Characterization of the lprG-Rv1410c operon in Mycobacterium tuberculosis

The global burden of Mycobacterium tuberculosis ( M.tb ) infection is a public health crisis for which new diagnostics, drugs, and vaccines are required. M.tb is an intracellular pathogen, and must survive in the face of innate and acquired immune responses to replicate intracellularly and produce disease. Illuminating the mechanisms by which the bacterium survives the host environment is crucial to the rational design of new drug therapies and the creation of new vaccines; yet our understanding of how this is accomplished is far from complete. The two genes of the lprG-Rv1410c operon are required by M.tb during infection, yet almost nothing is known about the biologic functions of the products of the operon. P55, the protein encoded by Rv1410c, is a small molecule transporter with no known physiologic substrates, and LprG is a lipoprotein of unknown function. Characterization of the M.tb proteins in M. smegmatis reveals a surprising functional relationship between LprG and P55: the transporter requires LprG for transport and normal function. In vivo analyses indicate that P55 is essential for M.tb virulence. An M.tb mutant of Rv1410c is dramatically attenuated in mice that lack essential components of host immunity, including the production of reactive radical species and IFNγ. Indeed, we find that P55 is avirulent in mice even in strains that lack an adaptive immune system. Mass spectral analysis or mycobacterial cell surface lipid reveals that alterations in cell wall composition are associated with loss of the products of the lprG-Rv1410c operon. Our evidence strongly suggests that LprG and P55 are responsible for the translocation of components of the mycobacterial cell wall.