National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, People's Republic of China.
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China.
Nat Microbiol. 2024 Nov;9(11):2909-2922. doi: 10.1038/s41564-024-01823-6. Epub 2024 Oct 16.
Vibrio cholerae causes cholera, an important cause of death worldwide. A fuller understanding of how virulence is regulated offers the potential for developing virulence inhibitors, regarded as efficient therapeutic alternatives for cholera treatment. Here we show using competitive infections of wild-type and mutant bacteria that the regulator of chitosan utilization, ChsR, increases V. cholerae virulence in vivo. Mechanistically, RNA sequencing, chromatin immunoprecipitation with sequencing and molecular biology approaches revealed that ChsR directly upregulated the expression of the virulence regulator, TcpP, which promoted expression of the cholera toxin and the toxin co-regulated pilus, in response to low O levels in the small intestine. We also found that chitosan degradation products inhibit the ChsR-tcpP promoter interaction. Consistently, administration of chitosan oligosaccharide, particularly when delivered via sodium alginate microsphere carriers, reduced V. cholerae intestinal colonization and disease severity in mice by blocking the chsR-mediated pathway. These data reveal the potential of chitosan oligosaccharide as supplemental therapy for cholera treatment and prevention.
霍乱弧菌引起霍乱，是全球重要的死亡原因。更全面地了解毒力是如何调节的，为开发毒力抑制剂提供了可能，毒力抑制剂被认为是治疗霍乱的有效替代疗法。在这里，我们通过野生型和突变型细菌的竞争感染表明，壳聚糖利用调节剂 ChsR 增加了霍乱弧菌的体内毒力。从机制上讲，RNA 测序、测序的染色质免疫沉淀和分子生物学方法表明，ChsR 直接上调了毒力调节剂 TcpP 的表达，TcpP 促进了霍乱毒素和毒素共调节菌毛的表达，以响应小肠中低氧水平。我们还发现壳聚糖降解产物抑制 ChsR-tcpP 启动子相互作用。一致地，壳聚糖寡糖的给药，特别是通过海藻酸钠微球载体给药，通过阻断 chsR 介导的途径，减少了小鼠中的霍乱弧菌肠道定植和疾病严重程度。这些数据揭示了壳聚糖寡糖作为霍乱治疗和预防的补充治疗的潜力。
