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Tina Iverson, Ph.D., and Mikio Tanabe, Ph.D., are studying how cells identify pathogens. (photo by Anne Rayner)

Meningitis protein structure reveals immune response ‘spark’

BY: LEIGH MACMILLAN

5/14/2010 - Opposites attract. And a simple electrical attraction — between positive and negative charges — appears to be the first step in activating an immune response to bacterial pathogens.

Vanderbilt University investigators determined the structure of a protein that resides in the outer membrane of the bacterium Neisseria meningitidis, a leading cause of bacterial meningitis.

The findings, reported in the Proceedings of the National Academy of Sciences, suggest that immune system receptors initially recognize bacteria based on charged structural features in their surface proteins.

“Our interest is in molecular recognition — how do cells know what's around them and respond to it,” said Tina Iverson, Ph.D., assistant professor of Pharmacology and Biochemistry. “If there's a pathogen out there, how does a cell know it's a pathogen.”

The human immune system responds quickly to pathogens in a non-specific way. This “innate” response provides immediate defenses — fever, inflammation — but does not confer long-lasting protection.

“We wondered what it is about different bacteria that's so conserved that Toll-like receptors (mediators of the innate immune response) can always identify them,” Iverson said.

Understanding how Toll-like receptors recognize bacteria could also shed light on autoimmune diseases. Variations that increase signaling by the Toll-like receptor TLR2 are associated with inflammatory bowel disease and Crohn's disease, suggesting that inappropriate reactions to normal intestinal bacteria may contribute to inflammation in these disorders.

Iverson and Mikio Tanabe, Ph.D., a postdoctoral fellow at the time, explored how bacteria are recognized by studying a model protein from N. meningitidis. The protein, called PorB, was known to contribute to bacterial survival and pathogenesis, and it was known to directly interact with Toll-like receptors.

The researchers determined the 3-D structure of PorB using X-ray crystallography. They found that three PorB molecules associate to form one complex, and that this complex contains a ring of positively charged amino acids (the building blocks of proteins) on its outer surface.

Analysis of the Toll-like receptor TLR1/2 revealed that it had a predominantly negatively charged outer surface.

“This negatively charged surface could be attracted to the ring of positive charges on PorB,” Tanabe said.

The ring of positive charges appears to be conserved among bacterial membrane proteins.

“When we looked at other bacterial outer membrane proteins — all of the ones that have had 3-D structures determined — we found that they have this similar feature,” Iverson said. “We think this non-specific feature of the protein is important in the non-specific recognition of bacteria by Toll-like receptors.”

But bacteria that harmlessly co-exist with humans also share this feature, so there's more to the story than a simple recognition event, Iverson said.

“There must be a cue to the Toll-like receptor that a particular bacterium is a pathogen, and we don't understand that yet. We think there's more than one event that sets off the immune response, and what we've found is the first molecular event — the recognition event.”

The PorB structure also revealed that the protein's pore — the opening that allows charged molecules (ions) and sugars to pass through — is not just a big hole as previously believed. Rather, the pore appears to have three different “channels,” or pathways: one for positively charged ions, one for negatively charged ions and one for sugars. These alternate pathways also appear in other bacterial pore proteins.

“We think these features represent general mechanisms that have been overlooked,” Iverson said.

Iverson and colleagues are working to determine the structure of PorB bound to the Toll-like receptor. They also will compare N. meningitidis outer membrane proteins with proteins from Neisseria bacteria that do not cause disease, to look for clues about the events that happen after initial recognition by Toll-like receptors.

Yi Wei Tang, M.D., Ph.D., professor of Pathology and Medicine, provided the clinical N. meningitidis sample for the studies. The National Institutes of Health supported the research.

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