Yuan Ming, Wu Mingrou, Hu Yunyi, Zhao Siyu, Khan Jehangir, Yuan Zhanhong, Huang Yun, He Tianqiong, Zhou Zhijun, Shen Jia, Wu Zhongdao
Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, Guangdong, China.
Key Laboratory of Tropical Disease Control of the Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, China.
Parasit Vectors. 2025 Jul 4;18(1):259. doi: 10.1186/s13071-025-06821-z.
Schistosomiasis, a parasitic disease affecting more than 240 million people worldwide, is characterized by chronic inflammation and tissue fibrosis primarily induced by parasite egg deposition. Bromodomain-containing protein 4 (BRD4), an epigenetic and transcriptional regulator, has emerged as a potential therapeutic target due to its dual role in modulating Schistosoma japonicum (S. japonicum) reproductive development and organ fibrosis. Despite these advances, the specific involvement of BRD4 in the host immune response during S. japonicum infection still remains completely unclear.
To explore the involvement of BRD4 in the immune response to S. japonicum, we performed a comparative time-series RNA-seq analysis of liver tissues from the non-permissive host Microtus fortis and the permissive host Mus musculus. BRD4-associated gene expression patterns were analyzed through correlation-based classification, followed by protein-protein interaction network construction and functional enrichment analyses. In addition, BRD4 was pharmacologically inhibited in vivo using JQ1, and hepatic inflammation and worm load were evaluated at 14 days post-infection.
BRD4 displayed distinct transcriptional dynamics between M. fortis and M. musculus. Genes positively correlated with BRD4 expression were significantly enriched in inflammatory and immune-related pathways, including Th17 cell differentiation and hallmark inflammatory response. These patterns suggest a potential regulatory role for BRD4 in mediating hepatic inflammation during infection. In vivo inhibition of BRD4 with JQ1 reduced liver inflammation, further supporting its association with proinflammatory responses.
Our findings reveal strong transcriptional correlations between BRD4 expression and immune activation, and further highlight BRD4 as a potential regulator of host inflammatory responses during S. japonicum infection. BRD4 may serve as a valuable molecular target for understanding host-pathogen interactions and developing adjunct therapies against schistosomiasis.
血吸虫病是一种影响全球超过2.4亿人的寄生虫病，其特征是主要由寄生虫卵沉积引起的慢性炎症和组织纤维化。含溴结构域蛋白4（BRD4）是一种表观遗传和转录调节因子，由于其在调节日本血吸虫（S. japonicum）生殖发育和器官纤维化中的双重作用，已成为一个潜在的治疗靶点。尽管有这些进展，但BRD4在日本血吸虫感染期间宿主免疫反应中的具体作用仍完全不清楚。
为了探究BRD4在对日本血吸虫免疫反应中的作用，我们对非适宜宿主东方田鼠和适宜宿主小家鼠的肝脏组织进行了比较性时间序列RNA测序分析。通过基于相关性的分类分析BRD4相关基因的表达模式，随后构建蛋白质-蛋白质相互作用网络并进行功能富集分析。此外，使用JQ1在体内对BRD4进行药理学抑制，并在感染后14天评估肝脏炎症和虫负荷。
BRD4在东方田鼠和小家鼠之间表现出不同的转录动态。与BRD4表达呈正相关的基因在炎症和免疫相关途径中显著富集，包括Th17细胞分化和标志性炎症反应。这些模式表明BRD4在感染期间介导肝脏炎症中具有潜在的调节作用。用JQ1在体内抑制BRD4可减轻肝脏炎症，进一步支持其与促炎反应的关联。
我们的研究结果揭示了BRD4表达与免疫激活之间存在强烈的转录相关性，并进一步强调BRD4是日本血吸虫感染期间宿主炎症反应的潜在调节因子。BRD4可能是理解宿主-病原体相互作用和开发血吸虫病辅助治疗方法的有价值分子靶点。
