Chang, J-S; Huggett, JF; Dheda, K; Kim, LU; Zumla, A; Rook, G; (2006) M. tuberculosis induces selective upregulation of Toll-like receptors in the mononuclear leukocytes of patients with active pulmonary tuberculosis. The Journal of Immunology , 176 (5) 3010 - 3018.
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Human and mouse studies indicate that Toll-like receptors (TLR) are important in mycobacterial infections. We investigated TLR gene expression in fresh unstimulated blood and bronchoalveolar lavage (BAL) from patients with pulmonary tuberculosis, using a well-validated real time PCR. A splice variant of TLR1, designated hsTLR1, was found in all donors tested. hsTLR1 mRNA lacks exon 2, which is a 77 bp region of the 5/ untranslated region, but contains the same coding sequence as TLR1. Compared to the matched controls, whole blood from patients had increased levels of mRNA encoding TLR2 (p = 0.0006), TLR1 (p = 0.004), hsTLR1 (p = 0.0003), TLR6 (p < 0.0001) and TLR4 (p = 0.0002). By contrast, expression of these TLR was not increased in BAL. An increased level of hsTLR1 mRNA was found in both CD3- (p = 0.0078) and in CD4+ cells (p = 0.028) resulting in an increased ratio of hsTLR1 mRNA to TLR1 and to TLR6 mRNA. An in vitro study in THP1 cells suggested that this relative increase in hsTLR1 might be attributable to a direct effect of mycobacterial components because it could be mimicked by mycobacterial preparations in the absence of IFN-? or T cells, and by the TLR1/2 agonist, Pam3CysK4. Half-life studies using blood from patients with pulmonary TB and THP1 cells exposed to M. tuberculosis in vitro showed p38 MAPK-independent stabilisation of mRNAs encoding hsTLR1 and TLR1. We conclude that M. tuberculosis exerts direct effects on patterns of TLR expression, partly via changes in mRNA half-life. The significance of these changes in the pathogenesis of disease deserves further investigation.
|Title:||M. tuberculosis induces selective upregulation of Toll-like receptors in the mononuclear leukocytes of patients with active pulmonary tuberculosis|
|Keywords:||human, bacterial, lung|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Infection and Immunity (Division of)|
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Surgery and Interventional Science (Division of) > Institute of Orthopaedics and Musculoskeletal Science
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