Mycobacterium tuberculosis induces selective upregulation of toll-like receptors in the mononuclear leukocytes of patients with active pulmonary tuberculosis

Toll like receptors (TLRs) belong to the pattern recognition receptor (PRR) family which plays an important role in innate immunity by recognising conserved pathogen associated-molecular patterns (PAMPs) present on a wide range of microbes. In general, TLR2 (as a homo- or heterodimer with TLR 1 or 6) recognises Gram (+) bacteria whilst TLR4 recognises Gram (-) bacteria. The aim of this project was to investigate the role of TLRs in innate immunity in response to TB. 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 TLR 1, designated hsTLRl, was found in all donors tested. hsTLRl mRNA lacks exon 2, which is a 77 bp region of the 57 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, TLR1, hsTLRl, TLR6 and TLR4. By contrast, expression of these TLR was not increased in BAL. An increased level of hsTLRl mRNA was found in both CD3" and in CD4+ cells resulting in an increased ratio of hsTLRl mRNA to TLR1 and to TLR6 mRNA. An in vitro study in THP1 cells suggested that this relative increase in hsTLRl 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 TB patients and THP1 cells exposed to Mtb showed p38 MAPK-independent stabilisation of mRNAs encoding hsTLRl 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.