Eradication of intracellular Francisella tularensis in THP-1 human macrophages with a novel autophagy inducing agent.
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.
Chiu
Hao-Chieh
HC
The Ohio State University, Columbus, 43210, USA. hcc6571@gmail.com
Soni
Shilpa
S
Kulp
Samuel K
SK
Curry
Heather
H
Wang
Dasheng
D
Gunn
John S
JS
Schlesinger
Larry S
LS
Chen
Ching-Shih
CS
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*
D000890:Anti-Infective Agents; D001428:Bacterial Vaccines; D004791:Enzyme Inhibitors; C500894:OSU 03012; D011720:Pyrazoles; D013449:Sulfonamides; D002738:Chloroquine