Abstract
Analysis of the mechanisms through which pathogenic mycobacteria interfere with macrophage activation and phagosome maturation have shown that engagement of specific membrane receptors with bacterial ligands is the initiating event. Mannosylated lipoarabinomannan (Man-LAM) has been identified as one of the ligands that modulates macrophage function. We evaluated the effects of Man-LAM derived from Mycobacterium avium subsp. paratuberculosis (MAP) on bovine macrophages. Man-LAM induced a rapid and prolonged expression of IL-10 message as well as transient expression of TNF-α. Preincubation with Man-LAM for up to 16 h did not suppress expression of IL-12 in response to interferon-γ. Evaluation of the effect of Man-LAM on phagosome acidification, phagosome maturation, and killing of Mycobacterium avium subsp. avium (MAA) showed that preincubation of macrophages with Man-LAM before addition of MAA inhibited phagosome acidification, phagolysosome fusion, and reduced killing. Analysis of signaling pathways provided indirect evidence that inhibition of killing was associated with activation of the MAPK-p38 signaling pathway but not the pathway involved in regulation of expression of IL-10. These results support the hypothesis that MAP Man-LAM is one of the virulence factors facilitating survival of MAP in macrophages.
Highlights
The immune response to mycobacterial infection involves phagocytosis of bacteria by mononuclear phagocytes and sequestration within phagosomes [1,2,3]
We have studied the interaction of Mycobacterium avium subsp. paratuberculosis (MAP), with bovine macrophages [6,7,8,9,10]
Expression of IL-10 at 6 and 16 h was greater than control but expression of IL-12p40 and of TNF-a were similar to the control for all concentrations of Mannosylated lipoarabinomannan (Man-LAM)
Summary
The immune response to mycobacterial infection involves phagocytosis of bacteria by mononuclear phagocytes and sequestration within phagosomes [1,2,3]. Pathogenicity of mycobacteria appears to depend on the capacity of the bacterium to prevent macrophage activation and phagosome maturation and to attenuate induction of a Th1 immune response [3,4]. The mechanisms by which mycobacteria interfere with macrophage antimicrobial mechanisms are complex but primarily involve initiation of cell signaling pathways through interaction with cell membrane receptors, blocking phagosome acidification and phagolysosome fusion, and attenuating presentation of bacterial antigens to the immune system [2,5]. We have studied the interaction of Mycobacterium avium subsp. MAP -infected macrophages rapidly phosphorylate Mitogen Activated Protein
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