The immunological aspects of latency in tuberculosis

Chan, John; Flynn, Jo Anne L.

doi:10.1016/s1521-6616(03)00210-9

Cited by 151 publications

(129 citation statements)

References 104 publications

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“…Dying neutrophils and macrophages shed blebs containing M. tuberculosis antigens or spill intact M. tuberculosis; both can be taken up by alveolar dendritic cells which migrate to the regional lymph nodes, where they present M. tuberculosis antigens to major histocompatibility complex (MHC) class-I restricted CD8 Tcells and MHC class-II restricted CD4 T-cells. In the lymph node, stimulated CD4 and CD8 T-cells differentiate into interferon (IFN)-c secreting T-helper (Th) type 1 or cytotoxic Tc1 cells, respectively, and granules of CD8 T-cells accumulate molecules such as granzymes and granulysin [18]. At the same time, B-cells differentiate into M. tuberculosis-specific antibodysecreting cells.…”

Section: Sectionmentioning

confidence: 99%

“…The larger the viable mycobacterial load and the remaining lesions are, the more likely constant antigen-specific re-stimulation of the memory/effector T-cell pool becomes. Conversely, the more encapsulated and quiescent the lesions and the smaller in size they are, the more likely it is that Th1 cell immunity will decline [18]. Indeed, a reversion from a positive to a negative tuberculin skin test can occur at a rate of 5%?yr -1 and there is evidence that IGRA positivity also wanes, and perhaps even more quickly, over time [30,31].…”

Section: Sectionmentioning

confidence: 99%

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LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement

Mack

Migliori

Sester

et al. 2009

European Respiratory Journal

508

446

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Tuberculosis control relies on the identification and preventive treatment of individuals who are latently infected with Mycobacterium tuberculosis. However, direct identification of latent tuberculosis infection is not possible. The diagnostic tests used to identify individuals latently infected with M. tuberculosis, the in vivo tuberculin skin test and the ex vivo interferon-c release assays (IGRAs), are designed to identify an adaptive immune response against, but not necessarily a latent infection with, M. tuberculosis. The proportion of individuals who truly remain infected with M. tuberculosis after tuberculin skin test or IGRA conversion is unknown. It is also uncertain how long adaptive immune responses towards mycobacterial antigens persist in the absence of live mycobacteria. Clinical management and public healthcare policies for preventive chemotherapy against tuberculosis could be improved, if we were to gain a better understanding on M. tuberculosis latency and reactivation. This statement by the TBNET summarises knowledge and limitations of the currently available tests used in adults and children for the diagnosis of latent tuberculosis infection.In summary, the main issue regarding testing is to restrict it to those who are known to be at higher risk of developing tuberculosis and who are willing to accept preventive chemotherapy.

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Section: Sectionmentioning

confidence: 99%

Section: Sectionmentioning

confidence: 99%

LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement

Mack

Migliori

Sester

et al. 2009

European Respiratory Journal

508

446

View full text Add to dashboard Cite

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“…1 Infection with M. tuberculosis is controlled in most infected individuals, while in a minority of cases containment of infection fails over time, and active TB disease develops. 2 Although only a minority of exposed individuals develop active disease, morbidity and mortality in humans worldwide remain high, with nearly 2 million deaths annually. 3,4 In the face of this major impact on global health, remarkably little progress has been made in the past towards the development of new tools and elucidation of key features involved in protection and pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Human gene expression profiles of susceptibility and resistance in tuberculosis

et al. 2010

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Tuberculosis (TB) still poses a profound burden on global health, owing to significant morbidity and mortality worldwide. Although a fully functional immune system is essential for the control of Mycobacterium tuberculosis infection, the underlying mechanisms and reasons for failure in part of the infected population remain enigmatic. Here, whole-blood microarray gene expression analyses were performed in TB patients and in latently as well as uninfected healthy controls to define biomarkers predictive of susceptibility and resistance. Fc gamma receptor 1B (FCGRIB)was identified as the most differentially expressed gene, and, in combination with four other markers, produced a high degree of accuracy in discriminating TB patients and latently infected donors. We determined differentially expressed genes unique for active disease and identified profiles that correlated with susceptibility and resistance to TB. Elevated expression of innate immune-related genes in active TB and higher expression of particular gene clusters involved in apoptosis and natural killer cell activity in latently infected donors are likely to be the major distinctive factors determining failure or success in controlling M. tuberculosis infection. The gene expression profiles defined in this study provide valuable clues for better understanding of progression from latent infection to active disease and pave the way for defining predictive correlates of protection in TB.

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“…As a consequence, several drug discovery programs have been established worldwide with the goal of finding new therapeutic agents that may complement or even replace the existing directly observed therapy short course (DOTS) for TB. These programs have to cope with the ability of the pathogen to enter the so-called dormant or latent phase (5,6), characterized by phenotypic drug resistance (11). Complete control of TB will therefore require finding drugs that are effective against the reservoir of nongrowing tubercle bacilli and, hence, the necessity of modeling this state in vitro and in vivo in order to screen for active compounds.…”

mentioning

confidence: 99%

Simple Model for Testing Drugs against Nonreplicating Mycobacterium tuberculosis

Sala

Dhar

Hartkoorn

et al. 2010

Antimicrob Agents Chemother

123

135

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Nonreplicating or dormant cells of Mycobacterium tuberculosis constitute a challenge to tuberculosis (TB) therapy because of their tolerance or phenotypic resistance to most drugs. Here, we propose a simple model for testing drugs against nongrowing cells that exploits the 18b strain of M. tuberculosis, a streptomycin (STR)-dependent mutant. Optimal conditions were established that allowed 18b cells to replicate in the presence of STR and to survive, but not multiply, following withdrawal of STR. In the presence of the antibiotic, M. tuberculosis 18b was susceptible to the currently approved TB drugs, isoniazid (INH) and rifampin (RIF), and to the experimental drugs TMC207, PA-824, meropenem (MER), benzothiazinone (BTZ), and moxifloxacin (MOXI). After STR depletion, the strain displayed greatly reduced susceptibility to the cell wall inhibitors INH and BTZ but showed increased susceptibility to RIF and PA-824, while MOXI and MER appeared equipotent under both conditions. The same potency ranking was found against nonreplicating M. tuberculosis 18b after in vivo treatment of chronically infected mice with five of these drugs. Despite the growth arrest, strain 18b retains significant metabolic activity in vitro, remaining positive in the resazurin reduction assay. Upon adaption to a 96-well format, this assay was shown to be suitable for high-throughput screening with strain 18b to find new inhibitors of dormant M. tuberculosis.Tuberculosis (TB) is one of the most important infectious diseases caused by a single pathogen and afflicts both healthy and immunocompromised individuals. One-third of the human population is reported to be latently infected with Mycobacterium tuberculosis, and millions of lives are lost every year (8). The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains (10), together with a deadly synergy with HIV, has worsened the global problem and forced the research community to look for new strategies to fight M. tuberculosis. As a consequence, several drug discovery programs have been established worldwide with the goal of finding new therapeutic agents that may complement or even replace the existing directly observed therapy short course (DOTS) for TB. These programs have to cope with the ability of the pathogen to enter the so-called dormant or latent phase (5, 6), characterized by phenotypic drug resistance (11). Complete control of TB will therefore require finding drugs that are effective against the reservoir of nongrowing tubercle bacilli and, hence, the necessity of modeling this state in vitro and in vivo in order to screen for active compounds.Latent TB is the result of complex host-pathogen interactions (26, 35), and mimicking this state may thus be partial and challenging. Different models have been proposed so far, each one based on a particular stress that the pathogen may encounter in the host. In particular, the oxygen depletion model mimics the hypoxic environment of the granuloma (30, 31) and the nutrient starvation model recapitulates the lack...

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The immunological aspects of latency in tuberculosis

Cited by 151 publications

References 104 publications

LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement

LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement

Human gene expression profiles of susceptibility and resistance in tuberculosis

Simple Model for Testing Drugs against Nonreplicating Mycobacterium tuberculosis

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