Intracellular Trafficking

The scientific contributions of our research are primarily in the area of cell biology with special emphasis on the regulation of intracellular trafficking. Intracellular transport is mediated by vesicle fusion of one compartment to another specific compartment. The specificity of the fusion process is regulated by a family of ras-related GTPases called Rab, distinct members of which are specifically localized in particular compartments. Various Rabs in conjunction with other cellular factors mediate the fusion between two specific vesicles. As many as 70 members of this family have been identified in mammalian cells, but functions of all Rabs are not fully characterized yet.

SNAREs are other major players which regulate intracellular membrane trafficking by conferring specificity to vesicular fusion events along with Rab GTPases. Around 36 members of this family of proteins are known in mammalian cells. Most SNAREs have a membrane-spanning region and a conserved heptad repeat of SNARE motif which is required for SNARE complex formation. Depending on the conserved residue in the SNARE motif, SNAREs are also classified as R-SNAREs (arginine containing SNAREs) and Q-SNAREs (glutamine-containing SNAREs), which is again sub divided into Qa, Qb and Qc SNAREs on the basis of their N-terminus domain. Vesicular fusion events require one member each of the Qa-, Qb-, Qc- and one cognate R-SNAREs to form functional four-helix complex. This brings the donor and acceptor membranes close together to drive membrane fusion.

Hypothesis

Microorganisms are internalized by phagocytic cells and are targeted to the acidic lysosomes following endocytic pathway where it is degraded. Thus, the first challenge of intracellular pathogens is to evade the lysosomal transport in host cells. Successful intracellular pathogens like Mycobacterium, Salmonella, Legionella, Leishmania  etc. have evolved various strategies to avoid their targeting to the lysosomes in the host cells. It is not very clearly established how they avoid lysosomal transport, therefore, current studies are focused to understand how these intracellular pathogens modulate endo-lysosomal pathway in the host cells to develop novel therapeutic target. 

Modulation of host intracellular trafficking by pathogens

Our initial studies have shown that Rab7 acts downstream of Rab5 in regulating vesicular transport events from early endosomes to lysosomes. Using this knowledge of regulation of endocytosis by Rab GTPases, we initiated series of studies to understand the mechanism of survival of intracellular pathogens within the host cells. The broad objective of our studies is to understand the fundamental issues in host pathogens interactions with an aim to develop a potentially new therapeutic target for their intervention.