The Innate Immune Response to Mycobacterium Tuberculosis is Dependent on Strain Lineage and on Host Population

The genome structure of Mycobacterium tuberculosis is strongly clonal, in the absence of horizontal gene transfer.Thus it is feasible that clonal lineages may exhibit particular phenotypic characteristics, which may, in turn, result in differences in virulence or influence their association with particular host populations.Indeed, the global distribution of M. tuberculosis strains is not uniform and certain strain lineages predominate in particular geographical areas.Further, there is evidence that some strain lineages are emerging, suggesting differences in virulence.Firstly, we investigated the association between strain genotype of M. tuberculosis and in vitro correlates of virulence such as growth phenotype and cytokine induction in the monocyte-derived macrophage (MDM) model.We report that 'modern' clinical M. tuberculosis isolates from Cape Town (Lineage 2 and Lineage 4 strains) exhibit both lineage-specific patterns of growth in vitro (in broth and MDM) as well as cytokine responses in MDM.Secondly, in order to study the interaction between host genetic background and the innate immune response to different strains of M. tuberculosis we conducted a cross sectional study comparing cytokine responses to in vitro infection of healthy donor MDM from individuals from different population groups with strains from different M. tuberculosis lineages.The inflammatory cytokines TNF, IL-12p40, IL-6, IL-1 and GM-CSF were secreted at higher levels in response to infection with lineage 4 and lineage 3 strains as compared to lineage 2 and lineage 1 strains.Principal component analysis and linear modeling identified three inflammatory cytokines (IL-6, IL-12p40, and GM-'granuloma' formation which triggers dormancy or latency of mycobacterial infection.A 'granuloma' consists of small numbers of infected phagocytes surrounded by blood derived monocytes, macrophages, epitheloid cells (differentiated macrophages) or foamy macrophages and CD4+, CD8+ lymphocytes along with fibroblasts and extracellular matrix protein.A characteristic feature of granulomas in tuberculosis infection is central solid necrotic tissue due to death of infected cells.Effective T cell