耶尔森氏菌宿主侵袭与生存机制研究

Yersinia spp. are Gram-negative bacteria with environmentally ubiquitous. Three species are the intestinal pathogens Y. enterocolitica and Y. pseudotuberculosis,and the plague bacillus Y. pestis, causing infectious diseases in animals and humans. The human infections are mainly considered as the collateral damages. Y.pestis is a young bacterial pathogen, directly evolved from Y. pseudotuberculosis within the last 1,5000-20,000 years. Y. pestis is the etiologic monster of bubonic and pneumonic plagues, which kill about two hundred million humans in mid-age. The question is how Y. pseudotuberculosis evolved to such a dangerous and remarkably different pathogen, Y. pestis. A distinctive characteristic between these two species is that Y. pseudotuberculosis possesses a long lipopolysaccharide (LPS) structure on the bacterial surface, while Y. pestis has short LPS frame. This is because parts of long LPS were lost during evolution in Y. pestis. Dendritic cells (DCs) are our host defense cells, which sometimes use one of their receptors,called DC-SIGN (CD209), to capture and then kill invading pathogens. Recently, we showed the evidence that DC-SIGN is a receptor for short LPS but not for long LPS,so that DCs can only capture and deliver Y. pestis rather than Y.pseudotuberculosis. Therefore, we hypothesize that becoming short LPS may be a key step in the evolution of Y. pestis, increasing its ability to establish and cause very different infection from its parental species; Y. pseudotuberculosis. The achievement of this project will help to establish a basis for novel vaccine development or treatment against infection of Yersinia spp..

鼠疫菌、假结核菌和小肠结肠炎3种耶尔森氏菌可引起人兽共患传染病。其中鼠疫菌可引起鼠疫，严重威胁人类和动物的安全和健康。目前，其耐药性和疫情呈上升趋势，因此明确耶尔森氏菌生存侵袭机制以制定有效防治策略尤其重要，但该方面研究甚少。病原菌通常经免疫细胞受体结合而侵袭宿主，随后干扰宿主免疫系统对其的清除并在体内生存，继而侵袭其他组织细胞导致感染，所以说感染本质是病原菌侵袭宿主与生存的过程。本项目将在前期细菌受体、毒力因子和信号通路研究基础上，围绕耶尔森氏菌对宿主免疫细胞的"侵袭机制"及其体内"生存机制"两个关键问题，深入探讨其感染机制。研究目标：①发现并确定耶尔森氏菌侵入宿主细胞的特异性受体，揭示其侵袭过程中相关信号转导通路；②探讨耶尔森氏菌在胞内生存过程中抵抗宿主免疫清除的几种分子机制，为制定更有效的相关疾病防治策略提供科学依据，还可为其他致病菌的防治提供新的模式和思路。

耶尔森氏菌属主要包括三种细菌：鼠疫耶尔森氏菌，假结核耶尔森氏菌和小肠结肠炎耶尔森氏菌。假结核菌耶尔森氏菌的感染主要导致腹泻，而鼠疫耶尔森氏菌的感染可以导致致死性的肺鼠疫和腺鼠疫;并且该菌可以作为生物武器威胁人类的生命安全。对耶尔森氏菌如何感染侵袭宿主机制的研究有助于制定有效防治策略。病原菌对宿主的感染中的关键一环是病原菌与宿主细胞表面受体之间的结合，进而在宿主细胞内达到生存的目的，并进一步在宿主体内发生远处播散。前期我们对革兰氏阴性细菌感染的细胞受体，以及相关的信号通路具有一定的研究基础，课题在此基础上进一步围绕耶尔森氏菌对宿主免疫细胞的“侵染机制”及其体内“生存适应机制”两个关键问题，对耶尔森氏菌感染的相关机制进行了相关探讨。在该项目的研究中，我们发现并确定耶尔森氏菌侵入宿主细胞的特异性受体：1. 证实C型凝集素受体Langrin是鼠疫菌的受体。2.证明假结核耶尔森氏菌可以利用其核心寡糖与CD209相互作用，利用抗原递呈细胞进行扩散至淋巴结，肝脏和脾脏，研究结论进一步支持鼠疫由假结核耶尔森氏菌进化而来，研究结果支持假结核耶尔森氏菌在进化过程中丢失了O抗原，进而可以利用抗原递呈细胞进行扩散。3.证实mSIGN-R1是鼠疫耶尔森氏菌核心寡糖的受体。鼠疫菌可以利用HIV-hDC-SIGN类似的作用以其核心寡糖与CD209相互作用，利用抗原递呈细胞进行扩散。4. 项目发现Ail在肺鼠疫模型中鼠疫菌的扩散中发挥作用。项目研究结果为进一步了解鼠疫的进化和致病提供了证据，对假结核菌的扩散机制进行了研究。为制定更有效的相关疾病防治策略提供科学依据。