Syndecans promote mycobacterial internalization by lung epithelial cells

Abstract

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.

Water-pipe smoke condensate increases the internalization of Mycobacterium Bovis of type II alveolar epithelial cells (A549)

“…Although the invasion of epithelial cells by MTB has been demonstrated [3, 28, 41, 42], the mechanisms of mycobacterial attachment or internalization in these nonprofessional phagocytes have not been elucidated [3, 41]. Garcıa-Perez and colleagues [41] demonstrated that MTB induced redistribution of actin filaments, the formation of lamellipodia, and increase fluid phase uptake in A549 cells.…”

“…Water-pipe smoking may enhance macropinocytosis internalization activity in epithelial cells through other pathways [42]. Syndecan 4 on alveolar epithelial cells acts as a receptor for the MTB mycobacterial heparin-binding hemagglutinin adhesin [42].…”

“…Syndecan 4 on alveolar epithelial cells acts as a receptor for the MTB mycobacterial heparin-binding hemagglutinin adhesin [42]. Activation of syndecan 4 stimulates signaling pathways such as RhoG and Rac1, leading to micropinocytosis [45].…”

Human isotype‐dependent inhibitory antibody responses against Mycobacterium tuberculosis

“…To determine the potential role of both plasmablast and memory B-cell antibodies in MTB infection, we tested a selected set of 41 MTB-reactive recombinant monoclonal antibodies in an in vitro infection assay with A549 human lung epithelial cells (Fig 5 and Appendix Table S4). A549 cells are type II alveolar epithelial cells that have been shown to play a role in early MTB infection (Bermudez & Goodman, 1996;Castro-Garza et al, 2002;Sato et al, 2002;Ryndak et al, 2015;Zimmermann et al, 2016). We initially expressed and tested a set of antibodies that had been cloned from IgA-positive plasmablasts including the anti-LAM antibody TB24PB037 ( Fig 5A and B).…”

Divergent Functions of TLR2 on Hematopoietic and Nonhematopoietic Cells during Chronic Mycobacterium tuberculosis Infection

“…Alveolar epithelial cells can phagocytose mycobacteria using syndecans (29) and also produce pro-inflammatory cytokines and chemokines in response to Mtb infection, including TNF, IFNγ, CXCL8, CCL5, IL-1β, IL-6, IL-18, and MCP-1, which play central roles in cellular recruitment (30). Mycobacteria can also promote the secretion of IL-10 and IL-22, anti-inflammatory cytokines, from alveolar epithelial cells by inhibiting NFκB signaling in these cells (31).…”