TY  - UNPB
ID  - discovery17419
TI  - Studies of the intercellular signalling actions of Mycobacterium tuberculosis chaperonins
N1  - Authorisation for digitisation not received
N2  - 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-? and promotes the phosphorylation of NF-?B p65,
p44/42MAPK and p38 MAPK while at picomolar concentrations, Cpn60.1 inhibits the
lipopolysaccharide-induced formation of TNF-? and the phosphorylation of NF-?B
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.
PB  - UCL (University College London)
UR  - https://discovery.ucl.ac.uk/id/eprint/17419/
M1  - Doctoral
Y1  - 2009/08//
AV  - none
A1  - Cehovin, A.
EP  - 229
ER  -