In the United States, as many as 10% of hospitalized patients develop a nosocomial infection, estimated to involve more than 2 million patients (and 58,000 deaths), and to cost more than $4.5 billion annually. Candida species represent the 6th most common nosocomial pathogen overall, and the 4th most common cause of nosocomial bloodstream infections. Mortality from systemic candidiasis ranges from 63% to 85% in untreated patients and from 33% to 54% in those who receive appropriate antifungal therapy. Patients at highest risk include immunosuppressed patients, trauma patients, and postsurgical patients. The intestinal tract is believed to be the major colonizing habitat, and the source of most Candida infection. C. albicans accounts for 60% to 80% of all Candida isolates and C. albicans is the most virulent species. C. albicans is eucaryotic and diploid, and it is not possible to construct isogenic mutants using techniques designed for procaryotic bacteria. However, using the """"""""Ura-blaster"""""""" method, it has recently become possible to construct isogenic strains of C. albicans that differ from a parent strain by disruption of a single gene; the gene INT1 has been associated with epithelial adhesion, morphogenesis (switching from yeast to hyphal forms), and virulence. In this proposal, well characterized wild-type and mutant strains of C. albicans (carrying two, one, or zero copies of INT1) are used to clarify the pathogenic significance of C. albicans adherence and morphogenesis, emphasizing the oral route of infection in clinically relevant mouse models of surgery and trauma, where experimental variables include antibiotic therapy, parenteral endotoxin, and hypoxia. Relevant in vitro cell culture systems (HT-29 and Caco-2 enterocytes) are also used where more defined conditions can be used to correlate the degree of C. albicans filamentation (production of germ tubes, pseudohyphae, true hyphae) with the degree of adherence, internalization, intracellular survival, and paracellular and transcellular migration. Results from in vitro cell culture systems are correlated with results from in vivo models. The working hypothesis is: Morphologic switching in C. albicans, that is conversion from yeast to hyphal forms, plays a key role in C. albicans adherence and invasion, and thus plays a key role in C. albicans pathogenesis and virulence. Thus, the overall aim is to clarify the relevance of adhesion and morphogenesis in C. albicans pathogenesis. The long term goal is to use this information to target novel treatment regimens to decrease the costly morbidity and mortality associated with systemic candidiasis in surgical patients and trauma patients.
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