铜绿假单胞菌ExoY调控选择性自噬降解TAB1从而抑制宿主免疫反应的机制研究

Pseudomonas aeruginosa (PA) infection usually causes pneumonia that progressed to sepsis and acute lung injury, especially in immunocompromised patients. During infection, P. aeruginosa utilize Type III Secretion System (T3SS) to inject exotoxin Y (ExoY) and other “effector” proteins directly into host cells. ExoY is a soluble nucleotidyl cyclase, similar to Bacillus anthracis edema factor (EF)，Bordetella pertussis CyaA and Multifunctional-Autoprocessing Repeats-in-ToXin (MARTX) effector domains in numerous bacterial species of the Vibrio genus. Once injected into host cell, ExoY massively increases the cytoplasmic levels of cGMP/cUMP, but its role in the regulation of host inflammatory responses remains unknown. Our preliminary results indicate that ExoY inhibits the host immune responses to PA infection. Further study revealed that ExoY promotes PKA-mediated phosphorylation and TRAF3-mediated ubiquitination of TAB1, thus promoting autophagic degradation of TAB1 to inhibit activation of TAK1. These results suggest ExoY as a key virulence factor, and regulation of TAK1 by TAB1 autophagic degradation as a novel mechanism Therefore, we are going further to study the mechanism of how ExoY and host itself regulate the innate immune responses a. Results from our research will not only provide more insights into the mechanism of host innate immune regulation, but also clarify the role of ExoY during PA infection, and potentiate the development of new PA diagnosis or treatment strategies.

铜绿假单胞菌通常可以会感染人群引起严重肺炎并进一步发展成脓毒症和急性肺损伤. 铜绿假单胞菌外毒素ExoY与其他细菌如炭疽杆菌（Bacillus anthracis）EF蛋白和百日咳杆菌（Bordetella pertussis）的 CyaA以及创伤弧菌(Vibrio vulnificus)的MARTX毒素区域一样，是一种宿主因子依赖的腺苷酸环化酶，但其对宿主免疫反应的调控作用及机制目前尚无报道.我们前期研究结果提示ExoY显著抑制宿主免疫炎症反应，而且其通过促进选择性自噬降解TAB1来抑制TAK1激活及下游免疫炎症反应通路的调控机制十分新颖。因此，本项目将进一步研究ExoY如何通过促进TAB1的磷酸化，泛素化和选择性自噬降解来抑制宿主免疫炎症反应的机制。研究结果将不仅加深我们对细菌腺苷酸环化酶抑制宿主免疫炎症反应调控机制的了解，为开发细菌感染性疾病的诊疗新手段提供理论基础。

铜绿假单胞菌（Pseudomonas aeruginosa）在自然界分布广泛，是院内感染的主要病原体之一，可长期存在于人体气道并造成慢性感染。呼吸道分离出铜绿假单胞菌的患者，预示着患者更严重的肺功能下降、更高的死亡率、住院率和更明显的生活质量下降，提示着更差的预后。目前临床上针对铜绿假单胞菌感染的治疗仍以抗生素为主。然而，广谱抗生素的过度应用使铜绿假单胞菌对抗生素的耐药率明显上升，因此，临床医生对慢性铜绿假单胞菌下呼吸道感染与定植所带来的感染与肺损伤的后果缺乏有效的干预手段。慢性铜绿假单胞菌感染与定植难以清除，形势严峻，是目前亟待解决的主要临床问题。气道微环境很可能参与了铜绿假单胞菌肺部感染及其所致肺损伤这一进程。然而，对于临床铜绿假单胞菌肺部定植的患者，气道微环境如何影响疾病进展目前尚不明确，本项目主要聚焦于铜绿假单胞菌感染后气道微环境如何影响疾病病理结局并取得一些进展。另外，我们还聚焦结核杆菌与宿主的相互作用的分子调控机制取得了一些重要进展。