Expression of apoptosis-related genes in an Ethiopian cohort study correlates with tuberculosis clinical status.
Mycobacterium tuberculosis remains one of the world's deadliest pathogens in part because of its ability to persist in the face of an active immune response. It has been suggested that apoptosis of infected macrophages is one way in which the host deals with intracellular pathogens and that M. tuberculosis can inhibit this process. To assess the relevance of this process for human disease, we compared the expression of multiple genes involved in the activation of the extrinsic ("death receptor initiated") pathway of apoptosis in 29 tuberculosis patients, 70 tuberculosis contacts and 27 community controls from Ethiopia. We found that there is a strong upregulation of genes for factors that promote apoptosis in PBMC from individuals with active disease, including TNF-alpha and its receptors, Fas and FasL and pro-Caspase 8. The anti-apoptotic factor FLIP, however, was also upregulated. A possible explanation for this dichotomy was given by fractionation of PBMC using CD14, which suggests that macrophage/monocytes may regulate several key molecules differently from non-monocytic cells (especially TNF-alpha and its receptors, a finding confirmed by protein ELISA) potentially reducing the sensitivity to apoptotic death of monocyte/macrophages--the primary host cell for M. tuberculosis. This may represent an important survival strategy for the pathogen.
Abebe
Markos
M
Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
Doherty
T Mark
TM
Wassie
Liya
L
Aseffa
Abraham
A
Bobosha
Kidist
K
Demissie
Abebech
A
Zewdie
Martha
M
Engers
Howard
H
Andersen
Peter
P
Kim
Louise
L
Huggett
Jim
J
Rook
Graham
G
Yamuah
Lawrence K
LK
Zumla
Alimuddin
A
D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D015331:Cohort Studies; D005002:Ethiopia / Q000453:epidemiology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D014376:Tuberculosis / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D055815:Young Adult