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Ivan Dikic (2014-2017)

Protein networks in the biogenesis of the proliferative niche of Salmonella

The endosomal/lysosomal system is a highly dynamic, membrane dependent compartment that is vital for the trafficking of cargo within the cell, ensuring it ends-up in the right place at the right time - whether it is targeted for the plasma membrane or for degradation in the lysosome. Rab7 is a prime target for intracellular pathogen manipulation. In particular, the intracellular replicating gram-negative bacterium Salmonella enterica serovar typhimurium (S. typhimurium; henceforth Salmonella), which is a causative agent of typhoid fever, paratyphoid fever and human gastroenteritis, replicates within a specialized compartment called a Salmonella containing vacuole (SCV) that is positive for lysosomal proteins LAMP1, and Rab7, but negative for Cathepsins. Salmonella subversion of the host cell endosome/lysosome system is mediated by excretion of virulence (effector) proteins into the host cytosol by the action of two type-3 secretion systems (T3SS) that are encoded by either the early (Salmonella pathogenicity island-I (SPI-1)) or the late (SPI-2) genes.  We aim to study how these effectors manipulate the host endo-membrane system for their own intracellular niche. Specifically, we will focus on key Salmonella effector proteins as regulators of the Salmonella containing vacuole, how they manipulate the endosomal network and which host proteins they recruit and interact with. We will also investigate the mechanisms by which Rab7, HOPS and other elements of the lysosomal membrane fusion machinery are recruited to the SCV and how Salmonella effector proteins may regulate this process through direct interaction or by the modification of the composition of the lysosomal membrane itself.

 

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