The effect of mycobacterial virulence and viability on MAP kinase signalling and TNF alpha production by human monocytes.
METHODS
The success of Mycobacterium tuberculosis as a human pathogen depends on its ability to tolerate and perhaps manipulate host defense mechanisms.


OBJECTIVE
To determine the induction of tumour necrosis factor-alpha (TNF alpha), a central mediator of immunity, by human monocytes infected with virulent M. tuberculosis, M. leprae and attenuated M. bovis BCG.


METHODS
Mycobacteria-induced cellular activation pathways of TNF alpha production was investigated using an inhibitor of protein tyrosine kinase (PTKs) and an inhibitor of mitogen-activated protein (MAP) kinases.


RESULTS
TNF alpha production was significantly lower during infection with virulent M. tuberculosis than with BCG and this differential response was independent of mycobacterial viability. TNF alpha production involved the PTK and MAP kinase pathways. Reduced TNF alpha induction by M. tuberculosis was associated with a reduction in the extent and duration of phosphorylation of extracellular-signal regulated kinases (ERK 1/2). Infection with M. leprae triggered low and transient ERK 1/2 activation as well as low TNF alpha production.


CONCLUSIONS
Maintenance of the differential response in both live and heat-killed preparations suggests that the reduced TNF alpha response associated with virulent mycobacteria is due to differences in the presence of components capable of triggering host pattern recognition receptors, rather than events associated with phagosome trafficking or the active release of intracellular modulators.
Hasan
Z
Z
Department of Microbiology, The Aga Khan University, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan. zahra.hasan@aku.edu
Shah
B H
BH
Mahmood
A
A
Young
D B
DB
Hussain
R
R
D001500:BCG Vaccine / Q000276:immunology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000276:immunology* / Q000382:microbiology; D009161:Mycobacterium / Q000276:immunology / Q000472:pathogenicity*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014774:Virulence
D001500:BCG Vaccine; D004791:Enzyme Inhibitors; D005419:Flavonoids; D014409:Tumor Necrosis Factor-alpha; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one