title: Dynamin2- and endothelial nitric oxide synthase-regulated invasion of bladder epithelial cells by uropathogenic Escherichia coli.
abstract: Invasion of bladder epithelial cells by uropathogenic Escherichia coli (UPEC) contributes to antibiotic-resistant and recurrent urinary tract infections (UTIs), but this process is incompletely understood. In this paper, we provide evidence that the large guanosine triphosphatase dynamin2 and its partner, endothelial nitric oxide (NO) synthase (NOS [eNOS]), mediate bacterial entry. Overexpression of dynamin2 or treatment with the NO donor S-nitrosothiols increases, whereas targeted reduction of endogenous dynamin2 or eNOS expression with ribonucleic acid interference impairs, bacterial invasion. Exposure of mouse bladder to small molecule NOS inhibitors abrogates infection of the uroepithelium by E. coli, and, concordantly, bacteria more efficiently invade uroepithelia isolated from wild-type compared with eNOS(-/-) mice. E. coli internalization promotes rapid phosphorylation of host cell eNOS and NO generation, and dynamin2 S-nitrosylation, a posttranslational modification required for the bacterial entry, also increases during E. coli invasion. These findings suggest that UPEC escape urinary flushing and immune cell surveillance by means of eNOS-dependent dynamin2 S-nitrosylation and invasion of host cells to cause recurrent UTIs.
authors.affiliation: Department of Pathology, Medical College of Georgia, Augusta, GA 30912, USA.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Wang
authors.forename: Ceba
authors.initials: C
authors.lastname: Humphrey
authors.forename: Nicole
authors.initials: N
authors.lastname: Frilot
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Wang
authors.forename: Zhongzhen
authors.initials: Z
authors.lastname: Nie
authors.forename: Nader H
authors.initials: NH
authors.lastname: Moniri
authors.forename: Yehia
authors.initials: Y
authors.lastname: Daaka
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003545:Cysteine / Q000378:metabolism; D034285:Dynamin II / Q000378:metabolism*; D004847:Epithelial Cells / Q000201:enzymology* / Q000382:microbiology*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D015538:Nitrosation; D001743:Urinary Bladder / Q000382:microbiology* / Q000473:pathology*; D056689:Uropathogenic Escherichia coli / Q000502:physiology*
chemical_list: D052250:Nitric Oxide Synthase Type III; D034285:Dynamin II; D003545:Cysteine