Abstract
Hematogenous dissemination of Mycobacterium tuberculosis (M. tb) occurs during both primary and reactivated tuberculosis (TB). Although hematogenous dissemination occurs in non-HIV TB patients, in ∼80% of these patients, TB manifests exclusively as pulmonary disease. In contrast, extrapulmonary, disseminated, and/or miliary TB is seen in 60–70% of HIV-infected TB patients, suggesting that hematogenous dissemination is likely more common in HIV+ patients. To understand M. tb adaptation to the blood environment during bacteremia, we have studied the transcriptome of M. tb replicating in human whole blood. To investigate if M. tb discriminates between the hematogenous environments of immunocompetent and immunodeficient individuals, we compared the M. tb transcriptional profiles during replication in blood from HIV- and HIV+ donors. Our results demonstrate that M. tb survives and replicates in blood from both HIV- and HIV+ donors and enhances its virulence/pathogenic potential in the hematogenous environment. The M. tb blood-specific transcriptome reflects suppression of dormancy, induction of cell-wall remodeling, alteration in mode of iron acquisition, potential evasion of immune surveillance, and enhanced expression of important virulence factors that drive active M. tb infection and dissemination. These changes are accentuated during bacterial replication in blood from HIV+ patients. Furthermore, the expression of ESAT-6, which participates in dissemination of M. tb from the lungs, is upregulated in M. tb growing in blood, especially during growth in blood from HIV+ patients. Preliminary experiments also demonstrate that ESAT-6 promotes HIV replication in U1 cells. These studies provide evidence, for the first time, that during bacteremia, M. tb can adapt to the blood environment by modifying its transcriptome in a manner indicative of an enhanced-virulence phenotype that favors active infection. Additionally, transcriptional modifications in HIV+ blood may further accentuate M. tb virulence and drive both M. tb and HIV infection.
Highlights
Infection with M. tuberculosis (M. tb) is initiated by the few bacilli in a droplet that are inhaled into the alveolus, which results either in establishment of infection and progression to primary TB or, by 4–5 weeks post-infection, elicitation of immune responses that control bacterial replication and result in latent TB
Our results demonstrate that esat6, the gene encoding ESAT-6, which plays an important role in dissemination of M. tb from the lungs, is upregulated in M. tb growing in blood [41,42], especially in bacteria growing in HIV+ patient blood
To investigate the transcriptome of M. tb in the hematogenous environment, we first evaluated the ability of M. tb H37Rv to survive and replicate in fresh whole blood from 10 HIV- and 15 HIV+ donors (Figure 1; TABLE S1)
Summary
Infection with M. tuberculosis (M. tb) is initiated by the few bacilli in a droplet that are inhaled into the alveolus, which results either in establishment of infection and progression to primary TB or, by 4–5 weeks post-infection, elicitation of immune responses that control bacterial replication and result in latent TB. Viable M. tb have been demonstrated in lungs, liver, spleen and kidneys of healthy individuals who died of causes unrelated to TB, in a TB endemic setting [5]. This again provides evidence of hematogenous dissemination of M. tb during primary infection resulting in latent TB [5]. Evidence for disseminated M. tb in patients who reactivated their latent infection exists [8]. Bacteremia and hematogenous dissemination of M. tb is an important component of the natural course of establishment of infection and progression to both primary and reactivated TB
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