Pathogenesis of EAST1 toxin in ETEC associated diarrhea disease

说明(申请人提供)：产肠毒素大肠埃希氏菌(ETEC)菌株被NIAID归类为B优先病原体。ETEC相关性腹泻每年在世界各地造成近100万人死亡，此外还导致免疫受损的个人和旅行者，包括部署的军事人员患病。ETEC相关性腹泻的关键毒力因子被认为是细菌黏附素或定植因子(CFAs)和肠毒素。肠聚集性大肠杆菌耐热肠毒素1(EAST1)是由引起人和动物腹泻的大肠杆菌菌株产生的肠毒素之一。然而，EAST1在腹泻中的毒力意义尚未确定，部分原因是尚未确定适用于关键测试的模型。我们的初步研究结果表明，使用K88ac受体阳性的灵芝仔猪和K88ac菌毛模型的相加模型可以很容易地评估肠毒素在大肠杆菌相关性腹泻中的毒力意义。在本方案中，我们将构建表达EAST1毒素和K88ac菌毛的模型病原体，以确定EAST1在腹泻中的毒力意义，以及它对同时表达其他毒素的大肠杆菌菌株引起的腹泻的协同作用。EAST1毒力的测定将为制定预防和治疗策略提供信息，以保护人类和动物免受腹泻疾病的侵袭。这项R15提案将招募有前途的本科生与专家研究团队一起接受培训，因为他们专注于EAST1毒素在腹泻中的生物学相关性。 产肠毒素大肠埃希菌(ETEC)是引起腹泻的主要原因。ETEC腹泻每年造成40万至80万人死亡，并给国际旅行者和军事人员带来健康担忧和经济后果。肠聚集性大肠杆菌耐热毒素1(EAST1)与腹泻有关。但EAST1毒素是否是腹泻的毒力决定因素尚不清楚。EAST1毒力意义的确定对于我们识别其他未知的腹泻毒力因子是必不可少的。这项拟议的研究旨在检验EAST1在腹泻中的毒力意义。确定EAST1毒素在腹泻病中的毒力意义将为预防或控制该病提供必要的信息。

DESCRIPTION (provided by applicant): Enterotoxigenic Escherichia coli (ETEC) strains are categorized as priority B pathogens by NIAID. ETEC-associated diarrhea is responsible for nearly one million deaths each year around the world in addition to causing of illness to immunocompromised individuals and travelers including deployed military personnel. The key virulence factors in ETEC- associated diarrhea are believed to be bacterial adhesins or colonization factors (CFAs) and enterotoxins. Enteroaggregative Escherichia coli heat stable enterotoxin 1 (EAST1) is among the enterotoxins produced by E. coli strains that cause diarrhea in humans and animals. However, the virulence significance of EAST1 in diarrhea has not been defined, in part because a suitable model for key tests has not been identified. Results from our initial studies demonstrated that an additive model using K88ac-receptor positive gnotobiotic piglets and K88ac-fimbrial E. coli model can be readily employed to assess virulence significance of enterotoxins in E. coli-associated diarrhea. In this proposal, we will construct model pathogens expressing EAST1 toxin and K88ac fimbria to define virulence significance of EAST1 in diarrhea and its synergetic contribution to diarrhea caused by E. coli strains that also express other toxins by using the additive piglet challenge model. Determination of EAST1 virulence will provide information for the development of prevention and treatment strategies to protect humans and animals from diarrhea disease. This R15 proposal will recruit promising undergraduate students to be trained with the expert research team as they focus on the biological relevance of EAST1 toxin in diarrhea. Enterotoxigenic Escherichia coli (ETEC) are the primary cause of diarrheal disease. ETEC diarrhea is responsible for 400,000 to 800,000 deaths each year, and brings health concerns and economic consequences in international travelers and military personnel. Enteroaggregative Escherichia coli heat stable toxin 1 (EAST1) is associated with diarrhea. But whether EAST1 toxin is the virulence determinant in diarrhea is unclear. Determination of virulence significance of EAST1 is essential for us to identify other unknown virulence factors in diarrhea. This proposed research is to examine the virulence significance EAST1 in diarrhea. The determination of virulence significance of EAST1 toxin in diarrheal disease will provide essential information to prevent or control this disease.