Virulence factor Mce protein (Mce)
Type: Family

The members of this family represent the protein products of all 24 genes associated with the four mammalian cell entry operons of Mycobacterium tuberculosis and their homologues in other Actinomycetales , including Lipoprotein LprN from M.tuberculosis. LprN stimulates the host (mouse) immune response. Previously sensitised mice infected with this bacteria have an exacerbated disease response, suggesting this lipoprotein may down-regulate the host's immune response .

Mycobacterial species are usually slender, curved rods with a unique cell wall of complex waxes and glycolipids. They are resistant to acids, alkalis and dehydration, and are very slow to grow
in vitro
. The human pathogenic Mycobacteria (Mycobacterium tuberculosis and Mycobacterium leprae) are becoming resistant to conventional treatments and, together with HIV-related diseases, are fast posing a global health threat. An essential requirement, particularly of M. tuberculosis, is to gain entrance to, and to resist, the hostile intra-cellular environment of epithelial cells .

The genome of M. tuberculosis contains four mammalian cell entry (mce) operons , which are widely distributed in both pathogenic and non-pathogenic mycobacteria suggesting that the presence of these putative virulence genes is not an indicator for the pathogenicity of the bacilli. At the 5' end of the transcriptional unit are two genes that have evolved from a tandem duplication, and whose products resemble YrbE, a conserved hypothetical protein found in Escherichia coli, Haemophilus influenzae and Porphyra purpurea. All of the YrbE proteins, including the eight from M. tuberculosis, are probable integral membrane proteins with six TM α helices. The next six genes in each operon, the mce genes, are related, their products ranging in size from 275 to 564 amino acid residues. The corresponding protein sequences contain a number of highly conserved motifs that define a 24-member family with a common organisation. Twenty of these proteins have a strongly hydrophobic segment at the NH2-terminal end that could span the lipid bilayer whereas the remaining four, all of which correspond to the seventh gene in their respective operons, mce1E to mce4E, are probably lipoprotein precursors. In all 24 cases the COOH-terminal domain of the mce proteins is predicted to be exposed on the external face of the cytoplasmic membrane .

The ability to gain entry and resist the antimicrobial intracellular environment of mammalian cells is an essential virulence property of M. tuberculosis. This property is conferred by Mce1A, the third gene of operon 1, which when expressed in E. coli conferred the ability to invade HeLa cells. The recombinant protein when used to coat latex spheres also promoted their uptake into HeLa cells. N terminus deletion constructs of Mce1A identified a domain located between amino acid positions 106 and 163 that was needed for this cell uptake activity. Mce1A contains hydrophobic stretches at the N terminus predictive of a signal sequence, and colloidal gold immunoelectron microscopy indicated that the corresponding native protein is expressed on the surface of M. tuberculosis. Recombinant Mce2A, which had the highest level of identity (67%) to Mce1A, was unable to promote the association of microspheres with HeLa cells and an mce-deletion mutant in Mycobacterium bovis greatly impaired the ability of the microbe to infect epithelial cells in vitro. Although the exact function of Mce1A is still unknown, it appears to serve as an effector molecule expressed on the surface of M. tuberculosis that is capable of eliciting plasma membrane perturbations in non-phagocytic mammalian cells .