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Allelic variants of Salmonella fimbrial adhesins

沙门氏菌菌毛粘附素的等位基因变异

基本信息

批准号：
8515328
负责人：
Dieter M. Schifferli
金额：
$ 18.8万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-25 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8515328
关键词：
Adhesions Adhesives Adult Affinity Alleles Amino Acid Substitution Antibiotic Resistance Antimicrobial Resistance Bacterial Adhesins Binding Biological Biological Assay Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Child Collection Complement Computer Simulation DNA DNA Sequence Data Development Disease Elderly Elements Environment Epithelial Cells Fimbrial Adhesins Food Contamination Future Gastroenteritis Gene Cluster Generations Genes Genetic Variation Genome Horizontal Gene Transfer Immune Immunocompromised Host In Vitro Infection Intestines Investigation Left Mediating Metadata Microbial Biofilms Molecular Chaperones Morbidity - disease rate Multi-Drug Resistance Pennsylvania Pharmaceutical Preparations Phenotype Play Prevalence Proliferating Property Publishing Regulation Reporting Resistance profile Role Salmonella Salmonella enterica Salmonella infections Specialist Species Specificity Specificity Surface System Systemic disease Systemic infection Techniques Testing Therapeutic Time Typhoid Fever Variant Virulence Factors antimicrobial base cell type clinically significant density fimbria foodborne foodborne illness high risk in vivo inhibitor/antagonist innovation mortality mutant novel novel strategies programs research study residence resistant strain transposon/insertion element

项目摘要

DESCRIPTION (provided by applicant): Salmonella enterica causes substantial morbidity and mortality worldwide. Foodborne salmonellosis is typically self-limiting and can generally be left untreated in healthy adults. However, antimicrobial therapy is often necessary to treat children, the elderly, and immunocompromised patients, as well as for the treatment of systemic infections, particularly when typhoidal serovars are involved. The observed increase in the prevalence of multiple drug resistant (MDR) strains of S. enterica raises substantial concerns regarding the efficacy of empiric antimicrobial therapy. Infection and colonization by S. enterica involves the participation of fimbrial adhesins that mediate binding to intestinal epithelial cells and innate immune cells. While gene clusters for many usher-chaperone types of fimbriae are carried by all S. enterica serovars, some have been shown to be host restricted, suggesting a potential role in regulation of host specificity. In support, several studies have highlighted how even a few amino acid substitutions in a Salmonella fimbrial adhesin significantly modulate host- and cell-type binding specificity. In addition, by mediating intestinal binding, adhesive fimbriae prolong the residence of locally proliferating Salmonella, thereby increasing their density in the intestines, an environment known to favor horizontal gene transfer (HGT) of antibiotic resistance genes. Thus, we hypothesize that cognate binding of adhesins to host-specific intestinal cells may actually contribute to the accumulation of antibiotic resistance genes in persistently colonizing Salmonella. For this project, a novel and successfully pretested sequencing strategy will be used to test our hypothesis that specific Salmonella adhesins and their allelic variants determine host species specificity and facilitate HGT. For this, we will utilize targeted and barcoded massive parallel sequencing to characterize allelic variation of adhesin genes from 600 well documented isolates from the Pennsylvania Salmonella Reference Center (200 independent isolates from each of the three major S. enterica serovars prevalent in the US). Correlations will be evaluated between strains that carry defined combinations of adhesin allelic variants and specific phenotypes such as host species, disease signs and antimicrobial resistance profiles. Finally, adhesin alleles with the most significant congruence for specific hos species or for antibiotic resistance will be studied in vitro and in vivo for cause effect relationships. The result of these investigations will guide future development of novel adhesion competitors or inhibitors to reduce both intestinal colonization by Salmonella and the expansion of MDR Salmonella.

描述（由申请人提供）：肠沙门氏菌在世界范围内引起大量发病率和死亡率。食源性沙门氏菌病通常具有自限性，健康成年人通常可以不予治疗。然而，对于治疗儿童、老年人和免疫功能低下的患者，以及治疗全身感染，特别是涉及伤寒血清型时，通常需要抗菌治疗。观察到的肠沙门氏菌多重耐药 (MDR) 菌株患病率的增加引起了人们对经验性抗菌治疗疗效的严重担忧。肠沙门氏菌的感染和定植涉及介导与肠上皮细胞结合的菌毛粘附素的参与和先天免疫细胞。虽然所有肠沙门氏菌血清型都携带许多引导分子伴侣类型菌毛的基因簇，但有些已被证明受到宿主限制，这表明在调节宿主特异性方面具有潜在作用。作为支持，一些研究强调了沙门氏菌菌毛粘附素中即使是少数氨基酸取代也如何显着调节宿主和细胞类型的结合特异性。此外，通过介导肠道结合，粘附菌毛延长了局部增殖的沙门氏菌的停留时间，从而增加了它们在肠道中的密度，而肠道是已知有利于抗生素抗性基因水平基因转移（HGT）的环境。因此，我们假设粘附素与宿主特异性肠细胞的同源结合实际上可能有助于沙门氏菌持续定殖的抗生素抗性基因的积累。对于这个项目，将使用一种新颖且经过成功预测试的测序策略来检验我们的假设，即特定的沙门氏菌粘附素及其等位基因变体决定宿主物种特异性并促进 HGT。为此，我们将利用靶向和条形码大规模平行测序来表征来自宾夕法尼亚沙门氏菌参考中心的 600 个有据可查的分离株（来自美国流行的三种主要肠沙门氏菌血清型中的每一个的 200 个独立分离株）的粘附素基因的等位基因变异。将评估携带粘附素等位基因变体的确定组合的菌株与特定表型（例如宿主物种、疾病体征和抗菌素耐药性概况）之间的相关性。最后，将在体外和体内研究与特定宿主物种或抗生素耐药性最显着一致的粘附素等位基因的因果关系。这些研究的结果将指导未来新型粘附竞争剂或抑制剂的开发，以减少沙门氏菌的肠道定植和耐多药沙门氏菌的扩张。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Allelic variation in Salmonella: an underappreciated driver of adaptation and virulence.

沙门氏菌的等位基因变异：适应性和毒力的一个未被充分认识的驱动因素。

DOI：
10.3389/fmicb.2013.00419
发表时间：
2014
期刊：
Frontiers in microbiology
影响因子：
5.2
作者：
Yue,Min;Schifferli,DieterM
通讯作者：
Schifferli,DieterM

Allelic variation contributes to bacterial host specificity.

DOI：
10.1038/ncomms9754
发表时间：
2015-10-30
期刊：
Nature communications
影响因子：
16.6
作者：
Yue M;Han X;De Masi L;Zhu C;Ma X;Zhang J;Wu R;Schmieder R;Kaushik RS;Fraser GP;Zhao S;McDermott PF;Weill FX;Mainil JG;Arze C;Fricke WF;Edwards RA;Brisson D;Zhang NR;Rankin SC;Schifferli DM
通讯作者：
Schifferli DM

Animal Enterotoxigenic Escherichia coli.