Role of the Cell Wall Phenolic Glycolipid-1 in the Peripheral Nerve Predilection of Mycobacterium leprae

Abstract

The cell wall of pathogenic mycobacteria is abundant with complex glycolipids whose roles in disease pathogenesis are mostly unknown. Here, we provide evidence for the involvement of the specific trisaccharide unit of the phenolic glycolipid-1 (PGL-1) of Mycobacterium leprae in determining the bacterial predilection to the peripheral nerve. PGL-1 binds specifically to the native laminin-2 in the basal lamina of Schwann cell-axon units. This binding is mediated by the alpha(2LG1, alpha2LG4, and alpha2LG5 modules present in the naturally cleaved fragments of the peripheral nerve laminin alpha2 chain, and is inhibited by the synthetic terminal trisaccharide of PGL-1. PGL-1 is involved in the M. leprae invasion of Schwann cells through the basal lamina in a laminin-2-dependent pathway. The results indicate a novel role of a bacterial glycolipid in determining the nerve predilection of a human pathogen.

Morphological and functional characterizations of Schwann cells stimulated with Mycobacterium leprae

“…PGL-I was provided by John S. Spencer (CST, Fort Collins, USA) and reconstituted in PBS (1 mg/ml, stored at 4°C). The purification of PGL-1 has been previously described by Ng et al (2000). The concentration of PGL-I used in this study was based on a dose-response curve performed by Ng et al (2000).…”

“…The purification of PGL-1 has been previously described by Ng et al (2000). The concentration of PGL-I used in this study was based on a dose-response curve performed by Ng et al (2000). All reagents used in the in vitro cultures were shown to contain less than 0.1 U/ml endotoxin as measured by the Limulus amebocyte lysate assay (Whittaker Bioproducts, Walkersville, USA).…”

Lepromatous leprosy patients produce antibodies that recognise non-bilayer lipid arrangements containing mycolic acids

“…The cellular membrane of M. leprae contains two characteristic lipopolysaccharides (lipoarabinomannan and lipomannan), whereas the cell wall consists of peptidoglycan covalently bound to arabinogalactan, and mycolic acids (MAs). The capsule contains a high level of mycobacterium-specific lipids, which are related to virulence and antibiotic resistance, including phthiocerol dimycocerosate, trehalose mycolates (including chord factor), trehalose sulpholipids (SL), phenolic glycolipid-1 (PGL-1) and MAs (Brennan & Barrow 1980, Britton et al 2000, Ng et al 2000, Rao et al 2006, Scollard et al 2006.…”

Novel 33-Kilodalton Lipoprotein fromMycobacterium leprae

“…The situation implies that there is a need to develop new vaccines and immunotherapeutic tools to control the disease. Moreover, there is increased concern about the disease due to the emergence of drug-resistant bacilli (16), complications due to severe reactions, and peripheral nerve injury due to the tropism of the bacilli to invade Schwann cells (13,20,24).Mycobacterial entities involved in the sequelae of immunoregulatory events are not clear as yet. Recently, lipoproteins are reported to influence both innate and adaptive immunity (12,21).…”

“…The situation implies that there is a need to develop new vaccines and immunotherapeutic tools to control the disease. Moreover, there is increased concern about the disease due to the emergence of drug-resistant bacilli (16), complications due to severe reactions, and peripheral nerve injury due to the tropism of the bacilli to invade Schwann cells (13,20,24).…”