Background
Mycobacterium tuberculosis and HIV act synergistically to enhance and accelerate the development of tuberculosis and progression of HIV infection to AIDS. Hematogenous dissemination of M. tuberculosis leading to extrapulmonary TB, disseminated TB and miliary TB is greatly increased in HIV+ TB patients. We have compared the transcriptome of M. tuberculosis replicating in whole blood from immunocompetent and immunodeficient individuals to understand how M. tuberculosis adapts to the blood environment during hematogenous dissemination.
Methodology
Whole genome microarray analysis was performed on RNA from M. tuberculosis replicating in whole blood from PPD negative HIV- healthy donors and HIV+ donors. Genes with a fold change of≥ 2, at a false discovery rate of < 2%, were considered significantly differentially expressed.
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Results
M. tuberculosis survives and replicates in blood, and enhances its virulence/pathogenic potential during adaptation to the hematogenous environment. The blood specific transcriptome reflects suppression of dormancy, induction of cell-wall remodeling, alteration in mode of iron acquisition, evasion of immune surveillance and enhanced expression of important virulence factors that drive active infection and dissemination. Compared to replication in HIV blood, these changes are accentuated during replication in blood from HIV patients. The expression of ESAT-6, known to play an important role in dissemination of M. tuberculosis from the lungs, is upregulated in M. tuberculosis growing in blood, and especially dramatically during growth in HIV+ blood.
Conclusion
M. tuberculosis modulates its aggressive progression to disseminated forms of TB by modifying its transcriptome to acquire a phenotype with enhanced virulence that favors active infection and dissemination.
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