Autophagy induction targeting mTORC1 enhances Mycobacterium tuberculosis replication in HIV co-infected human macrophages.
To survive and replicate in macrophages Mycobacterium tuberculosis (Mtb) has developed strategies to subvert host defence mechanisms, including autophagy. Autophagy induction has the potential to clear Mtb, but little is known about its effect during controlled tuberculosis and HIV co-infection. Mammalian target of rapamycin complex1 (mTORC1) inhibitors were used to induce autophagy in human macrophages pre-infected with HIV-1BaL and infected with a low dose of Mtb (co-infected), or single Mtb infected (single infected). The controlled Mtb infection was disrupted upon mTOR inhibition resulting in increased Mtb replication in a dose-dependent manner which was more pronounced during co-infection. The increased Mtb replication could be explained by the marked reduction in phagosome acidification upon mTOR inhibition. Autophagy stimulation targeting mTORC1 clearly induced a basal autophagy with flux that was unlinked to the subcellular environment of the Mtb vacuoles, which showed a concurrent suppression in acidification and maturation/flux. Overall our findings indicate that mTOR inhibition during Mtb or HIV/Mtb co-infection interferes with phagosomal maturation, thereby supporting mycobacterial growth during low-dose and controlled infection. Therefore pharmacological induction of autophagy through targeting of the canonical mTORC1-pathway should be handled with caution during controlled tuberculosis, since this could have serious consequences for patients with HIV/Mtb co-infection.
Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Anna-Maria
AM
Andersson
Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Blanka
B
Andersson
Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Christoffer
C
Lorell
Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Johanna
J
Raffetseder
Division of Molecular Virology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Marie
M
Larsson
Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Robert
R
Blomgran
D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D060085:Coinfection; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000235:genetics / Q000382:microbiology*; D054884:Host-Pathogen Interactions / Q000502:physiology; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology* / Q000821:virology; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D009287:Naphthyridines / Q000494:pharmacology; D010588:Phagosomes / Q000382:microbiology / Q000821:virology; D010766:Phosphorylation; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D014376:Tuberculosis / Q000378:metabolism / Q000821:virology
C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; D009287:Naphthyridines; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D000076222:Mechanistic Target of Rapamycin Complex 1; D020123:Sirolimus