Research Interests:

The principal focus of research in our laboratory is on the opportunistic fungus Candida albicans and in particular the role that morphogenetic and associated changes play in the virulence of the organism. C. albicans is a common commensal of humans, present on as many as 30-50% of the population, where it apparently lives in harmony with its host causing no apparent disease. The fungus is capable, however, of causing both generally minor surface-associated infections - normally seen as oral or vaginal thrush – and much more severe, life-threatening infections affecting almost all of the deep organs. These latter infections occur when the organism manages to enter the host’s bloodstream through either invasion of host tissues (rarely) or more commonly via a contaminated catheter or other medical device following surgical intervention and as such are generally confined to hospital patients, especially those undergoing immunosuppressive therapy or are otherwise immunocompromised. One of the major problems associated with these “haematogenously disseminated” C. albicans infections is that unlike bacterial infections, which are generally resolved satisfactorily by timely antibiotic treatment, mortality rates for fungal infections remain unacceptably high (in the 30 – 40% range) even with aggressive drug therapy. In addition, the cost of treatment of these hospital acquired fungal infections is significant (estimated at $2.8 billion for U.S. hospitals in FY 1998). Since Candida species are responsible for 75% of these nosocomial fungal infections and the bulk of those involve C. albicans, a great deal of effort has been conducted on studying the features of this organism that contribute to its pathogenic potential and how the human host, in particular the immune system, responds to the infection.

From the fungal point of view, several physiological features are believed to contribute to the virulence of C. albicans including morphological changes, secretion of proteases, phenotypic switching, adhesion to host tissues and iron assimilation among others. Of these features, perhaps the most well studied is the ability of C .albicans to switch between several different morphologies depending on the environmental conditions under which it is growing; these are principally an ovoid yeast form and two filamentous forms termed either hyphae or pseudohyphae on the basis of differences in the characteristics of the filament. The key role that morphological changes play in the pathogenic potential of C. albicans has been reinforced over the years by numerous studies using defined genetic mutants that are locked into either the yeast or filamentous form and are incapable of undergoing these changes: the discovery that mutants locked into either the yeast form or the filamentous form are avirulent has led to the widely accepted paradigm that it is the ability to undergo this developmental process, rather than the individual morphologies themselves, which is a key determinant in the progression and pathogenesis of the disease. Unfortunately, due to all of these mutants being trapped into one or other of the morphotypes, they cannot be used to assess the impact of these morphological transitions at the various stages of the infectious process nor how the host immune system responds to these changes. We therefore constructed a C. albicans strain in which this development process could be externally manipulated both in the laboratory and during the course of an infection within an animal host. Our initial studies using this strain have provided the most compelling evidence of the pivotal nature of morphological changes in C. albicans virulence. Surprisingly, these early trials also revealed that filament formation is not, as widely thought, a requirement for the fungus to leave the bloodstream and reach the deeper organs and that high fungal burdens are tolerated by the animal host as long as the infecting cells are maintained in the yeast form.

We are now using the manipulability of this modified strain to more fully characterize the role played by this important physiological process in the virulence and pathogenesis associated with C. albicans infections from both the host’s and the fungus’ perspective.

Publications:

• Simon, A. J., Y. Milner, S. P. Saville, A. Dvir, D. Mochly-Rosen & E. Orr (1991) The identification and purification of a mammalian-like PKC in the yeast, Saccharomyces cerevisiae. Proc. Roy. Soc. Lond 243 pp 165-171
  
  
• Martinez-Quiles, N., R. Rohatgi, I. M. Anton, M. Medina, S. P. Saville, H. Miki, H. Yamaguchi, T. Takenawa, J. H. Hartwig, R. S. Geha and N. Ramesh (2001) WIP regulates N-WASP-mediated actin polymerization and filopodium formation. Nat. Cell Biol. 3 pp 484-491
  
  
• Ramage, G., S.P. Saville, B.L. Wickes and J. L. López-Ribot. (2002). Inhibition of Candida albicans biofilm formation by farnesol, a quorum sensing molecule. Appl. & Env. Microbiology. 68 pp 5459-63
  
  
• Redding, S.W., W.R. Kirkpatrick, S. Saville, B.J. Coco, A. Fothergill, M. Rinaldi, T. Eng, T.F. Patterson and J.L. Lopez-Ribot. 2003. Multiple Patterns of Resistance to Fluconazole in Candida glabrata Isolates from a Patient with Oropharyngeal Candidiasis Receiving Head and Neck Radiation. J. Clin. Microbiol. 41 pp 619-622.
  
  
• Anton I.M., S. P. Saville, M. J. Byrne, C. Curcio, N. Ramesh, J. H. Hartwig and R. S. Geha (2003) WIP participates in actin reorganization and ruffle formation induced by PDGF.J. Cell Sci. 116(12) pp 2443-51
  
  
• Saville S. P., A. L. Lazzell, C. Monteagudo and J. L. Lopez-Ribot (2003) Engineered control of cell morphology in vivo reveals distinct roles for yeast and filamentous forms of Candida albicans during infection. Eukaryot. Cell. 2(5) pp 1053-60
  
  
• Chamilos, G., M. S. Lionakis, R. E. Lewis, J. L. Lopez-Ribot, S. P. Saville, N. D. Albert, G. Halder & D. P. Kontoniayannis. Drosophila melanogaster as a facile model for large-scale studies of virulence mechanisms and antifungal drug efficacy in Candida. J. Inf. Dis. In press
  
  
• Saville, S.P., A. L. Lazzell, C. Monteagudo and J.L. Lopez-Ribot. Examination of the pathogenic potential of Candida albicans filamentous cells in an animal model of haematogenously disseminated candidiasis. In preparation.
  
  Invited Reviews:
  
  
• Ramage, G., S.P. Saville, Thomas, D.P. and J. L. López-Ribot (2005) Candida biofilms: an update.  Eukaryot. Cell. 4 pp 633-638.

• Saville, S.P., D.P. Thomas and J.L. López-Ribot. (2005). Use of genome information for the study of the pathogenesis of fungal infections and the development of diagnostic tools. Rev. Iberoam. Micol. In press.