No abstract

Background: Candida glabrata virulence is poorly understood at the molecular level.Results: Inactivation of components of the C. glabrata glycosylation machinery results in changes in fungal mannan structure and altered virulence.Conclusion: Changes in C. glabrata cell wall architecture impact the host-pathogen interactions.Significance: Greater understanding of C. glabrata virulence will provide insights that can be adopted for development of novel diagnostic and therapeutic interventions.

No abstract

Candida albicans is a commensal organism that under certain circumstances can become pathogenic. During systemic infection C. albicans is disseminated via the circulation to distant organs, where it causes multiple organ failure. Despite the severity of systemic C. albicans infection, little is known about the mechanisms involved in the adhesion of this organism to the endothelium lining blood vessels. Previous studies have used static assays to examine adhesion. However, these do not realistically model blood vessels, where circulating C. albicans cells must adhere to the endothelium under conditions of flow and shear stress. Furthermore, there is conflicting evidence concerning the role played by yeast, pseudohyphal, and hyphal forms of C. albicans in adhesion to endothelium. To test the hypothesis that there may be differences in the abilities of these three morphogenic forms of C. albicans to adhere to endothelium under conditions of flow, we developed an in vitro flow adhesion assay. We found that all three forms of C. albicans rapidly bound to confluent endothelial cells under conditions of flow. Maximum adhesion was found at low shear stress levels similar to that found in postcapillary venules. Moreover, yeast forms bound in significantly greater numbers than did pseudohyphal and hyphal forms, respectively, contrasting with previous findings from static assays. These findings are consistent with recent in vivo data suggesting that yeast forms may be capable of adhering to the endothelium and migrating into the tissues before undergoing morphogenic change to cause tissue damage.

Expression of the glutathione S-transferase, GSTP1, is associated with phase 1 detoxification of the products of oxidative stress. Recently, GSTP1 expression has been implicated in the regulation of cell proliferation and apoptosis through direct interaction with the c-Jun N-terminal kinase, (JNK). GSTP1 is polymorphic and allelic variants have been associated with disease susceptibility and clinical outcome. However, the influence of GSTP1 alleles on proliferation and apoptosis has not been studied previously. To investigate this, we have examined the effects of inducible expression of wild-type GSTP1*A and mutant GSTP1*C haplotypes on cell proliferation and apoptosis in NIH3T3 fibroblasts. Cells expressing GSTP1*A displayed increased doubling times and a delayed G1-S phase transition compared with cells expressing GSTP1*C. Both GSTP1*A and GSTP1*C haplotypes protected cells from undergoing apoptosis when exposed to oxidative stress. However, analysis of JNK status revealed that only GSTP1*C expression led to a reduction in JNK activity compared with GSTP1*A-expressing cells and non-induced cells. We further examined the effect of GSTP1 alleles on colony-forming efficiency (CFE) in soft agar following exposure to oxidative stress and found that GSTP1*A-expressing clones had increased CFE compared with non-induced and GSTP1*C-expressing clones. Our data suggest that GSTP1 alleles have differential effects on proliferation and apoptosis; GSTP1*A reduces cellular proliferation and protects against apoptosis through a JNK-independent mechanism. In contrast, GSTP1*C does not influence cellular proliferation but protects cells from apoptosis through JNK-mediated mechanisms.