CD43 Is Required for Optimal Growth Inhibition of Mycobacterium tuberculosis in Macrophages and in Mice

Abstract

We explored the role of macrophage (Mφ) CD43, a transmembrane glycoprotein, in the pathogenesis of Mycobacterium tuberculosis. Using gene-deleted mice (CD43−/−), we assessed the association of the bacterium with distinct populations of Mφ and found that CD43−/− Mφ bound less M. tuberculosis than CD43+/+ Mφ. Increased infective doses did not abrogate this difference. However, reduced association due to the absence of CD43 could be overcome by serum components. Mφ from heterozygote mice, which express 50% of wild-type CD43, bound more bacteria than CD43−/− but less than CD43+/+, proving that the gene dose of CD43 correlates with binding of M. tuberculosis. Furthermore, the reduced ability of CD43−/− Mφ to bind bacteria was restricted to mycobacterial species. We also found that the survival and replication of M. tuberculosis within Mφ was enhanced significantly in the absence of CD43, making this the first demonstration that the mechanism of mycobacterial entry influences its subsequent growth. Most importantly, we show here that the absence of CD43 in mice aerogenically infected with M. tuberculosis results in an increased bacterial load during both the acute and chronic stages of infection and more rapid development of granulomas, with greater lung involvement and distinctive cellularity.

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

“…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…”

“…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.…”

“…-/-MF results in enhanced intracellular bacterial growth compared with CD43 +/+ MF (Randhawa et al, 2005). This enhanced intracellular growth has been shown to result from CD43 -/-MF releasing a reduced level of TNFa in response to M. tuberculosis challenge, resulting in higher levels of MF necrosis and lower levels of MF apoptosis (Randhawa et al, 2008).…”

“…-/-mice have a deficiency in controlling M. tuberculosis growth after aerosol infection, having both increased bacterial loads and more diffuse lung pathology compared with CD43 +/+ mice (Randhawa et al, 2005). This set of intriguing results served as the stimulus to investigate whether or not specific mycobacterial surface ligand(s) exist that interact with 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).…”