Syndecans promote mycobacterial internalization by lung epithelial cells.
Pulmonary tuberculosis (TB) is an airborne disease caused by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb). Alveolar epithelial cells and macrophages are the first point of contact for Mtb in the respiratory tract. However, the mechanisms of mycobacterial attachment to, and internalization by, nonprofessional phagocytes, such as epithelial cells, remain incompletely understood. We identified syndecan 4 (Sdc4) as mycobacterial attachment receptor on alveolar epithelial cells. Sdc4 mRNA expression was increased in human and mouse alveolar epithelial cells after mycobacterial infection. Sdc4 knockdown in alveolar epithelial cells or blocking with anti-Sdc4 antibody reduced mycobacterial attachment and internalization. At the molecular level, interactions between epithelial cells and mycobacteria involved host Sdc and the mycobacterial heparin-binding hemagglutinin adhesin. In vivo, Sdc1/Sdc4 double-knockout mice were more resistant to Mtb colonization of the lung. Our work reveals a role for distinct Sdcs in promoting mycobacterial entry into alveolar epithelial cells with impact on outcome of TB disease.
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.|Research Group of Molecular Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
Natalie
N
Zimmermann
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
Hiroyuki
H
Saiga
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
Erica
E
Houthuys
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
Pedro
P
Moura-Alves
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
Anne
A
Koehler
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
Silke
S
Bandermann
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
Anca
A
Dorhoi
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
Stefan H E
SH
Kaufmann
D000072283:A549 Cells; D018829:Adhesins, Bacterial / Q000235:genetics / Q000378:metabolism; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001422:Bacterial Adhesion / Q000187:drug effects; D004847:Epithelial Cells / Q000276:immunology / Q000382:microbiology*; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D008168:Lung / Q000276:immunology / Q000382:microbiology*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053668:Syndecan-1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D053671:Syndecan-4 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology / Q000473:pathology
D018829:Adhesins, Bacterial; D057134:Antibodies, Neutralizing; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C508304:SDC4 protein, human; C508242:Sdc1 protein, mouse; C508306:Sdc4 protein, mouse; D053668:Syndecan-1; D053671:Syndecan-4