Mycobacterial lipoarabinomannans modulate cytokine production in human T helper cells by interfering with raft/microdomain signalling

Shabaana, A. K.; Kulangara, Karina; Semac, Isabelle; Parel, Yann; Ilangumaran, Subburaj; Dharmalingam, Kuppamuthu; Chizzolini, Carlo; Hoessli, Daniel C.

doi:10.1007/s00018-004-4404-5

Cited by 41 publications

(53 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our model mimics the shedding of LAM from mycobacteria (27). Spontaneous incorporation of LAM has been observed by others (13,20). Several studies on the effects of LAM on phagosomal maturation are based on the use of latex beads coated with LAM (10,14).…”

Section: Discussionmentioning

confidence: 77%

“…The affinity of LAM for membrane rafts has previously been shown in human T helper cells (20) and in P1798 lymphoma cells (13), where the affinity of mycobacterial LAM for membrane rafts leads to modulation of signal transduction pathways. Shabaana et al (20) find that LAM, when successfully inserted into rafts through the GPI anchor, has a transbilayer effect on the raft signaling platform, leading to functional alterations on raft protein kinases and ultimately modification of cytokine production.…”

Section: Discussionmentioning

confidence: 86%

“…Shabaana et al (20) find that LAM, when successfully inserted into rafts through the GPI anchor, has a transbilayer effect on the raft signaling platform, leading to functional alterations on raft protein kinases and ultimately modification of cytokine production. We find that PIM blocks LAM incorporation into hMDM membrane rafts, which is consistent with a previous study (13), and this is likely due to the structural similarity between the GPI anchor of LAM and PIM.…”

Section: Discussionmentioning

confidence: 99%

“…Studies on human lymphocytes showed that LAM localizes to membrane rafts of the lymphocyte membrane, thereby interfering with signaling affecting cytokine production (20).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Incorporation ofMycobacterium tuberculosisLipoarabinomannan into Macrophage Membrane Rafts Is a Prerequisite for the Phagosomal Maturation Block

et al. 2008

View full text Add to dashboard Cite

Lipoarabinomannan (LAM) is one of the key virulence factors for Mycobacterium tuberculosis, the etiological agent of tuberculosis. During uptake of mycobacteria, LAM interacts with the cell membrane of the host macrophage and can be detected throughout the cell upon infection. LAM can inhibit phagosomal maturation as well as induce a proinflammatory response in bystander cells. The aim of this study was to investigate how LAM exerts its action on human macrophages. We show that LAM is incorporated into membrane rafts of the macrophage cell membrane via its glycosylphosphatidylinositol anchor and that incorporation of mannosecapped LAM from M. tuberculosis results in reduced phagosomal maturation. This is dependent on successful insertion of the glycosylphosphatidylinositol anchor. LAM does not, however, induce the phagosomal maturation block through activation of p38 mitogen-activated protein kinase, contradicting some previous suggestions.Mycobacterium tuberculosis, the etiological agent of tuberculosis, spreads by aerosol, mainly infecting alveolar macrophages, by which the bacterium is ingested (17). Through inhibition of macrophage functions, the bacterium modulates the host immune response (25). The best-characterized virulence factor of M. tuberculosis, lipoarabinomannan (LAM), is an abundant glycolipid, which is attached to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor and extends through the cell wall of the bacterium (5). During uptake of mycobacteria, LAM interacts with the cell membrane of the host macrophage via specific receptors, including the macrophage mannose receptor and complement receptor 3 (13,14,19), and can then be detected at multiple sites in the cell (27). The host cell exports LAM from the phagosome in an exocytosis-like manner, eliciting responses in bystander cells (1-3). The M. tuberculosis surface harbors mannose-capped LAM (ManLAM), whereas other, less pathogenic, mycobacteria contain LAM either with a phospho-myo-inositol cap (PILAM) or no cap (6). The type of capping and the presence of the GPI anchor is crucial for virulence (13,14). The effects of Man-LAM on the host cell are multiple, but the interference of ManLAM with phagosomal maturation is the best characterized (21) and has been demonstrated in murine and human macrophages (10,12,14).Studies on human lymphocytes showed that LAM localizes to membrane rafts of the lymphocyte membrane, thereby interfering with signaling affecting cytokine production (20).Membrane rafts are cholesterol-and glycosphingolipid-rich domains that act as platforms for cell signaling processes (16). The aim of this study was to investigate whether the effects of LAM are due to incorporation of LAM into membrane rafts of human macrophages. We establish that LAM is incorporated into membrane rafts of the macrophage cell membrane via its GPI anchor, resulting in reduced phagosomal maturation. MATERIALS AND METHODSAntigens and antibodies. ManLAM, cell wall fractions (CWF), and phosphatidylinositol mannosides (PIM) from the virulen...

