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Schistosomiasis is a neglected, and potentially lethal, parasitic disease that affects hundreds of millions of people worldwide. As part of the schistosome lifecycle, parasite eggs accumulate within the liver where they evoke intense granulomatous pathology, typified by a dense extracellular matrix (ECM) barrier, which serves to contain toxic egg secretions. In severe cases, this progressive and irreversible egg-evoked ECM deposition can lead to pathological scarring, impaired liver function and lethality. Thus, identifying the core regulators that govern ECM deposition may aid discovery of new therapeutic targets for schistosomiasis. The transcription factor Sex determining region Y-box 9 (Sox9) is a known regulator of pathological scaring. We found that, following Schistosoma mansoni infection, SOX9 was ectopically expressed in myofibroblasts within the granuloma and in surrounding hepatocytes. In the absence of SOX9, granuloma size was significantly diminished, and mice failed to produce a robust ECM barrier around eggs, resulting in more diffuse liver injury and scattered distribution of immune cells. Immunologically, SOX9 loss in both naïve and infected mice led to an increase in hepatic neutrophil and monocyte proportions, with the expansion of Ly6clo monocyte populations in infected SOX9 deficient mice only. Infected SOX9–deficient mice also displayed exaggerated Type 2 inflammation, including pronounced eosinophilia. These data highlight the importance of SOX9 for intact hepatic granuloma formation during schistosomiasis and suggest SOX9 or its related factors may provide attractive future targets for meeting the clinical need to limit and/or reverse fibrotic disease.

血吸虫病（Schistosomiasis）是一种被忽视的致死性寄生虫病，全球范围内影响数亿人口。作为血吸虫生活史的关键环节，寄生虫虫卵会在肝脏内蓄积，并诱发以致密细胞外基质（extracellular matrix, ECM）屏障为特征的剧烈肉芽肿性病理反应，该屏障可包裹毒性虫卵分泌物。重症病例中，这种由虫卵介导的进行性、不可逆的ECM沉积会引发病理性瘢痕形成、肝功能受损甚至致死。因此，解析调控ECM沉积的核心调控因子，或可为血吸虫病的新型治疗靶点开发提供思路。转录因子性别决定区Y框蛋白9（Sex determining region Y-box 9, Sox9）是已知的病理性瘢痕调控因子。本研究发现，曼氏血吸虫（Schistosoma mansoni）感染后，SOX9会在肉芽肿内的肌成纤维细胞（myofibroblasts）及周围肝细胞中异位表达。SOX9缺失后，肉芽肿体积显著缩小，小鼠无法在虫卵周围形成稳固的ECM屏障，进而导致肝损伤弥散、免疫细胞分布散乱。免疫学层面，在未感染与感染小鼠中敲除SOX9，均会导致肝内中性粒细胞与单核细胞比例升高；仅在感染的SOX9缺陷小鼠中，还观察到Ly6C低单核细胞群体的扩增。感染的SOX9缺陷小鼠还表现出过度激活的2型炎症反应，包括显著的嗜酸性粒细胞增多症（eosinophilia）。上述数据表明，SOX9在血吸虫病诱导的完整肝肉芽肿形成过程中发挥关键作用，提示SOX9及其相关因子或可成为满足临床限制乃至逆转纤维化疾病需求的潜在新型治疗靶点。