The S100A10–AnxA2 complex is associated with the exocytosis of hepatitis B virus in intrauterine infection

Abstract

Mother-to-child transmission (MTCT) is the major cause of chronic infection of hepatitis B virus (HBV) in patients. However, whether and how HBV crosses the placenta to cause infection in utero remains unclear. In this study, we investigate the mechanism as to how the HBV virions pass through layers of the trophoblast. Our data demonstrate the exocytosis of virions from the trophoblast after exposure to HBV where the endocytosed HBV virions co-localized with an S100A10/AnxA2 complex and LC3, an autophagosome membrane marker. Knockdown of either AnxA2 or S100A10 in trophoblast cells led to a reduction of the amount of exo-virus in Transwell assay. Immunohistochemistry also showed a high expression of AnxA2 and S100A10 in the placental tissue samples of HBV-infected mothers with congenital HBV-positive infants (HBV+/+). We conclude that in HBV intrauterine infection and mother-to-child transmission, a proportion of HBV hijacks autophagic protein secretion pathway and translocate across the trophoblast via S100A10/AnxA2 complex and multivesicular body (MVB)-mediated exocytosis. Our study provides a potential target for the interference of the mechanisms of HBV intrauterine infection and mother-to-child transmission.

Impact of Annexin A2 on virus life cycles

“…Further, an association of HBV Pol- S100A10 with PML is increased by exposure of cells to EGTA but reduced by valinomycin ( Choi et al, 2003 ), suggesting that S100A10 modulates HBV Pol function, signaling the importance of PML nuclear bodies and intracellular Ca 2+ in HBV replication. It is also reported that A2t is associated with the exocytosis of HBV in intrauterine infection, which is the major cause of mother-to-child transmission (MTCT) ( Bai et al, 2022 ). Briefly, AnxA2 transferred from the cytoplasm to the surface of autophagosomes harboring HBV recruits S100A10 to form the heterotetramer A2t, which in turn recruits VAMP2, SNAP25 for membrane fusion so that the autophagosome fuses with MBV ( Bai et al, 2022 ).…”

“…It is also reported that A2t is associated with the exocytosis of HBV in intrauterine infection, which is the major cause of mother-to-child transmission (MTCT) ( Bai et al, 2022 ). Briefly, AnxA2 transferred from the cytoplasm to the surface of autophagosomes harboring HBV recruits S100A10 to form the heterotetramer A2t, which in turn recruits VAMP2, SNAP25 for membrane fusion so that the autophagosome fuses with MBV ( Bai et al, 2022 ). Then, HBV translocation across the trophoblast via A2t and MVB-mediated exocytosis occurs ( Bai et al, 2022 ).…”

Cohort Profile: Zhejiang Environmental and Birth Health Research Alliance (ZEBRA) Maternity Cohort

“…Serum protein expression profiles of HBV were analysed by proteomics, and the expression of proteins related to intrauterine HBV transmission was further confirmed through immunohistochemistry and PCR techniques in both serum samples and placental tissues. After screening and identifying 35 differential proteins, we found that high expression levels of S100-family proteins and exocytosis mediated by the AnxA2-S100A10 complex were associated with intrauterine HBV transmission through the placenta 53,54 .…”

Intrauterine Infection and Mother-to-Child Transmission of Hepatitis B Virus: Route and Molecular Mechanism

“… 15 Our recent study demonstrated the transcytosis of HBV across trophoblasts using trophoblastic cell line Swan71 and primary trophoblasts. 51 BeWo cells could actively transcytose HBIG and the reduced virus transcytosis rate was thought to be due to the formation of HBV-IgG complexes which were internalized via the Fc γ receptor. 15 , 52 Additionally, HBV transcytosis efficiency was reduced with the fusion of cytotrophoblasts into syncytiotrophoblasts and with the addition of HBIG.…”