Eradication of intracellular Francisella tularensis in THP-1 human macrophages with a novel autophagy inducing agent |
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| Authors: | Hao-Chieh Chiu Shilpa Soni Samuel K Kulp Heather Curry Dasheng Wang John S Gunn Larry S Schlesinger Ching-Shih Chen |
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| Affiliation: | 1.Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA;2.Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210, USA;3.Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA;4.Division of Infectious Diseases, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA |
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| Abstract: | BackgroundAutophagy 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.Methods and resultsOur 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.ConclusionTogether, AR-12 represents a proof-of-principle that intracellular F. tularensis can be eradicated by small-molecule agents that target innate immunity. |
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