Human endogenous retrovirus activation contributes to biliary atresia pathogenesis through re-education of resident macrophages
biorxiv(2022)
摘要
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.
### Competing Interest Statement
The authors have declared no competing interest.
* BA
: Biliary atresia
scRNA-seq
: Single-cell RNA sequencing
CyTOF
: cytometry by time of flight
IHC
: immunohistochemistry
mIHC
: multiplex IHC
HERV
: Human endogenous retrovirus
HP
: Human parvovirus
ALT
: alanine aminotransferase
AST
: aspartate aminotransferase
AchE
: acetylcholin esterase
TBIL
: total bilirubin
ALP
: alkaline phosphatase
γ-GT
: γ-glutamyl transpeptidase
UMAP
: Uniform Manifold Approximation and Projection
HSNE
: Hierarchical Stochastic Neighbor Embedding
ICA
: independent components analysis
Teff
: T effector cells
Tem
: effector memory T cells
Trm
: resident T cells
Tcm
: central memory T cells
Treg
: regulatory T cells
NAC
: N acetylcysteine
DTR
: Diphtheria toxin receptor
DT
: Diphtheria toxin.
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