<i>Mycobacterium tuberculosis</i>
            Lipoproteins Directly Regulate Human Memory CD4
            <sup>+</sup>
            T Cell Activation via Toll-Like Receptors 1 and 2

Lancioni, Christina; Li, Qing; Thomas, J. D.; Ding, Xue Dong; Thiel, Bonnie; Drage, Michael G.; Pecora, Nicole; Ziady, Assem G.; Shank, Samuel; Harding, Clifford V.; Boom, W. Henry; Rojas, R.M.

doi:10.1128/iai.00806-10

Cited by 72 publications

(92 citation statements)

References 57 publications

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“…Some lipoproteins are potent agonists of Toll-like receptor 2, which can initiate responses by antigen-presenting cells that influence both innate and adaptive immunity (56). For example, the Toll-like receptor 2 agonists LpqH and LprG participate in the regulation of adaptive immunity by inducing cytokine secretion in innate immune cells or regulating the activation of memory T lymphocytes (57). LprA is a cell-wall-associated lipoprotein that also can induce cytokine responses and regulate APC function (58).…”

Section: Functional Distribution and Analysis Of The Cfpsmentioning

confidence: 99%

Analysis of the Secretome and Identification of Novel Constituents from Culture Filtrate of Bacillus Calmette-Guérin Using High-resolution Mass Spectrometry

Zheng

Ren

Wei

et al. 2013

Molecular & Cellular Proteomics

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Tuberculosis (TB) is an infectious bacterial disease that causes morbidity and mortality, especially in developing countries. Although its efficacy against TB has displayed a high degree of variability (0%-80%) in different trials, Mycobacterium bovis bacillus Calmette-Gué rin (BCG) has been recognized as an important weapon for preventing TB worldwide for over 80 years. Because secreted proteins often play vital roles in the interaction between bacteria and host cells, the secretome of mycobacteria is considered to be an attractive reservoir of potential candidate antigens for the development of novel vaccines and diagnostic reagents. In this study, we performed a proteomic analysis of BCG culture filtrate proteins using SDS-PAGE and high-resolution Fourier transform mass spectrometry. In total, 239 proteins (1555 unique peptides) were identified, including 185 secreted proteins or lipoproteins. Furthermore, 17 novel protein products not annotated in the BCG database were detected and validated by means of RT-PCR at the transcriptional level. Additionally, the translational start sites of 52 proteins were confirmed, and 22 proteins were validated through extension of the translational start sites based on N-terminus-derived peptides. There are 103 secreted proteins that have not been reported in previous studies on the mycobacterial secretome and are unique to our study. The physicochemical characteristics of the secreted proteins were determined. Major components from the culture superna-

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Section: Functional Distribution and Analysis Of The Cfpsmentioning

confidence: 99%

Analysis of the Secretome and Identification of Novel Constituents from Culture Filtrate of Bacillus Calmette-Guérin Using High-resolution Mass Spectrometry

Zheng

Ren

Wei

et al. 2013

Molecular & Cellular Proteomics

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“…The extracellular Mtb BMVs may traffic beyond the site of infection and interact with uninfected immune cells, thereby regulating host responses via the delivery of Mtb molecules, such as TLR2 agonists, to uninfected immune cells. Mtb TLR2 agonists have clear regulatory roles for macrophages (3, 5, 24, 37), dendritic cells (38, 39), and T cells (40, 41). Purified LAM has also been shown to directly prevent the activation of CD4+ T cells by interfering with T cell receptor signaling (42, 43).…”

Section: Discussionmentioning

confidence: 99%

Bacterial Membrane Vesicles Mediate the Release of Mycobacterium tuberculosis Lipoglycans and Lipoproteins from Infected Macrophages

Athman

Wang

McDonald

et al. 2015

The Journal of Immunology

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117

158

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Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that infects lung macrophages and releases microbial factors that regulate host defense. Mtb lipoproteins and lipoglycans block phagosome maturation, inhibit MHC-II antigen presentation, and modulate TLR2-dependent cytokine production, but the mechanisms for their release during infection are poorly defined. Furthermore, these molecules are thought to be incorporated into host membranes and released from infected macrophages within exosomes, 40-150 nm extracellular vesicles that derive from multivesicular endosomes. However, our studies revealed that extracellular vesicles released from Mtb-infected macrophages include two distinct, largely non-overlapping populations, one containing host cell markers of exosomes (CD9, CD63) and the other containing Mtb molecules (lipoglycans, lipoproteins). These vesicle populations are similar in size, but have distinct densities as determined by separation on sucrose gradients. Release of Mtb lipoglycans and lipoproteins from infected macrophages was dependent on bacterial viability, implicating active bacterial mechanisms in their genesis. Consistent with recent reports of extracellular vesicle production by bacteria (including Mtb), we propose that bacterial membrane vesicles are secreted by Mtb within infected macrophages and subsequently released into the extracellular environment. Extracellular vesicles released from Mtb-infected cells activate TLR2 and induce cytokine responses by uninfected macrophages. We demonstrate that these activities derive from the bacterial membrane vesicles rather than exosomes. Our findings suggest that bacterial membrane vesicles are the primary means by which Mtb exports lipoglycans and lipoproteins to impair effector functions within infected macrophages and circulate bacterial components beyond the site of infection to regulate immune responses by uninfected cells.

