Cross Amy, Harris James M, Arbe-Barnes Edward, Nixon Colin, Dhairyawan Rageshri, Hall Andrew, Quaglia Alberto, Issa Fadi, Kennedy Patrick T F, McKeating Jane A, Gill Upkar S, Peppa Dimitra
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
eGastroenterology. 2024 Aug;2(3). doi: 10.1136/egastro-2024-100067. Epub 2024 Jul 11.
The intrahepatic processes associated with chronic hepatitis B (CHB), especially in the context of hepatitis delta virus (HDV) and HIV co-infection, require a better understanding. Spatial transcriptomics can provide new insights into the complex intrahepatic biological processes, guiding new personalised treatments. Our aim is to evaluate this method characterising the intrahepatic transcriptional landscape, cellular composition and biological pathways in liver biopsy samples from patients with hepatitis B virus (HBV) and HDV or HIV co-infection.
The NanoString GeoMx digital spatial profiling platform was employed to assess expression of HBV surface antigen and CD45 in formalin-fixed paraffin-embedded (FFPE) biopsies from three treatment-naïve patients with chronic HBV and HDV or HIV co-infection. The GeoMx Human Whole Transcriptome Atlas assay quantified the expression of genes enriched in specific regions of interest (ROIs). Cell type proportions within ROIs were deconvoluted using a training matrix from the human liver cell atlas. A weighted gene correlation network analysis evaluated transcriptomic signatures across sampled regions.
Spatially discrete transcriptomic signatures and distinct biological pathways were associated with HBV infection/disease status and immune responses. Shared features including 'cytotoxicity' and 'B cell receptor signalling' were consistent across patients, suggesting common elements alongside individual traits. HDV/HBV co-infection exhibited upregulated genes linked to apoptosis and immune cell recruitment, whereas HIV/HBV co-infection featured genes related to interferon response regulation. Varied cellular characteristics and immune cell populations, with an abundance of γδT cells in the HDV/HBV sample, were observed within analysed regions. Transcriptional differences in hepatocyte function suggest disrupted metabolic processes in HDV/HBV co-infection potentially impacting disease progression.
This proof-of-principle study shows the value of this platform in investigating the complex immune landscape, highlighting relevant host pathways to disease pathogenesis.
与慢性乙型肝炎（CHB）相关的肝内过程，尤其是在丁型肝炎病毒（HDV）和HIV合并感染的情况下，需要更好地理解。空间转录组学可以为复杂的肝内生物学过程提供新的见解，指导新的个性化治疗。我们的目的是评估这种方法，以表征乙型肝炎病毒（HBV）与HDV或HIV合并感染患者肝活检样本中的肝内转录图谱、细胞组成和生物学途径。
采用NanoString GeoMx数字空间分析平台，评估来自3例未经治疗的慢性HBV与HDV或HIV合并感染患者的福尔马林固定石蜡包埋（FFPE）活检组织中HBV表面抗原和CD45的表达。GeoMx人类全转录组图谱分析定量了富集于特定感兴趣区域（ROI）的基因表达。使用来自人类肝脏细胞图谱的训练矩阵对ROI内的细胞类型比例进行反卷积分析。加权基因共表达网络分析评估了跨采样区域的转录组特征。
空间上离散的转录组特征和不同的生物学途径与HBV感染/疾病状态及免疫反应相关。包括“细胞毒性”和“B细胞受体信号传导”在内的共同特征在患者中是一致的，表明除个体特征外还有共同因素。HDV/HBV合并感染表现出与凋亡和免疫细胞募集相关的基因上调，而HIV/HBV合并感染则以与干扰素反应调节相关的基因为特征。在分析区域内观察到不同的细胞特征和免疫细胞群体，HDV/HBV样本中有大量γδT细胞。肝细胞功能的转录差异表明HDV/HBV合并感染中代谢过程受到破坏，可能影响疾病进展。
这项原理验证研究显示了该平台在研究复杂免疫格局方面的价值，突出了与疾病发病机制相关的宿主途径。
