title: Nifedipine affects the course of Salmonella enterica serovar Typhimurium infection by modulating macrophage iron homeostasis.
abstract: BACKGROUND
  Iron overload can adversely influence the course of infection by increasing microbial replication and suppressing antimicrobial immune effector pathways. Recently, we have shown that the calcium channel blocker nifedipine can mobilize tissue iron in mouse models of iron overload. We therefore investigated whether nifedipine treatment affects the course of infection with intracellular bacteria via modulation of iron homeostasis.
  
  
  METHODS
  The effect of nifedipine on intramacrophage replication of bacteria and modulation of cellular iron homeostasis was investigated in the murine macrophage cell line RAW264.7, and the impact of nifedipine treatment on the course of systemic infection was investigated in C57BL/6 mice in vivo.
  
  
  RESULTS
  In RAW264.7 cells, nifedipine treatment significantly reduced intracellular bacterial survival of Salmonella enterica serovar Typhimurium and Chlamydophila pneumoniae. This could be attributed to the induction of the iron exporter ferroportin 1, which limited the availability of iron for intracellular Salmonella. When C57BL/6 mice were infected intraperitoneally with Salmonella and subsequently injected with nifedipine for 3 consecutive days, bacterial counts in livers and spleens were significantly reduced and survival of the mice significantly was prolonged compared with solvent-treated littermates. Nifedipine treatment increased expression of ferroportin 1 in the spleen, whereas splenic levels of the iron storage protein ferritin and serum iron concentrations were reduced.
  
  
  CONCLUSIONS
  Our data provide evidence for a novel mechanism whereby nifedipine enhances host resistance to intracellular pathogens via limitation of iron availability.
authors.affiliation: Department of Internal Medicine I, Clinical Immunology and Infectious Diseases, Medical University of Innsbruck, Austria. guenter.weiss@i-med.ac.at
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Mair
authors.forename: Manfred
authors.initials: M
authors.lastname: Nairz
authors.forename: Rosa
authors.initials: R
authors.lastname: Bellmann-Weiler
authors.forename: Thomas
authors.initials: T
authors.lastname: Muehlbacher
authors.forename: Andrea
authors.initials: A
authors.lastname: Schroll
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
authors.forename: Patrizia L
authors.initials: PL
authors.lastname: Moser
authors.forename: Heribert
authors.initials: H
authors.lastname: Talasz
authors.forename: Ferric C
authors.initials: FC
authors.lastname: Fang
authors.forename: Guenter
authors.initials: G
authors.lastname: Weiss
mesh_terms: D000818:Animals; D058491:Bacterial Load / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000378:metabolism; D002460:Cell Line; D023521:Chlamydophila Infections; D016993:Chlamydophila pneumoniae / Q000187:drug effects / Q000254:growth & development*; D016207:Cytokines / Q000378:metabolism; D005293:Ferritins / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009543:Nifedipine / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism*; D012481:Salmonella Infections, Animal / Q000188:drug therapy / Q000378:metabolism* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000187:drug effects / Q000254:growth & development*; D013154:Spleen / Q000378:metabolism / Q000382:microbiology; D000098742:Ferroportin
chemical_list: D002121:Calcium Channel Blockers; D027682:Cation Transport Proteins; D016207:Cytokines; D012333:RNA, Messenger; D000098742:Ferroportin; D005293:Ferritins; D007501:Iron; D009543:Nifedipine