ISG-15 promotes de novo HBV infection after pediatric liver transplant via IL-18/STAT1 from HBcAb-positive donors.

INTRODUCTION AND

OBJECTIVES

Liver transplantation is the main therapy for pediatric end-stage liver disease, but use of hepatitis B core antibody-positive (HBcAb+) grafts increases the risk of de novo hepatitis B virus (HBV) infection. We examined whether ISG-15 promotes de novo HBV through IL-18/STAT1 signaling.

PATIENTS AND

METHODS

We retrospectively analyzed clinical data and conducted proteomics analysis. Liver biopsy specimens were randomly selected from eight pediatric recipients who developed de novo HBV infection and from 10 pediatric recipients who did not develop de novo HBV infection, after liver transplantation was performed between 2018 and 2019. In proteomic comparisons between the de novo and non-de novo HBV groups, we identified 5027 proteins, including 221 differentially expressed proteins. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were conducted to evaluate functional associations.

RESULTS

Differentially expressed proteins were primarily involved in the immune response, viral defense, and cell adhesion processes. In vitro experiments using small interfering RNA and plasmid transfection to knock down and overexpress ISG-15 in hepatoblastoma (HepG2.2.15) cells demonstrated that ISG-15 overexpression significantly enhanced cell proliferation and migration, whereas ISG-15 knockdown inhibited these biological processes. Treatment with the STAT1 inhibitor fludarabine and the agonist 2-nitropropane further confirmed that ISG-15 promotes HBV replication by regulating the IL-18/STAT1 signaling axis.

CONCLUSIONS

The findings of this study provide experimental evidence that can help in understanding the role of ISG-15 in HBV infection and offer potential targets for clinical intervention to prevent de novo HBV infection after liver transplantation using HBcAb-positive grafts.