Allelic variants of Salmonella fimbrial adhesins

描述（由申请人提供）：肠炎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是自限性的，健康成人一般可不予治疗。然而，对于治疗儿童、老年人和免疫功能低下患者，以及治疗全身感染，特别是涉及伤寒血清型感染时，通常需要使用抗菌药物治疗。观察到的肠链球菌多重耐药（MDR）菌株流行率的增加引起了对经验性抗菌药物治疗效果的实质性关注。肠链球菌的感染和定植涉及介导肠上皮细胞结合的菌毛粘附素的参与

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.