Because macrophages have an important role in the host immune defence mechanism that leads to containment of TB, and therefore the latent form of infection, the authors proposed that macrophages that are associated with different clinical manifestations of TB have different gene expression profiles. To investigate this hypothesis, the authors tested the expression of >38,500 genes from macrophages isolated from 12 human subjects who had previously developed latent, pulmonary or meningeal TB before and after ex vivo stimulation with M. tuberculosis. This revealed a more than twofold change in the expression of 1,608 genes and a more than fivefold change in the expression of 199 genes. Overall, gene expression patterns were significantly more similar among macrophages from the same clinical outcome group than among samples from different groups, which indicated that host genetics are involved in the clinical outcome of TB. Furthermore, several macrophage immune response genes, including tumour necrosis factor and interleukin-1β, were specifically upregulated only in macrophages from individuals that had a specific disease outcome. These results were subsequently confirmed in a 'validation' reverse transcription PCR expression analysis of TB-stimulated macrophage mRNA from 34 additional individuals who had been infected with latent, pulmonary or meningeal TB. In this analysis, 90% of a subset of these genes were also upregulated or downregulated in response to M. tuberculosis, but only one gene, CCL1 (CC-chemokine ligand 1), which stimulates the migration of human monocytes, was specifically associated with clinical outcome.
...the authors showed that the inflammatory mediator CCL1 is specifically associated with host susceptibility to pulmonary TB.
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