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
We report that the molecular basis of the neural tropism of Mycobacterium leprae is attributable to the specific binding of M. leprae to the laminin-alpha2 (LN-alpha2) chain on Schwann cell-axon units. Using recombinant fragments of LN-alpha2 (rLN-alpha2), the M. leprae-binding site was localized to the G domain. rLN-alpha2G mediated M. leprae binding to cell lines and to sciatic nerves of dystrophic dy/dy mice lacking LN-alpha2, but expressing laminin receptors. Anti-beta4 integrin antibody attenuated rLN-alpha2G-mediated M. leprae adherence, suggesting that M. leprae interacts with cells by binding to beta4 integrin via an LN-alpha2G bridge. Our results indicate a novel role for the G domain of LN-2 in infection and reveal a model in which a host-derived bridging molecule determines nerve tropism of a pathogen.
Assuntos
Laminina/fisiologia , Mycobacterium leprae/metabolismo , Neurônios/microbiologia , Células de Schwann/microbiologia , Animais , Antígenos CD/metabolismo , Aderência Bacteriana/fisiologia , Células COS/química , Células COS/microbiologia , Adesão Celular/fisiologia , Imunofluorescência , Gânglios Espinais/citologia , Humanos , Integrina beta4 , Integrinas/metabolismo , Laminina/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Neurônios/química , Neurônios/citologia , Estrutura Terciária de Proteína , Ratos , Receptores de Superfície Celular/metabolismo , Células de Schwann/química , Células de Schwann/citologia , Nervo Isquiático/química , Nervo Isquiático/citologia , Nervo Isquiático/microbiologiaRESUMO
Among mycobacteria, Mycobacterium leprae have a unique property to infect peripheral nerves, which is the cause of a variety of debilities seen in leprosy. The possibility of selective uptake of M. leprae by Schwann cells was studied using a rat Schwannoma cell line 33B and rat sciatic nerve-derived Schwann cells. M. leprae were phagocytosed by 33B cells but so also were seven other mycobacteria ("Mycobacterium w," BCG, M. tuberculosis H37Rv, M. nonchromogenicum, M. vaccae, ICRC bacillus, and M. smegmatis) which do not involve peripheral nerves. All three mycobacteria tested (M. leprae, M. tuberculosis and "Mycobacterium w") were phagocytosed by sciatic nerve-derived Schwann cells. Both Schwannoma and Schwann cells phagocytosed even inert latex particles. These results fail to demonstrate any M. leprae-specific uptake system in Schwann cells.