title: Counteracting suppression of CFTR and voltage-gated K+ channels by a bacterial pathogenic factor with the natural product tannic acid.
abstract: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause recurring bacterial infection in CF patients' lungs. However, the severity of CF lung disease correlates poorly with genotype. Antibiotic treatment helps dramatically prolong patients' life. The lung disease generally determines prognosis and causes most morbidity and mortality; early control of infections is thus critical. Staphylococcus aureus is a main cause of early infection in CF lungs. It secretes sphingomyelinase (SMase) C that can suppress CFTR activity. SMase C also inhibits voltage-gated K(+) channels in lymphocytes; inhibition of these channels causes immunosuppression. SMase C's pathogenicity is further illustrated by the demonstration that once Bacillus anthracis is engineered to express high levels of SMase C, the resulting mutant can evade the host immunity elicited by a live vaccine because additional pathogenic mechanisms are created. By screening a chemical library, we find that the natural product tannic acid is an SMase C antidote.
authors.affiliation: Department of Physiology, Perelman School of Medicine, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States.
authors.forename: Yajamana
authors.initials: Y
authors.lastname: Ramu
authors.affiliation: Department of Physiology, Perelman School of Medicine, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Physiology, Perelman School of Medicine, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States.
authors.forename: Hyeon-Gyu
authors.initials: HG
authors.lastname: Shin
authors.affiliation: Department of Physiology, Perelman School of Medicine, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Lu
mesh_terms: D000595:Amino Acid Sequence; D001408:Bacillus anthracis / Q000201:enzymology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000201:enzymology*; D013634:Tannins / Q000494:pharmacology*
chemical_list: D024642:Potassium Channels, Voltage-Gated; D020033:Protein Isoforms; D013634:Tannins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D013108:Sphingomyelin Phosphodiesterase
keywords: CFTR; cell biology; channel inhibition; phospholipase; potassium channels; sphingomyelinase; toxin; xenopus