show abstract

Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

“…Studies on human lymphocytes showed that LAM localizes to membrane rafts of the lymphocyte membrane, thereby interfering with signaling affecting cytokine production (20).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Incorporation ofMycobacterium tuberculosisLipoarabinomannan into Macrophage Membrane Rafts Is a Prerequisite for the Phagosomal Maturation Block

et al. 2008

View full text Add to dashboard Cite

show abstract

“…ManLAM from MTB induce the expression of IL-12 and apoptosis in macrophages [14], whereas in T cells, lipid microdomains suffer insertion of PILAM with no apparent interaction with a specific receptor, this phenomenon trigger Th2 cytokine production and a decreased Th1 cytokine expression [15].…”

Section: Lipoarabinomannan (Lam)mentioning

confidence: 99%

Virulence Factors and Pathogenicity of Mycobacterium

Echeverría-Valencia¹,

Flores-Villalva²,

Espitia³

2018

Mycobacterium - Research and Development

View full text Add to dashboard Cite

Virulence, is referred as the ability of a pathogen to cause disease, and for mycobacteria it depends on their ability to reside within host cells and evade the microbicidal mechanisms of macrophages. The outcome of tuberculosis (TB) infection is highly variable and it seems that the closest relationship between the Mycobacterium genre and humans has shaped the mycobacterial genome to encode bacterial factors that reflects a highly evolved and coordinated program of immune evasion strategies that interfere with both innate and adaptive immunity causing disease even in fully immunocompetent host. Although Mycobacterium tuberculosis (MTB) does not have classical virulence factors, it has described many virulence-associated genes and virulence lifestyle genes from Mycobacterium tuberculosis complex (MTBC). In this chapter, we describe the most important gene/molecule involved in the host defense modulation response, also the plethora of strategies to evade immune mechanisms of macrophage. We review the main genes whose inactivation in the mycobacterial genome leads to a measurable loss in virulence in the different validated TB models.

show abstract

How Mycobacterium tuberculosis subverts host immune responses

2008

View full text Add to dashboard Cite

Mycobacterium tuberculosis is the causative agent of pulmonary tuberculosis which has infected one third of the mankind and causes 2-3 million deaths worldwide each year. The persistence of the infection ensues from the ability of M. tuberculosis to subvert host immune responses in favor of survival and growth of mycobacteria in macrophages. The mechanisms by which M. tuberculosis manipulates the host immune system have only recently come to light. These activities are attributed to lipoarabinomannans (LAM) and their precursors lipomannans (LM), two predominant glycolipids of M. tuberculosis cell wall. LM are able to skew anti-mycobacterial immune responses into un-protective ones, while LAM evoke immunosupression upon binding to macrophage and dendritic cell receptors specialized in binding to "self" host components. A newly emerging idea implicates plasma membrane rafts in LM and LAM signaling. Depending on acylation patterns, the glycolipids may either directly incorporate into the raft membrane via mannosylphosphatidylinositol anchors or interact with raft-associated proteins to affect the assembly of receptor signaling complexes.

show abstract

Mycobacterial lipoarabinomannans modulate cytokine production in human T helper cells by interfering with raft/microdomain signalling

Cited by 41 publications

References 47 publications

Incorporation ofMycobacterium tuberculosisLipoarabinomannan into Macrophage Membrane Rafts Is a Prerequisite for the Phagosomal Maturation Block

Incorporation ofMycobacterium tuberculosisLipoarabinomannan into Macrophage Membrane Rafts Is a Prerequisite for the Phagosomal Maturation Block

Virulence Factors and Pathogenicity of Mycobacterium

How Mycobacterium tuberculosis subverts host immune responses

Contact Info

Product

Resources

About