that rotavirus can infect the biliary epithelium to cause biliary inflammation and obstruction, representing the pathogenesis of BA in humans. By using recently developed organoids technology, we now have demonstrated that human biliary organoids are susceptible to rotavirus infection, and this provokes active virus-host interactions and causes severe cytopathogenesis. Thus, our model recapitulates some essential aspects of BA development. Furthermore, we have demonstrated that antiviral drugs and neutralizing antibodies are capable of counteracting the infection and BA-like morphological changes, suggesting their potential for mitigating BA in patients.

Dataset Information

Rotavirus Reassortant-Induced Murine Model of Liver Fibrosis Parallels Human Biliary Atresia.

Publications

Rotavirus Reassortant-Induced Murine Model of Liver Fibrosis Parallels Human Biliary Atresia.

Similar Datasets

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