铁是病原菌毒力和致病性的关键调控因子，但其确切机制并未阐明。外膜蛋白是革兰氏阴性菌特有的外膜成分，可促进病原菌抵抗机体的免疫防御，是关键的致病因素。近年来，研究表明广泛存在于革兰氏阴性菌的外膜孔蛋白OmpW的表达受铁调控，且已证实其为毒力蛋白，与多种感染病的发生有关，但其机制未见报道。前期对EHEC O157:H7的研究发现，OmpW可促进细菌抗补体杀菌和抗吞噬，首次证实其抗先天免疫作用，为此我们认为铁调控OmpW抗先天免疫是病原菌致病的新机制。但OmpW抗先天免疫的分子机制及铁的调控机理尚不清楚。本项目进一步明确OmpW表达与铁平衡的关系，鉴定与铁结合并调控OmpW表达的转录因子，并着重从抑制补体系统杀菌及调理作用、对巨噬细胞产生羟自由基和细胞因子的影响等方面来阐明OmpW作用机制。本研究从病原菌抗免疫这一新角度来阐明其致病机制，并为感染病的防治提供新思路和药物作用新靶点。

Iron is a key regulator for pathogen virulence and pathogenicity, but its regulation mechanism has not clarified clearly as yet. At present, outer membrane proteins, particular to Gram-negative bacteria, have been shown to promote pathogens to evade the host immune defense. Recently years, OmpW, an outer membrane porin protein widespread in Gram-negative bacteria, which expression regulated by iron, has found form a unique narrow hydrophobic channel, and it may be serving as transporter of iron ion. More importantly, several results of basic and clinical research have discovered that OmpW can contribute bacteria virulence and pathogenicity, and therefore cause of infectious diseases, but its mechanism has not reported to date. Our previous study on enterohemorrhagic Escherichia coli (EHEC) O157:H7 indicate that OmpW can promote bacteria resistance to bactericidal by serum complement and phagocytosis by macrophages. This finding revealed a novel pathogenic mechanism which iron modulate OmpW resistance to host innate immune. However, the resistance mechanism of OmpW and regulation mechanism by iron are still remained undefined. Therefore, on the basis of our previous studies, this project is planned firstly to determine the relations between OmpW expression and iron homeostasis, and to identify transcription factors which regulate OmpW expression by binding ferrous iron. Then, we focus on clarifying the resistance mechanism of OmpW in the processes of inhibition of bactericidal and opsonization by the complement system and affection of production of hydroxyl radicals and cytokines by macrophage cells. The project is emphasis on bacteria resistance to host innate immune defenses via its outer membrane proteins, in a new perspective for clarifying of pathogenic mechanism, and it provide new insight into the treatment of infectious diseases and a new drug target.