Mycobacterium tuberculosis infection induces non-apoptotic cell death of human dendritic cells.
BACKGROUND
Dendritic cells (DCs) connect innate and adaptive immunity, and are necessary for an efficient CD4+ and CD8+ T cell response after infection with Mycobacterium tuberculosis (Mtb). We previously described the macrophage cell death response to Mtb infection. To investigate the effect of Mtb infection on human DC viability, we infected these phagocytes with different strains of Mtb and assessed viability, as well as DNA fragmentation and caspase activity. In parallel studies, we assessed the impact of infection on DC maturation, cytokine production and bacillary survival.


RESULTS
Infection of DCs with live Mtb (H37Ra or H37Rv) led to cell death. This cell death proceeded in a caspase-independent manner, and without nuclear fragmentation. In fact, substrate assays demonstrated that Mtb H37Ra-induced cell death progressed without the activation of the executioner caspases, 3/7. Although the death pathway was triggered after infection, the DCs successfully underwent maturation and produced a host-protective cytokine profile. Finally, dying infected DCs were permissive for Mtb H37Ra growth.


CONCLUSIONS
Human DCs undergo cell death after infection with live Mtb, in a manner that does not involve executioner caspases, and results in no mycobactericidal effect. Nonetheless, the DC maturation and cytokine profile observed suggests that the infected cells can still contribute to TB immunity.
Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Ireland.
Ruth C M
RC
Ryan
Mary P
MP
O'Sullivan
Joseph
J
Keane
D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D053938:DNA Fragmentation; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology*; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010587:Phagocytosis; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology
D016207:Cytokines; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7