Neural targeting of Mycobacterium leprae mediated by the G domain of the laminin-alpha2 chain.
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.
Rambukkana
A
A
Laboratory of Molecular Infectious Diseases, The Rockefeller University, New York, New York 10021, USA.
Salzer
J L
JL
Yurchenco
P D
PD
Tuomanen
E I
EI
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001422:Bacterial Adhesion / Q000502:physiology; D019556:COS Cells / Q000737:chemistry / Q000382:microbiology; D002448:Cell Adhesion / Q000502:physiology; D005455:Fluorescent Antibody Technique; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D039663:Integrin beta4; D016023:Integrins / Q000378:metabolism; D007797:Laminin / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009166:Mycobacterium leprae / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000382:microbiology*; D017434:Protein Structure, Tertiary; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D012583:Schwann Cells / Q000737:chemistry / Q000166:cytology / Q000382:microbiology*; D012584:Sciatic Nerve / Q000737:chemistry / Q000166:cytology / Q000382:microbiology
D015703:Antigens, CD; D039663:Integrin beta4; D016023:Integrins; D007797:Laminin; D011956:Receptors, Cell Surface