Heffron Lab
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Salmonella
is a gram negative bacterial pathogen that can infect diverse hosts including
birds, reptiles and mammals. Salmonella typhimurium causes a self
limiting gastroenteritis in humans whereas the closely related Salmonella
typhi causes frequently fatal typhoid fever. The ability of Salmonella
to survive within macrophages, professional phagocytes of the immune system,
is a critical component of virulence. Salmonella not only survives
within, but actually replicates within macrophages and eventually kills
them; presumably after using them as vehicles for dissemination into the
spleen and liver. Salmonella is also studied because it is a model
pathogen without parallel for dissecting basic pathogenic processes. Salmonella
is able to invade eukaryotic cells and can evade detection and destruction
by the immune system - traits that are essential to most human pathogens.
Further, an excellent murine model for studying Salmonella exists,
allowing for the dissection of the complex interactions that occur between
a pathogen and an intact mammalian immune system. Additionally, Salmonella
is easily cultivated, is genetically tractable, and amenable to molecular
biology manipulations. My primary interest is in the dissection of Salmonella
virulence. As described in the references above we have identified regulatory
networks required for systemic infection and are now dissecting individual
genes that play a key role along the infectious pathway.
One
of my hopes is that we will be able to alter Salmonella to deliver
protective antigens to the host when and where we want them delivered.
This will require removing many genes that make Salmonella too
pathogenic, adding genes that re-direct the bacteria to specific tissues,
and then adding a program telling the bacteria to make and release specific
proteins once it arrives. My laboratory has always been interested in
developing new technology that may assist in our goals. We have developed
a method to identify bacterial proteins that have access to the class
I MHC pathway as described in Ellefson above (see figure of contact between
a Salmonella infected macrophage and a specific T cell hybridoma).
These bacterial proteins will elicit the strongest T cell response and
are the ones that we are engineering for vaccines.
