Author: Wenfei WangPublisher:
ISBN:
Category :
Languages : de
Pages : 0
Book Description
Mycobacterium tuberculosis (M.tb), the etiologic agent of tuberculosis (TB), remains a significant global public health burden. The limitations of traditional antimycobacterial therapies led researchers in the tuberculosis community to focus on the possibility of modulating the host immune response as adjunctive therapy. We identified a genetic variation (rs8193036) in the promoter region of IL17A is associated with susceptibility to TB. Functional assay demonstrated that rs8193036 C allele exhibited significantly lower promotor transcription activities. The rs13120371 AA genotype was strongly associated with an increased risk of TB and increased xCT mRNA expression levels compared to those with the GG or AG genotype. rs13120371 is located on the 3' untranslated (UTR) region of the xCT gene, the rs13120371 AA genotype inhibited the binding of miR-42-3p to xCT. Pretreatment with sulfasalazine (SASP) alleviated bacterial burden in cells with the AA genotype but conferred no benefit in cells with the GG phenotype. We found that the expression of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase (mPGES)-1 increased significantly in monocyte-derived macrophages (MDM) which the infected M.tb still alive. After treatment with SASP, COX-2 gene expression and the level of PGE2 decreased to normal level. COX-2 might be a novel target for treatment of TB and that SASP might be a potential therapeutic drug which prevents severe inflammation in the pathogenesis process of TB. Together, this thesis provides evidence that infection of human macrophages by M.tb strongly induces eicosanoid pathway key enzyme expression along with pro-inflammatory cytokine formation, which is suppressed by SASP that facilitates M.tb clearance by macrophages. The repurposing of already available drugs known to modulate host responses may improve the future of host directed therapy (HDT) for TB.
