IMMUNE RECOGNITION OF CANDIDA--ROLE OF CELL WALL

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DESCRIPTION (Verbatim from Applicant's Abstract): Pathogenic fungi, such as Candida albicans, are increasingly common as opportunistic pathogens which cause significant morbidity and mortality in the immunocompromised host. Despite the growing significance of fungal pathogens there is much that is not known about their mechanisms of pathogenesis. Specifically, it is not clear how fungal pathogens interact with cellular components of the innate immune system. It is highly probable that the interaction of fungal pathogens with the innate immune system determines whether the infection proceeds to become systemic. Glucans are (1-3)-beta-D-linked polymers of glucose which are major carbohydrate constituents of fungal cell walls. Glucans are also released into the systemic circulation of patients with fungal infections. Our working hypothesis is that Candida cell wall (1-3)-beta-D-glucans play a major role in the recognition of Candida by immune competent cells, i.e. macrophages and neutrophils. To critically evaluate this hypothesis there are four specific aims. I. We will isolate and chemically characterize (1-3)-beta-D-glucans from Candida cell walls, glucans from Candida hyphae and the glucans which are released into the extracellular milieu as exopolymers. II. We will characterize the receptor mediated binding/internalization of Candida derived (1-3)-beta-D-glucans in human macrophages and neutrophils and determine whether the glucan receptor(s) mediate the uptake and/or killing of Candida. These studies will also address the questions of whether Candida glucans are recognized by the CR3 (CD11b/CD18) and/or Toll-like receptors on macrophages and neutrophils. III. We will investigate the in vitro effect of Candida glucans on activation of transcriptional regulatory proteins (NFkB and NF-IL6) and expression of inflammatory cytokines and chemokines in human macrophages and neutrophils. IV. We will investigate the in vivo effect of Candida derived (1-3)-beta-D-glucans on the transcriptional activator proteins NFkB and NF-IL6, expression of immunoregulatory and inflammatory mediators, TH1/TH2 switching and whether Candida glucans will protect against a fungal challenge. We will also compare and contrast the effects of Candida derived glucans and mannans in order to determine whether there are differences in response to these two common constituents of fungal cell walls. Our long-term objectives are to define the cellular and molecular mechanisms of fungal cell wall carbohydrates in the pathogenesis of fungal infections and to utilize this basic science data to identify potential drug targets and/or improved therapeutic strategies for the management of fungal sepsis.