title: Alpha-haemolysin of uropathogenic E. coli induces Ca2+ oscillations in renal epithelial cells.
abstract: Pyelonephritis is one of the most common febrile diseases in children. If not treated appropriately, it causes irreversible renal damage and accounts for a large proportion of end stage renal failures. Renal scarring can occur in the absence of inflammatory cells, indicating that bacteria may have a direct signalling effect on renal cells. Intracellular calcium ([Ca2+]i) oscillations can protect cells from the cytotoxic effects of prolonged increases in intracellular calcium. However, no pathophysiologically relevant protein that induces such oscillations has been identified. Here we show that infection by uropathogenic Escherichia coli induces a constant, low-frequency oscillatory [Ca2+]i response in target primary rat renal epithelial cells induced by the secreted RTX (repeats-in-toxin) toxin alpha-haemolysin. The response depends on calcium influx through L-type calcium channels as well as from internal stores gated by inositol triphosphate. Internal calcium oscillations induced by alpha-haemolysin in a renal epithelial cell line stimulated production of cytokines interleukin (IL)-6 and IL-8. Our findings indicate a novel role for alpha-haemolysin in pyelonephritis: as an inducer of an oscillating second messenger response in target cells, which fine-tunes gene expression during the inflammatory response.
authors.affiliation: Department of Women and Child Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, Stockholm, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Uhlén
authors.forename: A
authors.initials: A
authors.lastname: Laestadius
authors.forename: T
authors.initials: T
authors.lastname: Jahnukainen
authors.forename: T
authors.initials: T
authors.lastname: Söderblom
authors.forename: F
authors.initials: F
authors.lastname: Bäckhed
authors.forename: G
authors.initials: G
authors.lastname: Celsi
authors.forename: H
authors.initials: H
authors.lastname: Brismar
authors.forename: S
authors.initials: S
authors.lastname: Normark
authors.forename: A
authors.initials: A
authors.lastname: Aperia
authors.forename: A
authors.initials: A
authors.lastname: Richter-Dahlfors
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002460:Cell Line; D004847:Epithelial Cells / Q000382:microbiology; D004926:Escherichia coli / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D029968:Escherichia coli Proteins; D004963:Estrenes / Q000494:pharmacology; D005260:Female; D006460:Hemolysin Proteins / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D007668:Kidney / Q000166:cytology / Q000382:microbiology*; D009543:Nifedipine / Q000494:pharmacology; D011704:Pyelonephritis / Q000382:microbiology*; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001426:Bacterial Proteins; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D029968:Escherichia coli Proteins; D004963:Estrenes; D006460:Hemolysin Proteins; C036507:Hlya protein, E coli; D015850:Interleukin-6; D016209:Interleukin-8; D011760:Pyrrolidinones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D009543:Nifedipine; D002118:Calcium