(3bx) 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)