A Macrophage Invasion Mechanism for Mycobacteria Implicating the Extracellular Domain of Cd43

Abstract

We studied the role of CD43 (leukosialin/sialophorin), the negatively charged sialoglycoprotein of leukocytes, in the binding of mycobacteria to host cells. CD43-transfected HeLa cells bound Mycobacterium avium, but not Salmonella typhimurium or Shigella flexneri. Quantitative bacteriology showed that macrophages (Mφ) from wild-type mice (CD43+/+) bound M. avium, Mycobacterium bovis (bacillus Calmette-Guérin), and Mycobacterium tuberculosis (strain H37Rv), whereas Mφ from CD43 knockout mice (CD43−/−) did not. Fluorescence microscopy demonstrated that the associated M. avium had been ingested by the CD43+/+ Mφ. The inability of CD43−/− Mφ to bind M. avium could be restored by addition of galactoglycoprotein (Galgp), the extracellular mucin portion of CD43. The effect of Galgp is not due to opsonization of the bacteria, but required its interaction with the Mφ; other mucins had no effect. CD43 expression by the Mφ was also required for optimal induction by M. avium of tumor necrosis factor (TNF)-α production, which likewise could be reconstituted by Galgp. In contrast, interleukin (IL)-10 production by M. avium–infected Mφ was CD43 independent, demonstrating discordant regulation of TNF-α and IL-10. These findings describe a novel role of CD43 in promoting stable interaction of mycobacteria with receptors on the Mφ enabling the cells to respond specifically with TNF-α production.

Mycobacterium tuberculosis employs Cpn60.2 as an adhesin that binds CD43 on the macrophage surface

“…At the outset of this study, published findings provided evidence to show that CD43 plays an important role in the association of M. tuberculosis with MF (Fratazzi et al, 2000;Randhawa et al, 2005) and in the host's ability to control survival and growth of M. tuberculosis (Randhawa et al, 2005;Randhawa et al, 2008). Furthermore, it seems that the role of CD43 in mediating bacterial association is generally limited to mycobacteria (Fratazzi et al, 2000;Randhawa et al, 2005), although one report has also implicated CD43 in the phagocytosis of Streptococcus gordonii (Urano-Tashiro et al, 2008).…”

“…Based on earlier findings, it was hypothesized that CD43 expressed on the MF surface interacts with a surface ligand of M. tuberculosis (Fratazzi et al, 2000;Randhawa et al, 2005). Thus, we anticipated the CD43-Fc chimeric protein would interact with mycobacterial bacilli in a similar manner.…”

“…These effects appeared to be mycobacterialspecific, as tests with selected Gram-negative and Grampositive bacterial species did not reproduce these results (Fratazzi et al, 2000;Randhawa et al, 2005). Moreover, uptake of M. tuberculosis by CD43…”

“…Furthermore, CD43 has been associated with cell signalling events (Silverman et al, 1989;Rosenkranz et al, 1993;Montufar-Solis et al, 2005), including cytoskeletal rearrangement via the ezrin/ moesin/radixin (ERM) proteins and membrane raft association (Viola and Gupta, 2007), suggesting that it has both extracellular and intracellular functions. With respect to the relevance of CD43 in mycobacterial recognition, studies have shown that transfection of HeLa cells with CD43 confers the ability to bind mycobacteria (Fratazzi et al, 2000). Additionally, CD43…”

“…Hence, a detailed analysis of the initial surface interactions between the mycobacterial bacillus and the host MF is necessary to gain an improved understanding of events subsequent to infection.c mi_1496 1634.. 1647 The MF receptors involved in the binding of M. tuberculosis have received comparatively more detailed attention than the relevant M. tuberculosis ligands. Host receptors that have been implicated in the detection and binding of M. tuberculosis include the complement receptors (CR) 1, 3 and 4 (Schlesinger et al, 1990;Stokes et al, 1993;Hirsch et al, 1994), mannose receptor (MR) (Schlesinger, 1993), surfactant proteins (SP)-A and -D (Gaynor et al, 1995;Ferguson et al, 1999), scavenger receptors (Zimmerli et al, 1996;Ernst, 1998), dectin-1 (Yadav and Schorey, 2006;Rothfuchs et al, 2007), tolllike receptor (TLR) 2 (Aliprantis et al, 1999;Jones et al, 2001;Quesniaux et al, 2004;Gilleron et al, 2006), TLR-4/CD14 (Qazi et al, 2007), CD44 (Leemans et al, 2003) and more recently, CD43 (Fratazzi et al, 2000;Randhawa et al, 2005).…”