Steere, Mason Coauthor "Nature" Study of Iron "Pirates" that Support Virulent Meningitis-Causing Bacteria
- By Jennifer Nachbur
A new study, published in the February 12, 2012 online Nature clarifies how two important proteins “pirate” iron from their hosts to support a virulent pathogen called Neisseria, which accounts for hundreds of thousands of deaths annually worldwide. These findings offer a new potential target for vaccines and drug treatments to combat bacterial meningitis, septicemia – a life-threatening blood infection – and the sexually-transmitted infection gonorrhea.
Anne Mason, Ph.D., professor of biochemistry at the University of Vermont College of Medicine, and Ashley Steere, Ph.D., currently a postdoctoral associate in biochemistry who was mentored by Mason as a doctoral candidate, are coauthors on the study.
Neisseria bacteria need iron to grow and become virulent. This research reveals the role of two large iron-binding proteins in that process. Together, transferrin binding protein A (TbpA), which resides on the outer membrane of the organism, and transferrin protein B (TbpB), which is a receptor protein, essentially “mine” the iron from transferrin, a protein in human blood that allows the transport of iron in the body.
“These two bacterial proteins cooperate in an unexplained manner to specifically acquire iron directly from the human serum protein transferrin,” says Mason.
Human serum transferrin has two lobes. Each lobe features a binding cleft in which dietary iron binds tightly for transport around the body and receptor-mediated delivery of iron to cells. In order to test the specificity of this process, Mason and Steere designed and expressed recombinant – or genetically altered – transferrins and used them to evaluate the ability of TbpA and TbpB to recognize and discriminate between transferrins with iron in both lobes, iron in only one lobe, or without iron in either lobe. In addition, Mason explains, the team also produced isolated C-lobe that allowed the laboratory of lead author Susan Buchanan, Ph.D., of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), to determine a crystal structure, which was critical to interpreting the study’s findings.
By examining TbpA for iron from the C-lobe of human transferrin, the research team was able to zero in on the mechanism responsible for the “piracy” of iron. The group discovered that iron release from this lobe is initiated by insertion of a helical (spiral-shaped) “finger” into the binding cleft. Their work also reveals how TbpB facilitates the capture of transferrin with iron in the C-lobe and provides it to TbpA.
“The structures and the collective information from this study now provide a rational basis for vaccine and drug design to effectively combat these devastating pathogens,” Mason says. “The increase in antibiotic resistant strains adds urgency to this mission.”
Currently, there are no vaccines to protect against gonorrhea infections, and bacterial meningitis vaccines are limited in their effectiveness, according to an NIDDK news release regarding the study.
Steere, who recently received the 2012 Roberto Fabri Fialho scholarship from UVM’s Graduate College, was supported by a predoctoral research grant from the American Heart Association to conduct work for the study. Mason is funded by a U.S. Public Health Service grant.