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Studies of the intercellular signalling actions of Mycobacterium tuberculosis chaperonins

Mycobacterial chaperonin 60 (Cpn60) is an intracellular molecule essential for cellular function due to its protein folding actions. However, it has recently been established that Cpn60 can be released by certain bacteria and act as an extracellular signalling protein. Mycobacterium tuberculosis has two genes coding for Cpn60 proteins: cpn60.1 and cpn60.2 (also known as hsp65). It was recently shown that Cpn60.1 and Cpn60.2 are pro-inflammatory activators of myeloid cells and that the effects of Cpn60.1, but not Cpn60.2, depend on CD14. This PhD project shows that M. tuberculosis Cpn60.1 and Cpn60.2 proteins strongly bind to human peripheral blood monocytes but their binding sites are different. Both M. tuberculosis Cpn60 proteins depend on MyD88 for the maximal activation of intracellular signalling pathways but have different TLR requirements: Cpn60.1 signals exclusively through TLR4 while Cpn60.2 needs the presence of TLR2 and TLR4 for maximal induction of pro-inflammatory cytokines. A study has recently established that an M. tuberculosis mutant with an inactivated cpn60.1 gene is unable to induce granulomas in animal models suggesting that Cpn60.1 has inflammation-modulatory effects on myeloid cells. This PhD project identified that recombinant M. tuberculosis Cpn60.1 has bipolar effects on human circulating monocytes. At high concentrations Cpn60.1 induces the synthesis of TNF-α and promotes the phosphorylation of NF-κB p65, p44/42MAPK and p38 MAPK while at picomolar concentrations, Cpn60.1 inhibits the lipopolysaccharide-induced formation of TNF-α and the phosphorylation of NF-κB p65 without affecting the activation of MAP kinases. Gene expression analysis show that low concentrations of Cpn60.1 completely suppress cell activation while higher concentrations of Cpn60.1 down-regulate the expression of major pro-inflammatory cytokine and chemokine genes in human monocytes. It is therefore concluded that M. tuberculosis Cpn60.1 is an unusual protein with the ability to induce bipolar effects which may help explain the pathology of granuloma formation in tuberculosis.
Date January 2009
CreatorsCehovin, A.
PublisherUniversity College London (University of London)
Source SetsEthos UK
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation

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