Inhibition of human endothelial cell chemokine production by the opportunistic fungal pathogen Cryptococcus neoformans.
ABSTRACT Cryptococcus neoformans is an encapsulated fungal pathogen commonly acquired by inhalation. Extrapulmonary dissemination can lead to infection of the bloodstream and various organs, most commonly resulting in meningoencephalitis. However, infection with C. neoformans is often characterized by a scant inflammatory response. The leukocyte response to infection depends in part upon a gradient of chemotactic factors and adhesion molecules expressed by the host vascular endothelium, yet the inflammatory response of human endothelial cells (EC) to C. neoformans has not been previously investigated. We found that incubation of primary human EC with C. neoformans did not induce chemokine synthesis, and resulted in differential inhibition of cytokine-induced IL-8, IFN-gamma-inducible protein-10, and monocyte chemoattractant protein-1. In contrast, C. neoformans had little effect on EC surface expression of the leukocyte ligand, ICAM-1, as determined by flow cytometry. Modulation of chemokine production was dependent on the chemokine under study, the inoculum of C. neoformans used, fungal viability, and cell-cell contact, but independent of cryptococcal strain or encapsulation. These observations suggest a novel mechanism whereby C. neoformans can affect EC function and interfere with the host inflammatory response.
Article: Infectomic analysis of gene expression profiles of human brain microvascular endothelial cells infected with Cryptococcus neoformans.[show abstract] [hide abstract]
ABSTRACT: In order to dissect the pathogenesis of Cryptococcus neoformans meningoencephalitis, a genomic survey of the changes in gene expression of human brain microvascular endothelial cells infected by C. neoformans was carried out in a time-course study. Principal component analysis (PCA) revealed significant fluctuations in the expression levels of different groups of genes during the pathogen-host interaction. Self-organizing map (SOM) analysis revealed that most genes were up- or downregulated 2 folds or more at least at one time point during the pathogen-host engagement. The microarray data were validated by Western blot analysis of a group of genes, including beta-actin, Bcl-x, CD47, Bax, Bad, and Bcl-2. Hierarchical cluster profile showed that 61 out of 66 listed interferon genes were changed at least at one time point. Similarly, the active responses in expression of MHC genes were detected at all stages of the interaction. Taken together, our infectomic approaches suggest that the host cells significantly change the gene profiles and also actively participate in immunoregulations of the central nervous system (CNS) during C. neoformans infection.Journal of Biomedicine and Biotechnology 02/2008; 2008:375620. · 2.44 Impact Factor
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ABSTRACT: The YPS3 gene of Histoplasma capsulatum encodes a protein that is both resident in the cell wall and also released into the culture medium. This protein is produced only during the pathogenic yeast phase of infection and is also expressed differently in H. capsulatum strains that differ in virulence. We investigated the cellular localization of Yps3p. We demonstrated that the cell wall fraction of Yps3p was surface localized in restriction fragment length polymorphism class 2 strains. We also established that Yps3p released into the G217B culture supernatant binds to the surface of strains that do not naturally express the protein. This binding was saturable and occurred within 5 min of exposure and occurred similarly with live and heat-killed H. capsulatum. Flow cytometric analysis of H. capsulatum after enzymatic treatments was consistent with Yps3p binding to chitin, a carbohydrate polymer that is a component of fungal cell walls. Polysaccharide binding assays demonstrated that chitin but not cellulose binds to and extracts Yps3p from culture supernatants.Eukaryotic Cell 05/2005; 4(4):685-93. · 3.60 Impact Factor