创伤弧菌MARTX毒素RID结构域的致病分子机制研究

Vibrio vulnificus, widespread in the estuarine and marine environment, is a kind of conditional pathogenic bacteria and infects human mainly through consumption of raw seafood or contact with skin wounds. Vibrio vulnificus can quickly infect host tissue to cause systemic infection, which clinically often cause limb necrosis and sepsis. The fatality rate of Vibrio vulnificus infection is as high as 50%, causing a serious threat to human health. During the process of infection, Vibrio vulnificus secrets a MARTX toxin to disrupt host cell actin cytoskeleton and help pathogen infect host tissue. Upon entry into host cells, MARTX toxin is auto-processed to release several functional domains to interfere with host cell signaling pathways. RID is the major functional domain of MARTX toxin to destroy host actin cytoskeleton, but the molecular mechanism of cytoskeleton disruption by RID remains unclear. This project will combine multiple research methods including cell biology, biochemistry, bacterial genetics and structural biology to study its molecular mechanism. Our research will uncover the mechanism of rapid tissue damage caused by Vibrio vulnificus, and provide biochemical basis for the development of new drugs and therapies.

创伤弧菌是一类普遍存在于河口和海洋环境中的条件致病菌，主要通过生海鲜的食用或皮肤伤口而感染人类。创伤弧菌能迅速侵染宿主组织，引发系统性感染，临床上常造成肢体坏死及败血症，致死率高达50%，对人类健康造成严重威胁。在感染过程中，创伤弧菌分泌MARTX毒素，破坏宿主细胞微丝骨架从而帮助病原菌侵染宿主组织。MARTX毒素在进入细胞后会进行自剪切，释放出多个发挥功能的结构域。其中RID是MARTX毒素破坏细胞微丝骨架的主要结构域，但具体的分子机制仍不清楚。本项目将结合包括细胞生物学，生物化学，细菌遗传学以及结构生物学等多种研究手段，研究RID破坏宿主细胞微丝骨架、帮助创伤弧菌侵染组织的分子机制，为开发新的治疗药物和方案提供理论依据。

创伤弧菌广泛存在于河口和海洋环境中，通过生食海鲜或伤口接触感染人类，引发组织坏死，继而导致系统性感染、败血症的产生，严重威胁人类健康。创伤弧菌分泌的MARTX毒素是最重要的致病因子，其中的RID结构域能破坏宿主细胞微丝骨架，但具体的分子机制不清楚。在青年基金项目的资助下，我们完成了对创伤弧菌MARTX毒素RID结构域的致病分子机制研究。我们发现MARTX毒素保守的致病结构域RID是一种全新的赖氨酸脂肪酰基转移酶，特异性地修饰并失活宿主关键信号分子Rho家族小G蛋白，以拮抗宿主免疫防御反应，在创伤弧菌感染的过程中发挥重要作用，研究论文发表在Science杂志上。该研究为相关病原菌感染疾病治疗药物的开发提供了重要靶标。此外，我们还扩展研究了病原菌IVb型分泌系统接头蛋白IcmS-IcmW，揭示了该复合物蛋白在调节病原菌效应蛋白的分泌上发挥双重作用，研究论文发表在PNAS杂志上。在Nature Structural & Molecular Biology期刊上以共同通讯作者发表论文，揭示了噬菌体蛋白AcrF3抑制病原菌I-F型CRISPR-Cas免疫系统效应因子Cas3的分子机制。我们还在Current Issues in Molecular Biology上发表了综述论文，总结了病原菌效应因子及毒素分子调节巨噬细胞功能的最新研究进展。