RESUMO
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.
Assuntos
Antígenos de Bactérias , Parede Celular/metabolismo , Glicolipídeos/metabolismo , Mycobacterium leprae/citologia , Mycobacterium leprae/fisiologia , Nervo Isquiático/microbiologia , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Axônios/microbiologia , Axônios/ultraestrutura , Membrana Basal/efeitos dos fármacos , Membrana Basal/metabolismo , Membrana Basal/microbiologia , Membrana Basal/ultraestrutura , Sítios de Ligação , Parede Celular/química , Parede Celular/ultraestrutura , Células Cultivadas , Técnicas de Cocultura , Proteínas da Matriz Extracelular/metabolismo , Glicolipídeos/química , Humanos , Laminina/química , Laminina/metabolismo , Laminina/farmacologia , Microscopia Eletrônica , Microesferas , Mycobacterium leprae/patogenicidade , Mycobacterium leprae/efeitos da radiação , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/metabolismo , Fibras Nervosas/microbiologia , Fibras Nervosas/ultraestrutura , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Ratos , Células de Schwann/citologia , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Células de Schwann/microbiologia , Nervo Isquiático/citologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Trissacarídeos/metabolismo , Trissacarídeos/farmacologia , Células Tumorais CultivadasRESUMO
alpha-Dystroglycan (alpha-DG) is a component of the dystroglycan complex, which is involved in early development and morphogenesis and in the pathogenesis of muscular dystrophies. Here, alpha-DG was shown to serve as a Schwann cell receptor for Mycobacterium leprae, the causative organism of leprosy. Mycobacterium leprae specifically bound to alpha-DG only in the presence of the G domain of the alpha2 chain of laminin-2. Native alpha-DG competitively inhibited the laminin-2-mediated M. leprae binding to primary Schwann cells. Thus, M. leprae may use linkage between the extracellular matrix and cytoskeleton through laminin-2 and alpha-DG for its interaction with Schwann cells.