Lipid Phase Changes As a Mechanism of Microbial Pathogenesis

Research Interests:

The goal of my research is to investigate the role of lipid phase behavior in microbial pathogenesis with a two-fold objective: (1) to understand the basis of the host-microbe relationship in disease pathogenesis and (2) to exploit these naturally evolved schemes to engineer novel therapeutic agents and drug-delivery devices.

Current Work:

Cell membranes are complex structures that are naturally impermeable to large molecules, and pathogens have therefore developed a range of schemes to penetrate the membrane during disease pathogenesis, many of which are highly specific at the cell, protein, and/or lipid level.  Studying these interactions will provide insight into the mechanisms of disease progression, leading to the identification of potential therapeutic targets.  In addition, we can use these naturally targeted mechanisms as a template to create more effective drug-delivery and therapeutic devices.  

In this presentation, I will discuss some of the lipid-protein interactions involved in microbial pathogenesis, focusing on my current studies of the leukotoxin (LtxA) produced by the oral bacterium, Aggregatibacter actinomycetemcomitans.  During my postdoctoral fellowship, I have applied by background in lipid phase behavior and colloidal science to study this organism, and have uncovered several previously unidentified mechanisms that may be conserved among other bacterial toxins.  In particular, we have discovered the following LtxA-induced membrane and lipid changes:

1.      LtxA damages the host cell bilayer without forming a pore, instead inducing the formation of a nonlamellar (inverted hexagonal) phase.

2.      LtxA binds cholesterol, initiating a large-scale rearrangement of the toxin and its receptor into large, cholesterol-rich lipid rafts.

These newly defined mechanisms may be used by other bacterial toxins, including those produced by Bordetella pertussis (whooping cough), Vibrio cholerae (cholera), Escherichia coli, and Streptococcus pyogenes (streptococcal infections).

Future Directions:

The focus of my research group will be to study these interactions in more detail to determine how LtxA is able to exert these effects.  In addition, we will extend our studies to investigate other pathogens, including viruses and fungi.  The results of this work will provide information that will be valuable for the identification of potential therapeutic targets and the design biologically inspired therapeutic agents.

Potential Areas for Collaboration:

An understanding of lipid phase behavior and cell membrane functioning has applications beyond microbial pathogenesis, and could be applied in numerous fields including:

Drug Delivery - How do drugs and drug delivery devices penetrate the cell membrane?

Design of Antibiotics – How do antibiotics affect/damage bacterial cell membranes?

Biofilms and Quorum Sensing – How are bacterial signals passed through the membrane?

Funding:

NIH F32 Individual Postdoctoral Fellowship (Feb. 2010 – Jan 2013)