The Influence Of Host Genetics And Different <i>Mycobacterium tuberculosis</i> Strains On Macrophage Functions And Clinical Outcome Of Tuberculosis Disease

Abstract

Only 5-10 % of Mycobacterium tuberculosis (Mtb) infected individuals develop active pulmonary TB (PTB), and around Mtb isolates are associated with Mtb lineages and distinct host immune responses. I developed assays using ligand coated beads and Mtb reporter strain to measure the macrophage antimicrobial activities. Our assays were able to detect the variation in macrophage activities among different individuals. I investigated the macrophage antimicrobial functions and its association with different TB phenotypes. I measured the macrophage activities in 43 latent TB (LTB) and active TB (ATB) cases combining 54 PTB and 60 TBM patients. Our results showed that macrophages treated with ligands displayed higher antimicrobial activities in LTB than ATB, but no difference between PTB and TBM. Whereas, in Mtb-infected macrophages from both LTB and ATB, proteolysis was reduced due to the modulation of Mtb and there was no difference in their ability to control Mtb. Our data also indicated that the antimicrobial activities of macrophages were ligand-specific or pathway-dependent. The influence of host genetics on TB susceptibility was examined by the association of variants on phagocytic genes using a case-control study with 450 TBM, 450 PTB and 450 controls. Heterozygotes of Macrophage receptor with collagenous structure (MARCO) single nucleotide polymorphisms (SNPs) were associated with increased TB susceptibility, abnormal chest X-ray, infection by Beijing strains and also with impaired macrophage phagocytosis of ligand coated beads. The virulence of Mtb strains was examined by observing cell lysis of macrophages infected with 159 Mtb strains. Virulence phenotype was grouped as low, moderate and high. High virulence was associated with Beijing lineage, reduced TNF-α and IL-6 and increased IL-1β concentration. Overall, this thesis provides new insights into the influence of host and bacterial factors on TB susceptibility. It also provides a foundation for further studies on factors influencing TB susceptibility