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. 2025 Dec;45(12):e70405.
doi: 10.1111/liv.70405.

scRNA-Seq Reveals Sustained Pro-Inflammation by Innate Immune Activation in In Utero HBV-Exposed Neonates of High HBsAg Mothers

Prabhjyoti Pahwa  1 , Ravinder Singh  1 , Partha Chattopadhyay  2 , Priyanka Mehta  2 , Ashish Kumar Vyas  1   3 , Sharda Patra  4 , Shakun Tyagi  5 , Rajesh Pandey  2 , Shiv Kumar Sarin  6 , Nirupama Trehanpati  1
Affiliations

scRNA-Seq Reveals Sustained Pro-Inflammation by Innate Immune Activation in In Utero HBV-Exposed Neonates of High HBsAg Mothers

Prabhjyoti Pahwa et al. Liver Int. 2025 Dec.

Abstract

Background and aim: High levels of HBV DNA and HBsAg titres increase the risk of mother-to-child transmission. Development of adaptive immunity post HBV vaccination in neonates born to HBsAg-positive mothers may be determined by maternal HBsAg titres. We analysed pre- and post-HBV vaccination immune status in neonates.

Method: PBMCs were collected before and after vaccination for single cell multi-omics sequencing for infants born to mothers with low (Gr.1, sAgLo 1.65 × 102 IU/mL) and high (Gr.2, sAgHi 1.4 × 104IU/mL) HBsAg titres. Integrative analysis of whole transcriptome and surface marker expression was done using the Seurat R package. Functional validation of single-cell data was performed through immunophenotyping in both groups.

Results: scRNAseq revealed that, at pre-HBV vaccine, CD8+T cells of neonates born to mothers with HBsAgHi levels showed increased expression (p < 0.05) of TOX, CTLA4, PD1, LAG3, CD38 and CREM exhaustion markers and decreased expression of ATP1B3, MREG and TGFβ1 compared to sAgLo. Monocytes and NK cells had elevated CXCR3, TNFSF9, HIVEP3, WDPCP, ATP6V1G2, IL-6, GMCSF and GCSF (p < 0.0001) driving the inflammation and mitochondrial biogenesis through MAP/ERK kinase in sAgHi compared to sAgLo. Post-vaccination, despite anti-HBs titre ≥ 10 IU/mL, sAgHi, neonates showed persistently high TOX, CTLA4, PD1 and CREM in CD8+T cells (p < 0.0001). Functional validations by immune phenotyping also showed higher expression of LAG3, PD1, TIGIT and BTLA (p < 0.05) on CD8+T cells pre- and post-vaccination in sAgHi compared to sAgLo.

Conclusion: HBV exposure compromises adaptive immunity at birth; despite post-vaccination anti-HBs titres generation, there was a sustained pro-inflammatory state by the innate immune activation via metabolic alterations that persisted in neonates born to sAgHi mothers.

Keywords: adaptive immunity; hepatitis B virus; immune exhaustion; metabolic alteration; neonates; trained immunity; vaccination.

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References

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