Differential Expression of Chemokine and Matrix Re-Modelling Genes Explains Contrasting Schistosoma japonicum-induced Hepatopathology in Murine Models

The pathological outcomes of schistosomiasis are largely dependent on the molecular and cellular mechanisms of the host immune response. In this study, we demonstrate the variation of host gene expression which underlies the contrasting hepatic pathology observed between two inbred mouse strains following schistosome infection. Whole genome microarray analysis was employed in conjunction with histological and immunohistochemical analysis to define and compare the hepatic gene expression profiles and cellular composition associated with the hepatopathology observed in BALB/c and CBA mice during an active Schistosoma japonicum infection. Here, we show that the transcriptional profiles differ significantly between the two mouse strains with high statistical confidence. We identified specific genes correlating with the more severe pathology associated with CBA mice, as well as genes which may confer the milder degree of pathology associated with BALB/c mice. Generally, up-regulated genes were largely associated with immune and inflammatory responses, antigen processing and cytokine/chemokine activity. In BALB/c mice, neutrophil genes exhibited striking increases in expression, which coincided with significantly greater accumulation of neutrophils at granulomatous regions, compared to CBA mice. In contrast, up-regulated expression of eosinophil chemokine CCL24 in CBA mice paralleled the cellular influx of eosinophils to the hepatic granulomas. Additionally, there was greater down-regulation of genes involved in metabolic processes in CBA mice, reflecting the greater degree of liver damage in these mice. Genes involved in fibrosis showed similar levels of expression in both mouse strains. Genes associated with Th1 and Th2 responses showed no significant differences in expression between strains. These results provide a more complete picture of the molecular and cellular mechanisms which govern the pathological outcome of hepatic schistosomiasis. Furthermore, this improved understanding of schistosome immunopathogenesis in the murine model will provide the basis for a better appreciation of the complexities associated with chronic human schistosomiasis. The gene expression profile of murine livers (BALB/c and CBA strains) were examined at 4, 7 and 9 weeks post infection with Schistosoma japonicum in comparison to that of uninfected controls. Three mice were utilised per group (Uninfected, 4, 7 and 9 weeks), totalling 24 samples. Microarray analysis was performed on individual RNA samples from each mouse.血吸虫病的病理结局在很大程度上取决于宿主免疫应答的分子与细胞机制。本研究阐明了宿主基因表达的差异，该差异是两种近交系小鼠在血吸虫感染后出现迥异肝脏病理表现的分子基础。研究采用全基因组微阵列分析结合组织学与免疫组织化学分析，对日本血吸虫急性感染阶段BALB/c与CBA小鼠的肝脏病理相关的肝脏基因表达谱及细胞组成进行了定义与比较。结果显示，两种小鼠品系的转录组谱存在具有高统计学显著性的差异。本研究鉴定出了与CBA小鼠更严重病理相关的特异性基因，以及可能赋予BALB/c小鼠更轻微病理程度的基因。整体而言，上调表达的基因主要与免疫应答、炎症反应、抗原加工以及细胞因子/趋化因子活性相关。与CBA小鼠相比，BALB/c小鼠的中性粒细胞相关基因表达出现显著上调，这与肉芽肿区域中性粒细胞的大量聚集相吻合。与之相反，CBA小鼠中嗜酸性粒细胞趋化因子CCL24的表达上调，与嗜酸性粒细胞向肝脏肉芽肿的细胞浸润程度相一致。此外，CBA小鼠中参与代谢过程的基因下调程度更高，这反映出该品系小鼠肝脏损伤程度更为严重。与纤维化相关的基因在两种小鼠品系中的表达水平无显著差异。辅助性T细胞1型（Th1）、辅助性T细胞2型（Th2）应答相关的基因在两种小鼠品系间的表达无显著差异。本研究结果为阐明肝脏血吸虫病病理结局的分子与细胞机制提供了更为全面的认知。此外，通过小鼠模型对血吸虫免疫发病机制的深入理解，将为进一步认识人类慢性血吸虫病的复杂发病机制提供理论基础。本研究以未感染小鼠为对照，对日本血吸虫感染后第4、7、9周的BALB/c与CBA品系小鼠肝脏的基因表达谱进行了检测。每组（未感染组、感染4周组、感染7周组、感染9周组）各使用3只小鼠，总计24个样本。对每只小鼠的独立RNA样本进行了微阵列分析。