Creating efficient vaccine candidates against Tuberculosis using mutant Mycobacterium smegmatis

Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (M.tb.). M.tb relies on a large repertoire of evasion strategies including secretion of proteins that alter host signaling and trafficking. M.tb possess the specialized type VII secretion system (T7SS), which has been demonstrated to aid in altering host pathways and promote bacterial survival. M. tb contains a total of five T7SS, also called ESX, some of these, like Esx-1, has been shown to be required for virulence, Esx-3 is much less characterized. The Esx-3 locus is ubiquitously present in all mycobacterial species and is regulated by iron and zinc; also it has been shown that esx-3 is involved in siderophore mycobactin based iron uptake. EspG, a protein encoded by the esx-3 locus, has been demonstrated to be involved in protein secretion, iron uptake and immune stimulation. Recently, a mutant strain of M. smegmatis lacking esx-3, complemented with M. tb esx-3 has shown promise as a vaccine candidate, but the mechanism by which it activates the adaptive immune system is still unclear. We hope to answer this by studying the mechanism by which M.tb utilizes the esx-3 locus to evade the immune response. For this, we shall be carrying out various cell based and animal based studies. Thus, the interplay between the various immune responses towards eradicating the infection will be investigated, to generate better vaccines.