Pathogenic microorganisms have evolved a variety of strategies to overcome immune and non-immune barriers of the human host. Withholding of iron by the host is a common mechanism of non-specific immunity against infection. Expression of an iron-acquisition system by T. vaginalis is, thus, a prerequisite for establishment of infection. Our long-range goal is to understand the molecular mechanism of the trichomonad iron acquisition system and its linkage to iron-regulated virulence gene expression. To accomplish this goal our next objective, as described in this application, is to identify the components of the trichomonad iron-acquisition system and understand its regulation. The central hypothesis to be tested in this application is that iron homeostasis is achieved by transcriptional regulation of a five component iron-acquisition system. The rationale behind the proposed research focuses on the fact that iron-acquisition is critical to the survival of trichomonads in host-tissue. Thus, until the pathway and mechanism of iron-acquisition in trichomonads is fully defined. Thus, until the pathway and mechanism of iron-mechanism of iron-acquisition in trichomonads is fully defined, it cannot be determined whether or not components of this pathway can be targeted for therapeutic purposes. To accomplish the objectives of this application, we will pursue four specific aims: (1) establish the role of ferric reduction in iron- mobilization from lactoferrin; (2) identify membrane iron-binding proteins; (3) determine the sequence and proteins involved in iron exchange reactions; and (4) identify the iron-responsive components of the trichomonad iron-acquisition pathway. At the completion of this project we expect to have established the mechanism of iron removal from lactoferrin. Furthermore, we will have detailed and defined the molecules involved in the movement of lactoferrin iron throughout the cell and we will have established the regulatory basis of iron homeostasis. In addition, to contribution to an understanding of the basic pathogenic mechanisms of trichomonads, it is expected that the results will lead to new therapeutic strategies.
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