Induction of apoptosis in human neutrophils by Mycobacterium tuberculosis is dependent on mature bacterial lipoproteins.
Modulation of immune cell apoptosis is a key evasion strategy utilized by Mycobacterium tuberculosis (Mtb). To be able to multiply within macrophages, the bacterium delays apoptosis and down-regulates pro-inflammatory activation in these cells, whereas apoptosis is rapidly induced in the potently bactericidal neutrophils. Initial host-pathogen interactions between neutrophils and Mtb, subsequently leading to apoptosis, need to be investigated to understand the early features during Mtb infections. Opsonized Mtb were readily phagocytosed, and the immuno-mediated phagocytosis triggered early activation of anti-apoptotic Akt in the neutrophils but the bacteria still induced apoptosis to the same extent as non-phagocytosed Mtb. Mtb-induced apoptosis was strictly dependent on NADPH oxidase-generated reactive oxygen species, compounds shown to damage lysosomal granules. Despite this, we found no involvement of damaged azurophilic granules in Mtb-induced apoptosis in human neutrophils. Instead, the Mtb-induced apoptosis was p38 MAPK dependent and induced through the mitochondrial pathway. Moreover, Mtb deficient of mature lipoproteins lacked the determinants required for induction of neutrophil apoptosis. These results show that Mtb exert a strong intrinsic capacity to induce apoptosis in neutrophils that is capable of overcoming the anti-apoptotic signaling in the cell.
Persson
Alexander
A
Department of Molecular and Clinical Medicine, Linköping University, Sweden. alexander.persson@liu.se
Blomgran-Julinder
Robert
R
Eklund
Daniel
D
Lundström
Charlotte
C
Stendahl
Olle
O
D017209:Apoptosis; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D006801:Humans; D008074:Lipoproteins / Q000235:genetics / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology* / Q000276:immunology; D010587:Phagocytosis; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology
D001426:Bacterial Proteins; D008074:Lipoproteins; D048051:p38 Mitogen-Activated Protein Kinases