CIHR-UBC Strategic Training Program for
Translational Research in Infectious Diseases
Address: D452 – 2733 Heather Pavilion, Vancouver, BC V5Z 3J5
E-mail: tonychow@interchange.ubc.ca
Voice: (604) 875-5063 Fax: (604) 875-4013 Website: http://cmdr.ubc.ca/trainingprogram
Research Theme:
Pathogenomics, proteomics, vaccine development, diagnostics
Sub-theme:
Pathogenesis of M. tuberculosis and the M. avium complex – a search for novel
therapeutics and vaccines
Principal Investigator:
Dr. Richard W. Stokes, PhD
Telephone:
Fax:
E-mail:
604-875-2466
604-875-2226
rstokes@cbdn.ca
Approximately one third of the world's population are infected with Mycobacterium tuberculosis, the causative agent of
tuberculosis (TB). Every year this major pathogen of man is the cause of 3 million deaths worldwide and it is estimated
that there are 10 million new cases arising annually. The emergence of AIDS has accelerated the spread of TB and
resulted in the emergence of infections due to other mycobacteria, for example the M. avium complex (MAC).
Furthermore, recent data for North America indicates that there is an increase in the incidence of tuberculosis including
infections with multidrug resistant strains, which have become a serious problem in certain urban centres. My research
concentrates on studying the pathogenesis of TB and MAC in order to understand, at the molecular level, how they
interact with the host. Through this approach we hope to identify new ways to attack these bacteria through the use of
new and improved therapeutics or the design of a novel vaccine.
CURRENT RESEARCH PROJECTS:
1) Mycobacteria-macrophage interactions: The receptor/ligand interactions mediating uptake of M. tuberculosis by
host cell macrophages are being characterised. Current studies are directed at understanding the role of CD43
(sialophorin) and CD11b/CD18 (complement receptor 3) in the binding of TB to macrophages and at determining
whether or not the survival and replication of M. tuberculosis within macrophages is influenced by the receptor and/or
the type of macrophage which mediates the uptake of the mycobacterium. Knowledge about this interaction should help
us to design novel stategies and therapeutics that will subvert the ability of the bacteria to survive in the host cell.
2) The role of the mycobacterial capsule: I have shown that the capsule or Outer Layer of the Cell Wall Envelope (OLCWE) of M. tuberculosis acts to limit its interaction with macrophages and that the OL-CWE of opportunistic pathogens
(e.g. M. avium) and saprophytes (e.g. M. smegmatis) does not have a similar function. I hypothesize that the OL-CWE
of M. tuberculosis acts to limit the interaction of the bacteria with macrophages in a similar fashion to that of the capsule
present on other microbial pathogens. I am currently investigating the role that the OL-CWE of M. tuberculosis plays in
the pathogenesis of the bacteria. The specific objectives of this study are :- (i) To characterize the OL-CWE of
intracellular and axenically grown M. tuberculosis. (ii) To identify and characterize the component(s) within the OLCWE of M. tuberculosis that mediate the observed inhibition of the association of M. tuberculosis with macrophages.
(iii) To construct and characterize OL-CWE mutants.
3) Molecular definition of mycobacterial virulence factors: We are attempting to identify genes and their products which
enable mycobacteria to survive and multiply within their host. This will be achieved by identifying genes which are
only found in virulent isolates of mycobacteria but are absent in avirulent isolates. Using virulent and avirulent pairs of
M. tuberculosis and MAC strains, genes conferring virulence are being sought using a number of approaches
(proteomics, 2 dimensional DNA analysis, isolation of transposon mutants). Once these genes have been identified and
characterised, we hope to be able to design novel strategies to nullify these genes or their products and thus compromise
the survival of the mycobacteria.
Updated: August 2003
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