Zhu Dexin, Guo Jia, Deng Xingmei, Li Min, Wang Yong, Wang Zhen, Sun Zhihua, Cao Shuzhu, Zhao Tianyi, Xu Yimei, Liu Liangbo, Zhang Hui
College of Animal Science and Technology, Shihezi University, Shihezi, China.
Changji City Communist Youth League Committee, Changji, China.
Int Immunopharmacol. 2025 Feb 6;147:114001. doi: 10.1016/j.intimp.2024.114001. Epub 2025 Jan 9.
Pyroptosis, which is accompanied by inflammatory responses, is critical for pathogen clearance. However, the mechanism through which Brucella evades host pyroptosis remains unclear. The transcriptional regulator ArsR6 maintains bacterial intracellular homeostasis and possibly influences host cell death. However, whether ArsR6 acts on cellular pyroptosis is unknown. Therefore, we investigated pathogen-host interactions within macrophages infected with Brucella abortus (B. abortus), and found that ArsR6 is crucial for inhibiting host cell pyroptosis after B. abortus infection. The downstream target gene, BAB_RS28760 of ArsR6 was screened using chromatin immunoprecipitation sequencing. BAB_RS28760 belongs to the BA14K protein family and is strongly immunoreactive and induces humoral and cellular immune responses in the host during infection. Deleting ArsR6 in B. abortuspromotes pyroptosis and enhancs the intracellular survival of B. abortus. In addition, ArsR6 negatively regulated its target gene BAB_RS28760, whereas BAB_RS28760 deletion downregulated cellular pyroptosis by inhibiting endoplasmic reticulum stress and decreasing the intracellular survival of B. abortus. Our results reveal for the first time that Brucella ArsR6 reduces endoplasmic reticulum stress activation by negatively regulating its downstream target genes, thus inhibiting host cell pyroptosis. Our study provides new insights into the pathogenic mechanisms of Brucella, which can provide potential selectivity for the development of anti-Brucella therapies.
细胞焦亡伴随着炎症反应，对病原体清除至关重要。然而，布鲁氏菌逃避宿主细胞焦亡的机制仍不清楚。转录调节因子ArsR6维持细菌细胞内稳态，并可能影响宿主细胞死亡。然而，ArsR6是否作用于细胞焦亡尚不清楚。因此，我们研究了感染流产布鲁氏菌（B. abortus）的巨噬细胞内病原体与宿主的相互作用，发现ArsR6对抑制B. abortus感染后宿主细胞焦亡至关重要。利用染色质免疫沉淀测序筛选了ArsR6的下游靶基因BAB_RS28760。BAB_RS28760属于BA14K蛋白家族，具有强免疫反应性，在感染期间可诱导宿主产生体液免疫和细胞免疫反应。在B. abortus中缺失ArsR6会促进细胞焦亡，并增强B. abortus的细胞内存活能力。此外，ArsR6负向调节其靶基因BAB_RS28760，而缺失BAB_RS28760则通过抑制内质网应激和降低B. abortus的细胞内存活能力而下调细胞焦亡。我们的结果首次揭示，布鲁氏菌ArsR6通过负向调节其下游靶基因来降低内质网应激激活，从而抑制宿主细胞焦亡。我们的研究为布鲁氏菌的致病机制提供了新的见解，可为抗布鲁氏菌疗法的开发提供潜在的选择性。
