Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair.
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.
Divangahi
Maziar
M
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Chen
Minjian
M
Gan
Huixian
H
Desjardins
Danielle
D
Hickman
Tyler T
TT
Lee
David M
DM
Fortune
Sarah
S
Behar
Samuel M
SM
Remold
Heinz G
HG
D000818:Animals; D017209:Apoptosis; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism; D006056:Golgi Apparatus / Q000502:physiology; D006801:Humans; D044045:Lipoxins / Q000378:metabolism; D008247:Lysosomes / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*; D009336:Necrosis; D050857:Synaptotagmins / Q000378:metabolism; D014774:Virulence
D044045:Lipoxins; C494303:Syt7 protein, mouse; C040527:lipoxin A4; D050857:Synaptotagmins; D015232:Dinoprostone