Mycobacterium tuberculosis inhibition of phagolysosome biogenesis and autophagy as a host defence mechanism.
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 glycolipid 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 effector of innate and adaptive immunity. Induction of autophagy by physiological, pharmacological or immunological signals, including the major antituberculosis Th1 cytokine IFN-gamma 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.
Deretic
Vojo
V
Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE Albuquerque, NM 87131-001, USA. vderetic@salud.unm.edu
Singh
Sudha
S
Master
Sharon
S
Harris
James
J
Roberts
Esteban
E
Kyei
George
G
Davis
Alex
A
de Haro
Sergio
S
Naylor
John
J
Lee
Huang-Ho
HH
Vergne
Isabelle
I
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D010588:Phagosomes / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000276:immunology*; D020691:rab GTP-Binding Proteins / Q000378:metabolism
C096000:Ifi1 protein, mouse; D018129:Phosphatidylinositol Phosphates; C055525:phosphatidylinositol 3-phosphate; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D019204:GTP-Binding Proteins; D020691:rab GTP-Binding Proteins