The Roles And Underlying Mechanisms Of Uropathogenic Escherichia Coli Fimbrial Adhesin YadC In The Bacterial Colonization

Urinary tract infections(UTIs)are one of the most common infectious diseases caused by pathogens invading the urinary system,which are important causes of morbidity in infant boys,older men and females of all ages.Uropathogenic Escherichia coli(UPEC)is the leading cause of UTIs,the pathogenicity is closely related to several virulence factors,including fimbriae,toxins,siderophores,flagella,and surface polysaccharide structures,all of these virulence factors work together to play important roles.Fimbriae are hair-like structures expressed on the bacterial surface,fimbriae and the tip adhesin play important roles in UPEC colonization of the urinary tract system,which is the most critical step in the initial of UTIs.Impeding the association of fimbriae with the host can greatly reduce the occurrence of UTIs.Many different types of fimbriae have been described in UPEC,however,only a few fimbrial tip adhesins that mediate UPEC infections have been identified,limiting the development of treatment strategies for UTIs.Therefore,identification of other fimbrial adhesins that are important for UPEC infections and the corresponding anti-adhesion mechanisms could lead to novel strategies to treat and prevent UTIs.Yad fimbriae is one of the most common fimbriae in UPEC.In the present study,YadC,the tip adhesin of Yad fimbriae,was investigated for its mediation in UPEC pathogenicity.We constructed a deletion strain(?yad C)and a complementation strain(?yad C p-yad C)of CFT073,to perform adhesion and invasion assays in vitro,we demonstrated that YadC mediated UPEC adhesion and invasion of bladder epithelial cells.Furthermore,we demonstrated that YadC promoted UPEC colonization in bladder by acute cystitis mouse models in vivo.D-xylose,a five-carbon sugar that targets YadC,weas found to decrease UPEC adhesion and invasion of bladder cells in vitro,also showed prophylactic and therapeutic effects on UPEC colonization in vivo.In addition,annexin A2(ANXA2)was identified as a receptor for YadC on bladder epithelial cells by far-western blotting,mass spectrometry,and co-immunoprecipitation,and involved in YadC-mediated UPEC infections.Several ANXA2 inhibitors attenuated YadC-mediated UPEC infection of bladder cells in vitro and could treat UPEC infections in vivo.We also performed the phylogenetic analysis of yad C gene.In UPEC clinical isolates from patients with UTIs,the yad C gene was found conserved and widely.The abuse of antibiotics has led to a significant increase in bacterial resistance and a lack of appropriate medication,developing non-antibiotic strategies is urgently needed.Therefore,the role of YadC and ANXA2,in addition with effects of compounds targeting YadC and ANXA2 in acute UTIs,may lead to novel treatment strategies for urinary tract infections.