Mycobacterium tuberculosis Mce3C promotes mycobacteria entry into macrophages through activation of β2 integrin-mediated signalling pathway.

Establishment of infection by facultative intracellular pathogen Mycobacterium tuberculosis (Mtb) requires adherence to and internalisation by macrophages. However, the effector molecules exploited by Mtb for entry into macrophages remain to be fully understood. The mammalian cell entry (Mce) proteins play an essential role in facilitating the internalisation of mycobacteria into mammalian cells. Here, we characterized Mtb Mce3C as a new mycobacterial surface protein that could promote mycobacterial adhesion to and invasion of macrophages in an RGD motif-dependent manner. We then further demonstrated that β2 integrin was required for Mce3C-mediated cell entry. In addition, we found that binding of Mce3C recruited β2 integrin-dependent signalling adaptors and induced local actin rearrangement at the site of mycobacterial invasion. By using specific antibodies and pharmacological inhibitors, we further demonstrated the involvement of Src-family tyrosine kinases, spleen tyrosine kinase, Vav, Rho, and Rho-associated kinase in Mce3C-mediated mycobacterial invasion. Our results reveal a novel mechanism by which Mtb Mce3C exploits integrin-mediated signalling cascade for Mce, providing potential targets for the development of therapies against Mtb infection.