Research

Synthesis of  Bacterial Cell Wall Fragments

The bacterial cell wall, a peptidoglycan, is a highly conserved structure found in all bacteria. The peptidoglycan is a mesh-like carbohydrate polymer that provides the mechanical support necessary to prevent the cells from bursting as the osmotic pressure fluctuates.  Humans do not have bacterial cell walls and thus it makes an ideal structure for our innate immune systems to recognize the presence of bacteria.  It has long been known that small fragments of bacterial cell wall, such as muramyl dipeptide (see figure) are able to stimulate an immune response.  In order to identify the receptors of these molecules, we use chemical synthesis to construct a variety of probes.  The ability to design and synthesize a host of immunostimulatory molecules with a variety of functionality gives us a set of unique tools to dissect innate immune signaling.

Important Research Questions:
What is the best functionality to add to a small molecule without destroying its activity?
Can inhibitors of this pathway be designed?

Synthesis of Large Bacterial Cell Wall Fragments

We use a combination of chemoenzymatic synthesis and bacterial engineering to prepare larger fragments of bacterial cell wall.  Chemoenzymatic synthesis uses a combination of chemically synthesized precursors (provided by us the chemists) and enzymes (provided by Nature) to make large, immunostimulatory fragments of cell wall.  Bacterial engineering takes advantage of the bacterial cell wall biosynthetic machinery to produce unique cell walls with desired properties.  We aim to synthesize unique bacterial-derived biomaterials and use these to study how the human immune system processes an intact bacterial cell.

Important Research Questions:
When is it best to use an enzyme in a synthesis?
How can we quickly access a diverse set of cell wall-derived intermediates?

Biochemistry of Innate Immune Proteins

What is innate immunity?

We study the activation of the innate immune system by a bacterial threat.  The innate immune system is the body’s first line of defense against invading pathogens.  This ancient system has evolved to live in a symbiotic relationship with some commensal bacteria and at the same time recognize and destroy virulent bacteria.    Understanding the molecular details of this system is extremely important, as chronic inflammatory disorders, such as Inflammatory Bowel Disease, arise from an inappropriate immune response to bacteria.

Nod-Like-Receptors

Our program focuses on a class of proteins in the innate immune system known as the Nod-Like Receptors (NLRs).  These proteins police the intracellular space of the cell for bacteria and/or their traces.   NLRs are called receptors and are assumed to bind bacterial-derived fragments.  However, no biochemical or biophysical data exist for these proposed interactions.

For each NLR that we study, we ask three fundamental questions:
(1):  How and where are the immunostimulatory molecules of bacterial cell wall generated?
(2):  Do these bacterial molecules interact with a given NLR? and
(3):  How is the NLR activated for down-stream signaling?
In order to answer these questions we make use of a variety of techniques such as protein expression, solution and solid phase binding assays and mass spectrometry.

Important Research Questions:
How does the innate immune system recognize “good” bacteria vs “bad” bacteria?
Are there similarities between the innate immune systems of plants and humans?
How do other human pathogens such as yeast recognize bacteria in the human body?

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