The role of CD43 in the growth and pathogenesis of Mycobacterium tuberculosis within the mammalian host

Mycobacterium tuberculosis exploits various molecules on host cells to gain entry and establish a niche for survival and replication. We characterized the role of the glycoprotein CD43 in the pathogenesis of M. tuberculosis. Using gene-deleted mice (CD43-/-), we assessed association of the bacterium with macrophages and found that CD43 was required for optimal binding of M. tuberculosis strain Erdman by splenic, peritoneal, alveolar, and bone marrow-derived macrophages. Macrophages from heterozygote (CD43+/-) mice, which express 50% less CD43 than wild type (CD43+/+) mice, bound more bacteria than CD43-/- but less than CD43+/+ indicating that the surface expression of CD43 correlates with binding of M. tuberculosis. The role of CD43 in binding bacteria may be restricted to mycobacterial species as CD43-/- macrophages also bound less Mycobacterium avium and Mycobacterium tuberculosis H37Rv, but there was no observed role in the binding of Salmonella typhimurium or Listeria monocytogenes. Although absence of CD43 resulted in decreased binding of M. tuberculosis, the subsequent growth of the bacterium within CD43-/- macrophages was enhanced as illustrated by increased bacterial numbers and decreased doubling times, indicating that that the mechanism of entry may influence subsequent. To elucidate mechanisms by which CD43 controls of growth of M. tuberculosis, we examined the induction of antimycobacterial activities. In response to M. tuberculosis, CD43-/- macrophages were deficient in the production of nitric oxide, TNF-⍺, and IL-12. Furthermore, M. tuberculosis induced less apoptosis, but more necrosis, in CD43-/- macrophages compared to CD43+/+. The enhanced growth of M. tuberculosis was abrogated by IFN-Ɣ-stimulation with whereas addition of TNF-⍺ restored both the intracellular growth rates and amounts of apoptosis to wild type levels. To investigate the role of CD43 in vivo, we infected CD43-/- and CD43+/+ mice with M. tuberculosis and assessed bacterial loads and organ pathology. Absence of CD43 resulted in increased bacterial loads in lungs and spleens during both acute and chronic stages of infection, and formation of granulomas occurred more quickly in CD43-/- mice. These data point to a dual role for CD43 in the uptake and subsequent growth of M. tuberculosis in macrophages and mice.

Name thesis:degree_name

Doctor of Philosophy - PhD

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Experimental Medicine

Grantor dc:publisher

University of British Columbia

Year dc:date

2007

Author dc:creator

• Randhawa, April Kaur

Statement dc:rights

• Attribution-NonCommercial-NoDerivatives 4.0 International

Licence

• http://creativecommons.org/licenses/by-nc-nd/4.0/

Language dc:language

eng

Handle dc:identifier

http://hdl.handle.net/2429/258

OAI identifier oai:identifier

oai:circle.library.ubc.ca:2429/258