M. tuberculosis Mce3C promotes mycobacterial mammalian cell entrance and enhances mycobactrial intracellular survival.

Abstract

Abstract It has been suggested that the mammalian cell entry (Mce) proteins are involved in the macrophage cell entry process and the subsequent intracellular survival of Mycobacterium tuberculosis during infection. However, relatively little is known about the specific roles of Mce3C in modulation of phagocytosis and host innate immune defenses. Here we demonstrate that Mce3C can promote the entry of mycobacteria into macrophage cells in a RGD motif-dependent manner. During our attempt to screen for potential Mce3C-interacting host proteins utilizing yeast two-hybrid assay, we found that Mce3C interacts with integrin β2 subunit, which renders it very likely that Mce3C binds β2 family of leukocyte integrins including αLβ2,αMβ2 and αXβ2 through its RGD motif, thus enhancing phagocytosis of mycobacteria by macrophage cells. Furthermore, Mce3C blocks the activation of ERK1/2 signaling pathway, leading to the suppression of Tnf and Il-1β expression, and the promotion of mycobacterial survival within macrophages. Finally, we discover that Mce3C undermines apoptosis of macrophage cells during the course of mycobacterial infection, which further facilitates the intracellular survival of mycobacteria. Thus, these results indicate that M. tuberculosis Mce3C not only strengthens the internalization of macrophage cells by mycobacteria via RGD-mediated interaction with β2 family of leukocyte integrins, but also enhances the intracellular survival of mycobacteria through inhibition of ERK1/2 signaling pathway and apoptosis in macrophage cells.