Understanding the Pathogenesis of bacterial meningitis - How does E.coli cross the blood brain barrier?

Deepshika Datta, Nagarajan Vaidehi, Wely Floriano, William Goddard III

Materials and Process Simulation Center, Caltech

Prasadarao Nemani and K. S. Kim

Division of Infectious Diseases, Childrens Hospital of Los Angeles, Los Angeles.

E.coli is the most common bacteria that causes meningitis during the neonatal period leading to death or neurological sequelae. Experimental evidence has shown that an outer membrane protein on E.coli, OmpA, plays a key role in the invasion process. Studies have also indicated that OmpA binds to sugar moieties that are present on the glycoprotein of Brain microvascular endothelial cells(Ecgp). This step has been shown to be critical to invasion. At MSC, our aim is to understand the interaction between OmpA and the glycoprotein especially the glycosylated regions of the glycoprotein and suggest a therapeutic strategy to block this invasion. As a first step we have modeled the interaction of sugars to OmpA. The sugars chitobiose, fucosyl substituted chitobiose, cellobiose and lactose have been experimentally tested for invasion blocking. We have used a HIER-DOCK protocol and come up with two possible binding sites that are specific to the ligands tested. Our simulation results correlate well with the experimental evidences. We have been able to find a binding pocket for biose in OmpA and also a region that may be important for specific recognition. We are now trying to understand the specific interactions between the ligand and the protein that will aid us in designing an inhibitor that could be used in drug design.

Funding for this project is from NIH- NICHD.

Chitobiose bound to the Outer Membrane Protein A