Two transferrin-binding proteins, TbpA and TbpB are components of a surface-exposed, human transferring receptor expressed by Neisseria gonorrhoeae. These proteins, in addition to gonococcal TonB are necessary for efficient utilization of transferrin-bound iron. Because the receptor is expressed by all gonococci and the protein components are well conserved, their potential as vaccine targets is being explored. The overall goal of the proposed study is to determine how the gonococcal transferrin receptor complex accomplishes iron internalization and if the components of the receptor induce a protective immune response.
The specific aims of the application address the following questions:
Aim 1. What is the molecular mechanism by which the components of the transferrin receptor complex accomplish the three phases of transferrin-iron acquisition: Tf binding, iron removal, and iron transport? The goals of this aim are to probe the structure/function relationships in TbpA, TbpB and TonB using a combination of mutagenesis and biochemical characterization of receptor function. A detailed understanding of the mechanism of transferrin-iron transport will focus vaccine strategies on the functional relevance of particular epitopes.
Aim 2 : What molecular mechanisms coordinately control expression of TbpA, TbpB and TonB? Characterization of the promoter and regulatory stimuli that impact expression of these proteins will lead to a better understanding of how optimal amounts of transferrin receptor components are achieved. Moreover, the optimized function of the receptor is a result of the coordinated expression of the individual components.
Aim 3 : What are the biological activities of the anti-Tbp antibodies and are these antibodies protective? Antibody responses elicited against TbpA, TbpB and epitopes thereof, will be characterized following vaccination of laboratory animals. Elected antigens, combined with mucosal adjuvants, will be further evaluated for their ability to elicit a protective immune response in mice. ? ?
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