Individual RD1‐region genes are required for export of ESAT‐6/CFP‐10 and for virulence of <i>Mycobacterium tuberculosis</i>

Guinn, Kristi M.; Hickey, Mark J.; Mathur, Sanjeev Kumar; Zakel, Kelly L.; Grotzke, Jeff E.; Lewinsohn, David; Smith, Sherilyn; Sherman, David R.

doi:10.1046/j.1365-2958.2003.03844.x

Cited by 457 publications

(495 citation statements)

References 54 publications

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“…Moreover, D-Mtb-infected macrophages maintain their capacity to digest proteins in acidic compartments differently from R-Mtb-infected macrophages. These results indicate that D-Mtb is not endowed with the ability to arrest the phagosome maturation that characterizes R-Mtb, showing in this respect analogy with HK M. tuberculosis, BCG, and other M. tuberculosis mutant strains (41).…”

Section: Discussionmentioning

confidence: 77%

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: Discussionmentioning

confidence: 77%

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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“…Immune response to MTB infection is primarily mediated by T cells (Lockhart et al 2006). In previous research of human pulmonary TB, T cells responding to ESAT-6 are observed in approximately half of the patients (Guinn et al 2004;Reiley et al 2008). ESAT-6, a vital immune-dominant antigen encoded by region of difference-1 (RD1) and RD2, has been reported to have the potential for human MTB diagnosis (Sang and Zhang 2012;Li et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Early Diagnosis of Tuberculosis-Associated IgA Nephropathy with ESAT-6

Zhao

Sun

et al. 2017

Tohoku J. Exp. Med.

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IgA nephropathy (IgAN) is the most common cause of primary renal diseases worldwide, and the early secreted antigenic target of 6 (ESAT-6) which was secreted by Mycobacterium tuberculosis (MTB) may be involved in the development and progression of IgAN. This study aimed to investigate the role of ESAT-6 for early diagnosis of IgAN caused by MTB infection. From 2011 to 2014, 21 patients with renal tuberculosis (RTB), 25 with IgAN, and 46 with IgAN infected with MTB (IgAN/MTB) were enrolled. Serum levels of antibodies against Mycobacterium tuberculosis antigen 85A (Ag85A) were measured by ELISA. Urine culture and phage amplified biologically assay were performed to detect MTB. HE staining was used to observe the morphological changes in kidney tissues. Immunohistochemistry was applied to detect the expression of ESAT-6. Immunofluorescence staining was conducted to detect IgA1. Positive rates of serum anti-Ag85A antibody and urine culture for MTB were higher in the RTB and IgAN/MTB groups than those in the IgAN group. The positive rates of plaques were also higher in RTB and IgAN/MTB groups than the positive rate in the IgAN group. By contrast, the positive rate of ESAT-6 was lower in the IgAN group than that in the RTB group or the IgAN/MTB group, whereas the expression levels of IgA1 were higher in the IgAN and IgAN/MTB groups, compared with the RTB group. Our findings suggest that ESAT-6 and IgA1 may be helpful for early diagnosis of IgAN caused by MTB infection.

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“…Sec substrates are translocated across the cytoplasmic membrane in an unfolded state, whereas Tat substrates are translocated in a folded conformation. M. tuberculosis also has at least two specialized protein export pathways: the SecA2-dependent system and the ESX-1 (ESAT-6) system (Braunstein et al, 2003;Guinn et al, 2004;Hsu et al, 2003;Pym et al, 2003;Stanley et al, 2003). Interestingly, both pathways appear capable of secreting specific subsets of proteins that lack conventional Sec or Tat signal sequences.…”

Section: Introductionmentioning

confidence: 99%

β-Lactamase can function as a reporter of bacterial protein export during Mycobacterium tuberculosis infection of host cells

et al. 2007

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Mycobacterium tuberculosis is an intracellular pathogen that is able to avoid destruction by host immune defences. Exported proteins of M. tuberculosis, which include proteins localized to the bacterial surface or secreted into the extracellular environment, are ideally situated to interact with host factors. As a result, these proteins are attractive candidates for virulence factors, drug targets and vaccine components. Here we describe a b-lactamase reporter system capable of identifying exported proteins of M. tuberculosis during growth in host cells. Because b-lactams target bacterial cell-wall synthesis, b-lactamases must be exported beyond the cytoplasm to protect against these drugs. When used in protein fusions, b-lactamase can report on the subcellular location of another protein as measured by protection from b-lactam antibiotics. Here we demonstrate that a truncated TEM-1 b-lactamase lacking a signal sequence for export (9BlaTEM-1) can be used in this manner directly in a mutant strain of M. tuberculosis lacking the major blactamase, BlaC. The 9BlaTEM-1 reporter conferred b-lactam resistance when fused to both Sec and Tat export signal sequences. We further demonstrate that b-lactamase fusion proteins report on protein export while M. tuberculosis is growing in THP-1 macrophage-like cells. This genetic system should facilitate the study of proteins exclusively exported in the host environment by intracellular M. tuberculosis.

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Individual RD1‐region genes are required for export of ESAT‐6/CFP‐10 and for virulence of Mycobacterium tuberculosis

Cited by 457 publications

References 54 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

Early Diagnosis of Tuberculosis-Associated IgA Nephropathy with ESAT-6

β-Lactamase can function as a reporter of bacterial protein export during Mycobacterium tuberculosis infection of host cells

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