Human endogenous retrovirus activation contributes to biliary atresia pathogenesis through re-education of resident macrophages

Sheng, J.; Zhang, J.; Zhao, Y.; Song, J.; Tang, J.; Wang, X.; Ji, Y.; Wu, J.; Li, T.; Zhang, H.; Tano, V.; Langley, S. R.; Bai, X.; Liang, T.

doi:10.1101/2022.03.11.483921

bioRxiv · 10.1101/2022.03.11.483921

Human endogenous retrovirus activation contributes to biliary atresia pathogenesis through re-education of resident macrophages

Sheng, J.·Zhang, J.·Zhao, Y.·Song, J.·Tang, J.·Wang, X.·Ji, Y.·Wu, J.·Li, T.·Zhang, H.·Tano, V.·Langley, S. R.·Bai, X.·Liang, T.

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Abstract

Biliary atresia (BA) is a life-threatening neonatal fibro-inflammatory disease characterized by hepatic fibrosis, cirrhosis, and end-stage liver failure. BA is also the most frequent indication of pediatric liver transplantation globally. Despite the devastating condition of BA, the pathogenesis mechanism is unknown. Viral infection has been suggested to be associated with BA, but definitive evidence to support this hypothesis is not available. To elucidate the virus-associated pathogenesis mechanism of BA and to understand the immune ecosystem, we performed single-cell transcriptomic and proteomic profiling of BA livers. We detected human endogenous virus (HERV) in infants with BA and their parents. HERV was mainly found in FOLR2+ resident macrophages, T cells, and NK cells. In addition, HERV activation re-educated the fetal-derived FOLR2+ resident macrophages, and reactive oxygen species scavenging neutrophil recruitment was impaired in patients with BA and HERV+, due to FOLR2+ resident macrophage re-education. Furthermore, we showed depletion of FOLR2+ resident macrophage and N-acetylcysteine treatment could rescue the liver damage in BA. Overall, our study revealed the HERV-associated immunopathology mechanism of BA. These results contribute to potential diagnosis and immunotherapy strategies for BA.

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Sheng, J., Zhang, J., Zhao, Y., Song, J., Tang, J., Wang, X., Ji, Y., Wu, J., Li, T., Zhang, H., Tano, V., Langley, S. R., Bai, X., Liang, T.. 2022-03-14. Human endogenous retrovirus activation contributes to biliary atresia pathogenesis through re-education of resident macrophages. https://doi.org/10.1101/2022.03.11.483921

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