-
[show abstract]
[hide abstract]
ABSTRACT: The pathogenicity of mycobacterial infections depends on virulence factors that mediate survival inside host macrophages. These virulence factors are generally believed to be specific for pathogenic species and absent or mutated in non-pathogenic strains. The serine/threonine protein kinase G (PknG) mediates survival of mycobacteria within macrophages by blocking lysosomal delivery. Here we describe a gene of the non-pathogenic species Mycobacterium smegmatis that is 78% identical with pknG of Mycobacterium tuberculosis and M. bovis bacillus Calmette-Guérin (BCG). When cloned into expression vectors, the M. smegmatis pknG orthologue produced an active kinase and performed the same function as its M. bovis BCG counterpart in intracellular survival. In addition, similar levels of pknG transcripts were found in M. bovis BCG and M. smegmatis. However, virtually no translation product of chromosomal pknG could be detected in M. smegmatis both after in vitro growth and after macrophage infection. This lack of efficient translation was shown to be caused by regulatory elements in the upstream region of the M. smegmatis gene. The data reveal dramatically increased translational efficiency of a virulence gene in a pathogenic mycobacterium compared with a non-pathogenic mycobacterium suggesting that changes in expression levels may underlie evolution of pknG and other pathogenicity genes in mycobacterium.
Molecular Microbiology 02/2009; 72(1):41-52. · 5.01 Impact Factor
-
R Andres Floto,
Paul A MacAry,
Jessica M Boname,
Tan Suet Mien,
Beate Kampmann,
James R Hair,
Oh Seen Huey, Edith N G Houben,
Jean Pieters,
Cheryl Day,
Wulf Oehlmann,
Mahavir Singh,
Kenneth G C Smith,
Paul J Lehner
[show abstract]
[hide abstract]
ABSTRACT: An effective host immune response to mycobacterial infection must control pathogen dissemination without inducing immunopathology. Constitutive overexpression of mycobacterial heat shock protein (myHsp70) is associated with impaired bacterial persistence, but the immune-mediated mechanisms are unknown. We found that myHsp70, in addition to enhancing antigen delivery to human dendritic cells, signaled through the CCR5 chemokine receptor, promoting dendritic cell aggregation, immune synapse formation between dendritic cells and T cells, and the generation of effector immune responses. Thus, CCR5 acts as a pattern-recognition receptor for myHsp70, which may have implications for both the pathophysiology of tuberculosis and the use of myHsps in tumor-directed immunotherapy.
Science 11/2006; 314(5798):454-8. · 31.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Pathogenic mycobacteria, in particular Mycobacterium tuberculosis, the causative agent of tuberculosis, have the remarkable capacity to circumvent destruction within one of the most hostile cell types of a vertebrate host: the macrophage. The ability of pathogenic mycobacteria to survive inside macrophages has been known for more than 30 years; yet, only recently have advances in molecular genetics, biochemistry, immunology, as well as global analysis of gene expression, started to unravel the strategies utilized by these pathogens for intracellular persistence. In addition, the definition of key molecules that are important for intracellular survival opens the possibility to develop new drugs to combat mycobacterial diseases.
Current Opinion in Microbiology 03/2006; 9(1):76-85. · 7.93 Impact Factor
