Research in the Little lab focuses on post-translational mechanisms that underlie host-pathogen interactions
Post-translational regulation of the type III secretion system
The type III secretion system is a protein translocation pathway used by Gram-negative bacteria to deliver toxins (called effectors) into host cells. The type III secretion system is a key mediator for host infection delivering effectors that subvert normal host processes in benefit of the bacteria. We are interested in understanding how the type III secretion system is regulated at the post-translational level, with a special emphasis on protein effectors and their cognate chaperones. Understanding how chaperones control the delivery of effectors into the host holds promise for the identification or generation of type III secretion system inhibitors that could prove valuable for further mechanistic studies or therapeutic intervention.
Molecular mechanisms of bacterial tyrosine phosphorylation
A well known post-translational modification broadly conserved across the kingdom of life is protein phosphorylation. Protein phosphorylation of tyrosine residues is poorly understood in bacteria with only a few classes of Bacterial tYrosine (BY)-kinases identified to date. We are interested in identifying and characterizing new BY-kinases and determining the molecular basis for tyrosine phosphorylation using E. coli as a model system. Identifying functional differences between BY-kinases compared to their eukaryotic counterparts will significantly advance our understanding of cellular signaling and the role it plays in bacterial adaptation. This fundamental knowledge can be harnessed to identify first generation inhibitors of bacterial tyrosine phosphorylation and uncover novel targets for the design of antimicrobial control strategies.
Biosynthesis and secretion of surface associated and extracellular polysaccharides
Bacteria often exist in aggregated cellular communities held together by self-produced extracellular substances (commonly referred to as a biofilm). These heavily coated bacterial communities contribute to a wide range of human infections, and can be difficult to eradicate for various reasons, such as decreased efficacy of antibiotics or steric occlusion from host cell phagocytosis. Since polysaccharides are a regular component of bacterial aggregates, we are interested in their biosynthesis and their contribution to host interaction and infection. Understanding the molecular basis for polysaccharide production will guide our efforts in the search for new strategies to inhibit bacterial aggregation, opening new avenues for therapeutic intervention against aggregate-associated chronic bacterial infections.
Protein engineering for the development of molecular probes
By understanding the structure and function of a protein, one can use this information to employ engineering methods for the design and development of diagnostic agents and/or for use as a functional probe within living systems. We are broadly interested in bacterial and viral systems, but our current focus is on COVID-19. Current projects involve producing recombinant protein reagents for the development and validation of an immunoassay for the detection of SARS-CoV-2 immunity elicited from natural infection or vaccination.