Structural Characterization of LpqH (19 kDa surface antigen), an Immunomodulatory Lipoprotein of Mycobacterium tuberculosis.

Tuberculosis, caused by Mycobacterium tuberculosis, is predominantly a disease of the lungs acquired by inhaling mycobacteria from infected individuals via airborne droplets. As soon as Mycobacterium reaches the lungs, its first encounter happens to be with the resident alveolar macrophages which immediately can phagocytose, but cannot kill the pathogen. Thus, the pathogen-laden macrophages now disseminate to other organs, aiding in the spread of infection in an undetected manner. Certain mycobacterial surface motifs known as pathogen-associated molecular patterns (PAMPs), recognize specific pattern recognition receptors (PRRs) present on the host cell surface, thereby mediating these early interactions of the mycobacteria with macrophages. A major group of these bacterial PAMPs includes mycobacterial lipoproteins, of which, the 19 kDa surface antigen LpqH, have a critical role in shaping the host immunological response in tuberculosis. The protein pleiotropically modulates the host immune response by interacting with Toll-Like Receptors (TLRs) such as TLR2 homodimers and TLR1/TLR2, TLR2/TLR4, and TLR2/TLR6 heterodimers. On one hand, it acts as an apoptosis-inducing factor for macrophages whereas on the other, it shows that prolonged exposure of LpqH to TLRs eventually favours immune evasion, thereby allowing the dissemination of the pathogen. Despite the essential role of LpqH in tuberculosis,till date, the detailed structure-function relation of this protein remains to be elucidated. We have determined the high-resolution crystal structure of Mycobacterium tuberculosisLpqH at a resolution of 1.26Å and refined to R and R of 14.29% and 17.79%, respectively. It has been observed that the structural architecture of LpqH is indeed unique and has never been previously described. Furthermore, sequence identity between LpqH and other well-known mycobacterial lipoproteins is very low, which further implies that the protein is indeed unique and its structural characterization is vital to the overall understanding of its pathogenesis in case of active tuberculosis.