Research Projects

The ubiquitin-proteasomal system plays a crucial role in the clearance of cell invaded pathogens, but many microbes subvert these pathways to gain access to the host cytosol for unrestricted proliferation. The ubiquitin-proteasomal system has been implicated in sensing and eliminating these pathogens, but the size of bacteria is larger than the proteasomal barrel, making it impossible for bacteria to enter the proteasomal core and its degradation. A new hypothesis suggests that ubiquitinated proteins from the bacterial surface could be extracted through mechanical force by host-specific molecular machines, such as an AAA ATPase. The findings suggest that an AAA-ATPase, p97/VCP (valosin-containing protein), associates with the surface of cytosol-exposed bacteria, triggering the collapse of the bacterial membrane and leading to its death. Lowering the expression or inhibition of p97 activity significantly hampers the host cell's ability to eliminate intracellular pathogens. This study aims to evaluate the potential of p97 in clearance of invasive bacterial infections in both in vitro and in vivo systems. The study will also evaluate the effect of post-translational modification, particularly phosphorylation, on p97's substrate processivity and its effect on bacterial killing. Lastly, using pharmacological agents, the study will assess p97's ability to clear bacterial infection in an established pneumococcal septicemia model of infection.