Myobacterium tuberculosis induces selective up-regulation of TLRs in the mononuclear leukocytes of patients with active pulmonary tuberculosis.
Human and mouse studies indicate that TLRs are important in mycobacterial infections. We investigated TLR gene expression in fresh unstimulated blood and bronchoalveolar lavage from patients with pulmonary tuberculosis using a well-validated, real-time PCR. A human 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 with 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 TLRs was not increased in bronchoalveolar lavage. An increased level of hsTLR1 mRNA was found in both CD3- (p = 0.0078) and 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-gamma or T cells and by the TLR1/2 agonist Pam3CysK4. Half-life studies using blood from patients with pulmonary tuberculosis and THP1 cells exposed to Myobacterium tuberculosis in vitro showed p38 MAPK-independent stabilization 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.
Chang
Jung-Su
JS
Centre for Infectious Diseases and International Health, Royal Free and University College Medical School, London, United Kingdom.
Huggett
Jim F
JF
Dheda
Keertan
K
Kim
Louise U
LU
Zumla
Alimuddin
A
Rook
Graham A W
GA
D017398:Alternative Splicing; D001483:Base Sequence; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism; D055666:Lipopeptides; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D020871:RNA Stability; D012333:RNA, Messenger / Q000097:blood; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051194:Toll-Like Receptor 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D051193:Toll-Like Receptors / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D010455:Peptides; D012333:RNA, Messenger; D051194:Toll-Like Receptor 1; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases