Identification of gene targets against dormant phase Mycobacterium tuberculosis infections

Murphy, Dennis J.; Brown, James R.

doi:10.1186/1471-2334-7-84

Cited by 138 publications

(149 citation statements)

References 124 publications

(140 reference statements)

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“…We show that D-Mtb downmodulates expression of the esat6 gene, suggesting that in dormancy M. tuberculosis secretes reduced amounts of ESAT-6 in comparison with R-Mtb. Moreover, expression of the gene Rv3309c, which encodes for SapM, was previously found downregulated in D-Mtb obtained with the same Wayne culture method we used and in stressed mouse macrophages (46). Taken together, these data are highly suggestive for the pivotal role played by the reduced expression of esat6 and SapM as a possible mechanism used by D-Mtb to permit phagosome maturation and downstream events leading to an increased Ag processing and presentation to specific CD4 + T lymphocytes.…”

Section: Discussionsupporting

confidence: 58%

Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes

Mariotti

Pardini

Gagliardi

et al. 2013

The Journal of Immunology

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Dormancy is defined as a stable but reversible nonreplicating state of Mycobacterium tuberculosis. It is currently thought that dormant M. tuberculosis (D-Mtb) is responsible for latent tuberculosis (TB) infection. Recently, D-Mtb was also shown in sputa of patients with active TB, but the capacity of D-Mtb to stimulate specific immune responses was not investigated. We observed that purified protein derivative–specific human CD4+ T lymphocytes recognize mycobacterial Ags more efficiently when macrophages are infected with D-Mtb instead of replicating M. tuberculosis (R-Mtb). The different Ag recognition occurs even when the two forms of mycobacteria equally infect and stimulate macrophages, which secrete the same cytokine pattern and express MHC class I and II molecules at the same levels. However, D-Mtb but not R-Mtb colocalizes with mature phagolysosome marker LAMP-1 and with vacuolar proton ATPase in macrophages. D-Mtb, unlike R-Mtb, is unable to interfere with phagosome pH and does not inhibit the proteolytic efficiency of macrophages. We show that D-Mtb downmodulates the gene Rv3875 encoding for ESAT-6, which is required by R-Mtb to block phagosome maturation together with Rv3310 gene product SapM, previously shown to be downregulated in D-Mtb. Thus, our results indicate that D-Mtb cannot escape MHC class II Ag-processing pathway because it lacks the expression of genes required to block the phagosome maturation. Data suggest that switching to dormancy not only represents a mechanism of survival in latent TB infection, but also a M. tuberculosis strategy to modulate the immune response in different stages of TB.

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Section: Discussionsupporting

confidence: 58%

Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes

Mariotti

Pardini

Gagliardi

et al. 2013

The Journal of Immunology

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“…The host immune response restricts the development of active infection by quarantining M. tuberculosis in granuloma, while the M. tuberculosis bacterium can persist in granulomatous lesions in a non-replicative state, with the ability to resume growth and activate disease [14]. It has been demonstrated that the stress conditions such as nutrient deprivation and oxygen limitation play a role in inducing non-replicacing persistence [15]. Under normal growth conditions, the antitoxin and toxin are coexpressed from a TA operon and form a stable complex.…”

Section: Rv1991c Rv1991amentioning

confidence: 99%

Biochemical characterization of a chromosomal toxin–antitoxin system in Mycobacterium tuberculosis

Zhao

Zhang

2008

FEBS Letters

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In the present paper, we report the biochemical characterization of a chromosomal toxin-antitoxin (TA) system in Mycobacterium tuberculosis, consisting of the Rv1991c gene and its upstream open reading frame (ORF) termed Rv1991a. Rv1991c was characterized as a toxin with ribonuclease activity and Rv1991a as the antitoxin against Rv1991c. Rv1991a interacted with Rv1991c to form a complex. A promoter located immediately upstream of Rv1991a was identified. Both Rv1991a and the Rv1991a-Rv1991c complex were able to bind to the promoter region of the Rv1991a-Rv1991c operon, indicating that the expression of the Rv1991a-Rv1991c operon can be autoregulated.

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“…The existence of NrdE in the cell wall fraction of MTB was initially reported by Rosenkrands et al, (2000) (55). Quantitative RT-PCR studies by Murphy et al (2007) on nrdEF2 using the Wayne's model have shown a ten-fold decrease in the expression of nrdEF2 when MTB culture was shifted from log phase to NRP1, followed by a two to three-fold increase from there as the cells entered NRP2 (56). The absence of the NrdF2 protein at NRP1 in our study correlates well with the drastic decrease in expression of nrdEF2 observed by them.…”

Section: Validation Of Quantitative Proteomic Data By Qpcr-tomentioning

confidence: 99%

Profiling the Proteome of Mycobacterium tuberculosis during Dormancy and Reactivation

Gopinath

Raghunandanan

Gomez

et al. 2015

Molecular & Cellular Proteomics

114

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Tuberculosis, caused by Mycobacterium tuberculosis, still remains a major global health problem. The main obstacle in eradicating this disease is the ability of this pathogen to remain dormant in macrophages, and then reactivate later under immuno-compromised conditions. The physiology of hypoxic nonreplicating M. tuberculosis is well-studied using many in vitro dormancy models. However, the physiological changes that take place during the shift from dormancy to aerobic growth (reactivation) have rarely been subjected to a detailed investigation. In this study, we developed an in vitro reactivation system by re-aerating the virulent laboratory strain of M. tuberculosis that was made dormant employing Wayne's dormancy model, and compared the proteome profiles of dormant and reactivated bacteria using label-free onedimensional LC/MS/MS analysis. The proteome of dormant bacteria was analyzed at nonreplicating persistent stage 1 (NRP1) and stage 2 (NRP2), whereas that of reactivated bacteria was analyzed at 6 and 24 h post reaeration. Proteome of normoxially grown bacteria served as the reference. In total, 1871 proteins comprising 47% of the M. tuberculosis proteome were identified, and many of them were observed to be expressed differentially or uniquely during dormancy and reactivation. The number of proteins detected at different stages of dormancy (764 at NRP1, 691 at NRP2) and reactivation (768 at R6 and 983 at R24) was very low compared with that of the control (1663). The number of unique proteins identified during normoxia, NRP1, NRP2, R6, and R24 were 597, 66, 56, 73, and 94, respectively. We analyzed various biological functions during these conditions. Fluctuation in the relative quantities of proteins involved in energy metabolism during dormancy and reactivation was the most significant observation we made in this study. Proteins that are up-regulated or uniquely expressed during reactivation from dormancy offer to be attractive targets for therapeutic intervention to

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Identification of gene targets against dormant phase Mycobacterium tuberculosis infections

Cited by 138 publications

References 124 publications

Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes

Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes

Biochemical characterization of a chromosomal toxin–antitoxin system in Mycobacterium tuberculosis

Profiling the Proteome of Mycobacterium tuberculosis during Dormancy and Reactivation

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