宿主因子对致急性肝胰腺坏死病副溶血弧菌毒力的影响机制

Vibrio parahaemolyticus containing a unique virulence plasmid (i.e. VPAHPND) can cause acute hepatopancreatic necrosis disease (AHPND), which is responsible for the severe losses in penaeid shrimp culture. Previous work of our lab has demonstrated that the pathogenicity of VPAHPND is a strain characteristic as some strains can be highly virulent, whereas other strains are less virulent. Moreover, the extracts of shrimp tissues could significantly enhance the virulence of VPAHPND, and a higher increasing level was observed in the high-virulent strains, suggesting that host factors in the extracts of shrimp tissues play an essential role in the virulence of VPAHPND. However, the mechanism by which VPAHPND responses to the host factors is not yet completely understood. The present research aims at determining the impact of host signaling on the virulence of VPAHPND. The specific objectives include 1) screening and verifying the major host factors that can significantly induce the virulence of VPAHPND; 2) identifying the receptors of host factors in VPAHPND; 3) evaluating the potentials of different host factors antagonists as antivirulence agents to combat infections caused by VPAHPND. In general, the present study will improve our understanding of the pathogenicity mechanisms by which VPAHPND causes infection, and will facilitate the development of novel approach for preventing and controlling bacterial diseases in shrimp culture.

近年来，由携带特殊致病基因的副溶血弧菌(VPAHPND)引发的对虾急性肝胰腺坏死病(AHPND)频繁爆发，严重危害了对虾养殖业的健康发展。申请人所在课题组的前期研究工作表明，不同VPAHPND菌株的对虾致病性存在显著差异，经对虾匀浆液处理后，它们的毒力均有所增强，且强致病株的毒力提高程度要显著大于弱致病株，这说明对虾组织中的宿主因子对VPAHPND毒力有着重要影响。目前尚不清楚VPAHPND感应宿主信号以促进自身感染的具体机制。本项目拟从病原—宿主信号通讯的角度研究宿主信号对VPAHPND毒力的影响机制，具体包括：1. 鉴定对VPAHPND毒力有显著影响的宿主因子；2. 结合基因组信息筛选并验证VPAHPND感应宿主因子的关键受体；3. 评估受体抑制剂用于对虾病害防控的潜力。本研究将促进对副溶血弧菌致病机理和病原—宿主相互作用机制的深入理解，为研发无公害的对虾新型细菌防治技术提供新思路。

近几年来，对虾急性肝胰腺坏死病(Acute Hepatopancreatic Necrosis Disease，AHPND)对全球对虾养殖构成了严重威胁，该疾病由携带了PirAvp/PirBvp毒素质粒的副溶血弧菌及其它弧菌所引起，且不同副溶血弧菌菌株的致病力存在显著差异。本项目旨在从对宿主感应的角度确定该致病力差异产生的原因，探索宿主信号对致急性肝胰腺坏死病副溶血弧菌毒力的影响机制。经过研究发现，宿主在应激条件下所产生的儿茶酚胺类应激激素，如肾上腺素、去甲肾上腺素和多巴胺均可显著促进致急性肝胰腺坏死病副溶血弧菌的生长、泳动性、及关键毒力因子pirABvp的表达，且致病力较强的致急性肝胰腺坏死病副溶血弧菌对此类宿主应激激素的感应更为敏感。接下来我们结合基因框内缺失突变技术及转录组分析进一步确定了该菌感应儿茶酚胺激素的特异性蛋白为存在于QseBC双组分系统中的QseC蛋白，且此蛋白的缺失不仅使致急性肝胰腺坏死病副溶血弧菌失去了对宿主应激激素的感应能力，还导致了该菌多种毒力因子的产生及其对不同宿主致病力的降低。我们选用QseC蛋白的特异性阻断剂LED209抑制QseC与儿茶酚胺激素的结合，并降低了致急性肝胰腺坏死病副溶血弧菌的致病力，该阻断剂的工作浓度在nM级别，在病害防控方面具有广阔的应用前景。此外，我们还通过比较基因组学及转录组学分析初步确定了致急性肝胰腺坏死病副溶血弧菌其它的关键毒力基因。该项目的研究结果不仅为致急性肝胰腺坏死病副溶血弧菌发病机制的研究提供了重要的科学依据，还为对虾细菌性病害的防控提供了新思路。

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