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“…Although TLR signaling in APCs induces microbicidal and inflammatory effectors, de novo MHC class II antigen processing and presentation, these functions are inhibited by prolonged signaling with agonists of TLR2, TLR9, and TLR4 [Ferwerda et al, 2005;Pathak et al, 2005;Stenger and Modlin, 2002;Yoshida et al, 2009]. Downregulation of antigen presentation is not specific to M. tuberculosis, as it can be induced by components from many microorganisms; however, it could be especially pronounced during persistent infection with intravacuolar pathogens that survive microbicidal mechanisms and that can persistently co-localize with TLRs in phagosomes for prolonged TLR signaling, such as M. leprae (TLR2 can be recruited to phagosomes as well as reside on the plasma membrane) Lancioni et al, 2010;Simmons et al, 2010].…”

mentioning

confidence: 98%

Clinical, immunological, and genetic aspects in leprosy

Simon

Scherlock

Duthie

et al. 2011

Drug Development Research

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Leprosy is a chronic infection caused by Mycobacterium leprae. It affects the skin and peripheral nerves and can cause irreversible chronic disabilities. The worldwide registered number of cases in 2009 was 213,036. This review discusses clinical aspects of the disease, including leprosy reactions and neuronal damage, as well as immunological and immunogenetic aspects influencing disease susceptibility and outcome. The cardinal signs of leprosy are skin lesions with altered sensation, thickened peripheral nerves, and presence of alcohol acid-resistant bacilli in skin biopsy or lymph. Confirmatory examinations include (1) bacteriological examination, which allows patients' classification into two operational groups, multibacillary (MB) and paucibacillary (PB); and (2) histopathological examination, which permits stratification in different clinical forms. These clinical forms differ not only by histopathology but also according to the host's immune response to M. leprae. These forms comprise the extremes of (1) tuberculoid leprosy (TT), with a specific Th1 response and control of M. leprae multiplication; (2) lepromatous leprosy (LL) without Th1 response and preserved Th2 response; and (3) the interpolar clinical forms, borderline tuberculoid (BT), borderline borderline (BB), borderline lepromatous (BL), and indeterminate form (IL). Appropriate treatment is based on smear examination or the number of lesions at diagnosis. In the evolution of leprosy, acute inflammation, known as reactions, may occur during or after treatment. These reactions are classified into two main types: the type I reaction or reversal reaction (RR), and the type II reaction or erythema nodosum leprosum (ENL). The role of innate immune response to control the infection is supported by immunological and genetic studies. Drug Dev Res 72:509-527, 2011.

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Mycobacterium tuberculosis Lipoproteins Directly Regulate Human Memory CD4 ⁺ T Cell Activation via Toll-Like Receptors 1 and 2

Cited by 72 publications

References 57 publications

Analysis of the Secretome and Identification of Novel Constituents from Culture Filtrate of Bacillus Calmette-Guérin Using High-resolution Mass Spectrometry

Analysis of the Secretome and Identification of Novel Constituents from Culture Filtrate of Bacillus Calmette-Guérin Using High-resolution Mass Spectrometry

Bacterial Membrane Vesicles Mediate the Release of Mycobacterium tuberculosis Lipoglycans and Lipoproteins from Infected Macrophages

Clinical, immunological, and genetic aspects in leprosy

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Mycobacterium tuberculosis Lipoproteins Directly Regulate Human Memory CD4 + T Cell Activation via Toll-Like Receptors 1 and 2

Cited by 72 publications

References 57 publications

Analysis of the Secretome and Identification of Novel Constituents from Culture Filtrate of Bacillus Calmette-Guérin Using High-resolution Mass Spectrometry

Analysis of the Secretome and Identification of Novel Constituents from Culture Filtrate of Bacillus Calmette-Guérin Using High-resolution Mass Spectrometry

Bacterial Membrane Vesicles Mediate the Release of Mycobacterium tuberculosis Lipoglycans and Lipoproteins from Infected Macrophages

Clinical, immunological, and genetic aspects in leprosy

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Mycobacterium tuberculosis Lipoproteins Directly Regulate Human Memory CD4 ⁺ T Cell Activation via Toll-Like Receptors 1 and 2