期刊
JOURNAL OF INNATE IMMUNITY
卷 3, 期 5, 页码 508-518出版社
KARGER
DOI: 10.1159/000325297
关键词
Mycobacterium tuberculosis; Macrophages; Phagosomes; Phagosomal maturation; Phagolysosomal fusion lysosomes; Mycobacteria
类别
资金
- Swedish Research Council [529-2003-5994, 2005-7046, 2006-5968, 2007-2673, 2009-3821]
- Bill and Melinda Gates Foundation
- SIDA/SAREC
- Ekhaga Foundation
- Carl Trygger Foundation
- King Gustaf V 80-Year Memorial Foundation
- County Council of Ostergotland
- Swedish Heart Lung Foundation
- Oskar II Jubilee Foundation
- Clas Groschinsky Foundation
- Soderbergs Foundation
- Colorado State University, Fort Collins (NIH, NIAID) [HHSN26620040 0091C]
The best characterized survival mechanism of Mycobacterium tuberculosis inside the macrophage is the inhibition of phagosomal maturation. Phagosomal maturation involves several steps including fusion with lysosomes and acidification. However, it has not been elucidated which components of phagosomal maturation correlate with growth restriction of virulent mycobacteria in human macrophages, and we aimed to study this. We infected human monocyte-derived macrophages with M. tuberculosis and assessed bacterial replication, translocation of CD63 to the phagosome, and phagosomal acidification. We found that unstimulated human macrophages were able to control infection with M. tuberculosis upon inoculation at a low multiplicity of infection (MOI) of 1, but not at a high MOI of 10. The low MOI resulted in a macrophage-controlled balance between host cells and bacteria. Both H37Rv and H37Ra infection, at high and low MOI, led to equally ineffective translocation of CD63 to the phagosome. On the other hand, acidification of mycobacterial phagosomes was more efficient at MOI 1 than 10 with both mycobacterial strains, consistent with a direct or indirect role for phagosomal acidification in restricting M. tuberculosis growth. Furthermore, inhibition of the vacuolar H ATPase as well as of cathepsin D led to enhanced mycobacterial replication inside the macrophage. This again shows the importance of phagosomal acidification for control of mycobacterial growth, through the activation of lysosomal hydrolases. We conclude that acidification and related functional aspects of the mature phagosome are important factors for restriction of M. tuberculosis replication in human macrophages. Copyright (C) 2011 S. Karger AG, Basel
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