Trehalose 6,6′-dimycolate on the surface of Mycobacterium tuberculosis modulates surface marker expression for antigen presentation and costimulation in murine macrophages

Kan-Sutton, Celestine; Jagannath, Chinnaswamy; Hunter, Robert L.

doi:10.1016/j.micinf.2008.10.006

Cited by 42 publications

(30 citation statements)

References 29 publications

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“…Furthermore, the N. brasiliensis wall-associated lipids inhibited the expression of the T cell costimulatory molecules CD86 and CD40 in macrophages activated with IFN-␥. A similar observation has been reported for macrophages infected with benzine-delipidated M. tuberculosis, demonstrating higher expression of MHC-II, CD40, and CD86 than macrophages infected with wild-type bacteria (24), suggesting TDM as the main compound involved in the inhibition of the expression of MHC-II and T cell costimulatory molecules by macrophages. Because of the presence of TDM in our lipid extract preparation, it is also possible that the effects observed in vitro in the macrophages stimulated with the N. brasiliensis wall-associated lipids were caused by TDM.…”

Section: Discussionsupporting

confidence: 84%

Nocardia brasiliensis Cell Wall Lipids Modulate Macrophage and Dendritic Responses That Favor Development of Experimental Actinomycetoma in BALB/c Mice

et al. 2012

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Nocardia brasiliensis is a Gram-positive facultative intracellular bacterium frequently isolated from human actinomycetoma. However, the pathogenesis of this infection remains unknown. Here, we used a model of bacterial delipidation with benzine to investigate the role of N. brasiliensis cell wall-associated lipids in experimental actinomycetoma. Delipidation of N. brasiliensis with benzine resulted in complete abolition of actinomycetoma without affecting bacterial viability. Chemical analyses revealed that trehalose dimycolate and an unidentified hydrophobic compound were the principal compounds extracted from N. brasiliensis with benzine. By electron microscopy, the extracted lipids were found to be located in the outermost membrane layer of the N. brasiliensis cell wall. They also appeared to confer acid-fastness. In vitro, the extractable lipids from the N. brasiliensis cell wall induced the production of the proinflammatory cytokines interleukin-1␤ (IL-1␤), IL-6, and CCL-2 in macrophages. The N. brasiliensis cell wall extractable lipids inhibited important macrophage microbicidal effects, such as tumor necrosis factor alpha (TNF-␣) and nitric oxide (NO) production, phagocytosis, bacterial killing, and major histocompatibility complex class II (MHC-II) expression in response to gamma interferon (IFN-␥). In dendritic cells (DCs), N. brasiliensis cell wall-associated extractable lipids suppressed MHC-II, CD80, and CD40 expression while inducing tumor growth factor ␤ (TGF-␤) production. Immunization with delipidated N. brasiliensis induced partial protection preventing actinomycetoma. These findings suggest that N. brasiliensis cell wall-associated lipids are important for actinomycetoma development by inducing inflammation and modulating the responses of macrophages and DCs to N. brasiliensis.

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Section: Discussionsupporting

confidence: 84%

Nocardia brasiliensis Cell Wall Lipids Modulate Macrophage and Dendritic Responses That Favor Development of Experimental Actinomycetoma in BALB/c Mice

et al. 2012

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“…TDM- and BSA-coated microspheres were prepared as previously described (32). Beads were briefly sonicated before use, and added to cells at a ratio of 10 beads per cell in the presence or absence of 100 µg/ml lactoferrin.…”

Section: Methodsmentioning

confidence: 99%

Lactoferrin modulation of mycobacterial cord factor trehalose 6-6'-dimycolate induced granulomatous response

Welsh¹,

Hwang²,

Hunter³

et al. 2010

Translational Research

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The immune system responds to tuberculosis (TB) infection by the formation of granulomas. However, subsequent immune-mediated destruction of lung tissue is a cause of significant morbidity and contributes to disease transmission. Lactoferrin, an iron-binding glycoprotein, has demonstrated immunomodulatory properties which decrease tissue destruction and promote T H 1 immune responses, both of which are essential for controlling TB infection. The cord factor trehalose 6,6'-dimycolate (TDM) model of granuloma formation mimics many aspects of TB infection, with similar histopathology accompanied by proinflammatory cytokine production. C57BL/6 mice were intravenously injected with TDM. A subset of mice was given 1 mg bovine lactoferrin 24 hours post-TDM challenge. Lung tissue was analyzed for histological response and production of proinflammatory mediators. C57BL/6 mice demonstrated granuloma formation that correlated with increased production of IL-1β, IL-6, TNF-α, IL-12p40, IFN-γ, and IL-10 protein. Mice treated with lactoferrin post-challenge had significantly fewer and smaller granulomas compared to those given TDM alone. Proinflammatory and T H 1 cytokines essential to the control of mycobacterial infections, such as TNF-α and IFN-γ, were not significantly different in mice treated with lactoferrin. Furthermore, the anti-inflammatory cytokines IL-10 and TGF-β were increased. A potential mechanism for decreased tissue damage seen in the lactoferrin treated mice is proposed. Because of its influence to modulate immune responses, lactoferrin may be a useful adjunct in the treatment of granulomatous inflammation occurring during mycobacterial infection.

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“…The lower order PIMs (fewer mannose molecules), which are found more commonly in less virulent mycobacteria, can enhance phagosomal fusion with early endosomes [179]. Glycolipids such as TDM can interfere with membrane trafficking, preventing phagosome maturation [244]. Recent studies have focused on the utilization of host fatty acid stores and fatty acid metabolism for persistence of Mtb in the phagosome [245–247].…”

Section: Macrophage Interaction With Mtbmentioning

confidence: 99%

Macrophages in tuberculosis: friend or foe

2013

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Tuberculosis (TB) remains one of the greatest threats to human health. The causative bacterium, Mycobacterium tuberculosis (Mtb) is acquired by the respiratory route. It is exquisitely human-adapted and a prototypic intracellular pathogen of macrophages, with alveolar macrophages (AMs) being the primary conduit of infection and disease. The outcome of primary infection is most often a latently infected healthy human host, in whom the bacteria are held in check by the host immune response. Such individuals can develop active TB later in life with impairment in the immune system. In contrast, in a minority of infected individuals, the host immune response fails to control the growth of bacilli, and progressive granulomatous disease develops, facilitating spread of the bacilli via infectious aerosols coughed out into the environment and inhaled by new hosts. The molecular details of the Mtb-macrophage interaction continue to be elucidated. However, it is clear that a number of complex processes are involved at the different stages of infection that may benefit either the bacterium or the host. Macrophages demonstrate tremendous phenotypic heterogeneity and functional plasticity which, depending on the site and stage of infection, facilitate the diverse outcomes. Moreover, host responses vary depending on the specific characteristics of the infecting Mtb strain. In this chapter, we describe a contemporary view of the behavior of AMs and their interaction with various Mtb strains in generating unique immunologic lung specific responses.

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Trehalose 6,6′-dimycolate on the surface of Mycobacterium tuberculosis modulates surface marker expression for antigen presentation and costimulation in murine macrophages

Cited by 42 publications

References 29 publications

Nocardia brasiliensis Cell Wall Lipids Modulate Macrophage and Dendritic Responses That Favor Development of Experimental Actinomycetoma in BALB/c Mice

Nocardia brasiliensis Cell Wall Lipids Modulate Macrophage and Dendritic Responses That Favor Development of Experimental Actinomycetoma in BALB/c Mice

Lactoferrin modulation of mycobacterial cord factor trehalose 6-6'-dimycolate induced granulomatous response

Macrophages in tuberculosis: friend or foe

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