SCAN:Characterization of the Fe regulon and siderophore-mediated Fe uptake in the fungal human pathogen C. glabrata

Abstract

Iron (Fe) acquisition plays a critical role in microbial pathogenesis. Capitalizing on the essential role of Fe for cellular growth and proliferation, the vertebrate host has evolved mechanisms of Fe limitation and withholding that contribute towards the containment of microbial expansion. Not surprisingly perhaps, whereas defects in microbial Fe acquisition have been linked to the attenuation of virulence, Fe overload diseases are often associated with increased susceptibility to recurrent infections.

Candida glabrata is an opportunistic fungal human pathogen and a rising cause of candidemia in immunocompromised individuals. Genome-wide expression analyses show that upon a shift to conditions of Fe limitation, the expression of components of both high- and low-affinity systems for Fe acquisition is increased. Among the most highly induced genes in this Fe regulon, we find SIT1, encoding a putative siderophore transporter. Studies have revealed that Sit1 is a plasma membrane transporter that mediates the uptake/utilization of hydroxamate-containing siderophore Fe chelates of fungal origin. Hypothesizing that the acquisition and homeostatic regulation of intracellular Fe levels will play a relevant role in virulence, we are currently investigating the importance of Sit1-mediated siderophore utilization in C. glabrata survival in macrophages. As a member of one of the 17 fungal-specific protein families, Sit1 stands as an attractive target for the future development of anti-fungal therapeutics.
 

Short CV

1991-1994, B.Sc. - Genetics - University of Leeds, UK

1994-1995, M.Sc. - Medical Genetics with Immunology - University of London
at Brunel

2001- 2005, Ph.D. - Biochemistry - ITQB under the supervision of Professor
Claudina Rodrigues-Pousada

February 2006 to July 2006 - Post-doctoral fellow at ITQB in the
laboratory of Professor Claudina Rodrigues-Pousada

Since August 2006 - Post-doctoral fellow at Duke University Medical Center
in the laboratory of Dr. Dennis J. Thiele