title: Eradication of intracellular Francisella tularensis in THP-1 human macrophages with a novel autophagy inducing agent.
abstract: BACKGROUND
  Autophagy has been shown recently to play an important role in the intracellular survival of several pathogenic bacteria. In this study, we investigated the effect of a novel small-molecule autophagy-inducing agent, AR-12, on the survival of Francisella tularensis, the causative bacterium of tularemia in humans and a potential bioterrorism agent, in macrophages.
  
  
  RESULTS
  Our results show that AR-12 induces autophagy in THP-1 macrophages, as indicated by increased autophagosome formation, and potently inhibits the intracellular survival of F. tularensis (type A strain, Schu S4) and F. novicida in macrophages in association with increased bacterial co-localization with autophagosomes. The effect of AR-12 on intracellular F. novicida was fully reversed in the presence of the autophagy inhibitor, 3-methyl adenine or the lysosome inhibitor, chloroquine. Intracellular F. novicida were not susceptible to the inhibitory activity of AR-12 added at 12 h post-infection in THP-1 macrophages, and this lack of susceptibility was independent of the intracellular location of bacteria.
  
  
  CONCLUSIONS
  Together, AR-12 represents a proof-of-principle that intracellular F. tularensis can be eradicated by small-molecule agents that target innate immunity.
authors.affiliation: The Ohio State University, Columbus, 43210, USA. hcc6571@gmail.com
authors.forename: Hao-Chieh
authors.initials: HC
authors.lastname: Chiu
authors.forename: Shilpa
authors.initials: S
authors.lastname: Soni
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.forename: Heather
authors.initials: H
authors.lastname: Curry
authors.forename: Dasheng
authors.initials: D
authors.lastname: Wang
authors.forename: John S
authors.initials: JS
authors.lastname: Gunn
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry; D001343:Autophagy; D001428:Bacterial Vaccines / Q000276:immunology; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005604:Francisella tularensis / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000382:microbiology*; D008856:Microscopy, Fluorescence / Q000379:methods; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D014406:Tularemia / Q000382:microbiology*
chemical_list: D000890:Anti-Infective Agents; D001428:Bacterial Vaccines; D004791:Enzyme Inhibitors; C500894:OSU 03012; D011720:Pyrazoles; D013449:Sulfonamides; D002738:Chloroquine