OHSU

Crosa Lab

Overview

Our main interest concerns the molecular mechanisms used by bacterial pathogens to modulate expression of their genes in response to environmental stimuli, such as the iron concentration that mimic the environment found during infection of the vertebrate hosts. We use a combination of molecular, genetic, and biochemical approaches to investigate:

  • The genetics and assembly line enzymology of siderophore biosythesis in bacteria
  • Structure-function studies of iron transport proteins
  • Signal transduction and transcriptional regulation of iron uptake genes involved in virulence
  • The control of bacterial cell division and DNA replication during infection

in detail

Siderophores

Siderophores are small molecular weight, high-affinity iron-binding compounds that can scavenge the iron away from the high-affinity iron-binding proteins. Click to enlarge.

The ability of bacteria to cause disease depends on many parameters that work in concert to establish the pathogen in the vertebrate host. One of these factors is its ability to compete with the host organism for iron. Iron is an essential metal for nearly all living systems; however, in biological fluids it exists only as a complex with iron binding proteins, making it essentially unavailable. Therefore in order to establish an infection invasive microorganisms must depend on their ability to use the iron found in the host which is complexed to high-affinity iron-binding proteins such as transferrin, or lactoferrin or is part of heme in the red cells. To accomplish this endeavor, microorganisms possess receptors in the outer membrane that allow them to acquire directly the iron from the complexes with the high-affinity iron-binding eukaryotic proteins. However, a more common strategy among microorganisms is the synthesis of siderophores which are small molecular weight, high-affinity iron-binding compounds that can scavenge the iron away from the high-affinity iron-binding proteins in the host to present it as a ferric-siderophore complex to the cognate outer membrane protein receptors and subsidiary iron transport proteins (Fig. 1). We are interested on the mechanisms that control iron transport gene expression in bacteria belonging to the genus Vibrio and their influence on the expression of pathogenicity. The interplay between positive and negative regulatory molecules which include proteins and small RNAs is currently being studied. Bacteria that belong to the genus Vibrio (Fig. 2 is a micrograph of the typical curved rod with a polar flagellum)are commonly found as etiological agents of disease in humans and animals. One of the most studied members of this group is Vibrio cholerae. Other important members of this group are the marine pathogens Vibrio vulnificus and Vibrio anguillarum. V. vulnificus causes highly fatal hemorrhagic septicemias in humans as well as marine animals while V. anguillarum is responsible for the haemorrhagic septicemic disease vibriosis in salmonid fishes. We are using these two systems in a program to understand the contribution of iron transport to virulence.