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Mycobacterium tuberculosis EspB protein suppresses interferon-gamma-induced autophagy in murine macrophages.

Huang D., Bao L.

Mycobacterium tuberculosis (Mtb) persists within immature phagosomes by preventing their maturation into phagolysosomes. Although the early secretory antigenic target 6 (ESAT-6) system 1 (ESX-1) secretion-associated protein B (EspB) of Mtb is strongly linked to immunogenicity and virulence of this organism, its mechanism of action remains largely unclear. This study aimed to investigate EspB effects on autophagy in murine ANA-1 macrophage cells.EspB gene was amplified by polymerase chain reaction from Mtb H37Rv genomic DNA to express recombinant EspB protein. Levels of autophagic markers, including Microtubule-associated protein 1 light chain 3 beta (LC3B-I and -II), phosphorylated signal transducer and activator of transcription (STAT)1 and total STAT1 in ANA-1 cells treated with EspB proteins were assessed by Western blotting. In addition, autophagic vacuoles were detected by fluorescence microscopy. Finally, IFN-γR1 expression was evaluated by semiquantitative reverse transcriptase polymerase chain reaction and flow cytometry.EspB gene was expressed in Escherichia coli cells to yield a soluble N-terminal glutatione S-transferase tag fusion protein used in subsequent experiments. Preincubation with EspB significantly suppressed autophagosome formation and LC3B expression induced by interferon (IFN)-γ stimulation, in a dose-dependent manner. These results were confirmed by the reduced incorporation of monodansylcadaverine, a marker for the acidic compartment of autolysosomes, after treatment with EspB. Interestingly, we found that IFN-γ receptor 1 mRNA and protein levels were decreased in EspB-stimulated ANA-1 cells in comparison with untreated cells. Finally, EspB protein also inhibited IFN-γ-activated STAT1 phosphorylation, thereby downmodulating macrophage responsiveness to IFN-γ.EspB inhibits autophagosome formation in murine macrophages, at least in part by downregulating IFN-γ receptor 1 expression. Overall, EspB should be considered a relevant factor in the pathogenesis of mycobacterial infections in humans.

J. Microbiol. Immunol. Infect. 49:859-865(2016) [PubMed] [Europe PMC]

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