Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair

• DOI: 10.1038/ni.1758
• Publication Date: 2009-06-28T17:42:52Z
• Authors: Maziar Divangahi; Minjian Chen; Huixian Gan; Danielle Desjardins; Tyler T Hickman; David M Lee; Sarah Fortune; Samuel M Behar; Heinz G Remold
• Keywords: 0301 basic medicine; Cell Membrane Permeability; Virulence; Macrophages; Cell Membrane; Golgi Apparatus; Apoptosis; Mycobacterium tuberculosis; Article; Dinoprostone; 3. Good health; Lipoxins; Mice; Necrosis; Synaptotagmins; 03 medical and health sciences; Animals; Humans; Lysosomes; Cells, Cultured

Induction of macrophage necrosis is a strategy used by virulent Mycobacterium tuberculosis (Mtb) to avoid innate host defense. In contrast, attenuated Mtb causes apoptosis, which limits bacterial replication and promotes T cell cross-priming by antigen-presenting cells. Here we show that Mtb infection causes plasma membrane microdisruptions. Resealing of these lesions, a process crucial for preventing necrosis and promoting apoptosis, required translocation of lysosomal and Golgi apparatus-derived vesicles to the plasma membrane. Plasma membrane repair depended on prostaglandin E(2) (PGE(2)), which regulates synaptotagmin 7 (Syt-7), the calcium sensor involved in the lysosome-mediated repair mechanism. By inducing production of lipoxin A(4) (LXA(4)), which blocks PGE(2) biosynthesis, virulent Mtb prevented membrane repair and induced necrosis. Thus, virulent Mtb impairs macrophage plasma membrane repair to evade host defenses.