Mycobacterium tuberculosis inhibition of phagolysosome biogenesis and autophagy as a host defence mechanism

Vojo Deretic, Sudha Singh, Sharon Master, James Harris, Esteban Roberts, George Kyei, Alex Davis, Sergio de Haro, John Naylor, Huang Ho Lee, Isabelle Vergne

Research output: Contribution to journalReview ArticleResearchpeer-review

225 Citations (Scopus)

Abstract

A marquee feature of the powerful human pathogen Mycobacterium tuberculosis is its macrophage parasitism. The intracellular survival of this microorganism rests upon its ability to arrest phagolysosome biogenesis, avoid direct cidal mechanisms in macrophages, and block efficient antigen processing and presentation. Mycobacteria prevent Rab conversion on their phagosomes and elaborate glycolypid and protein trafficking toxins that interfere with Rab effectors and regulation of specific organellar biogenesis in mammalian cells. One of the major Rab effectors affected in this process is the type III phosphatidylinositol 3-kinase hVPS34 and its enzymatic product phosphatidylinositol 3-phosphate (PI3P), a regulatory lipid earmarking organellar membranes for specific trafficking events. PI3P is also critical for the process of autophagy, recently recognized as an effect or of innate and adaptive immunity. Induction of autophagy by physiological, pharmacological or immunological signals, including the major antituberculosis Th1 cytokine IFN-γ and its downstream effector p47 GTPase LRG-47, can overcome mycobacterial phagosome maturation block and inhibit intracellular M. tuberculosis survival. This review summarizes the findings centred around the PI3P-nexus where the mycobacterial phagosome maturation block and execution stages of autophagy intersect.

Original languageEnglish
Pages (from-to)719-727
Number of pages9
JournalCellular Microbiology
Volume8
Issue number5
DOIs
Publication statusPublished - May 2006
Externally publishedYes

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