Inhibition of Human Endothelial Cell Chemokine Production by the Opportunistic Fungal Pathogen Cryptococcus neoformans

Department of Microbiology and Immunology, Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
The Journal of Immunology (Impact Factor: 4.92). 09/2000; 165(3):1541-7. DOI: 10.4049/jimmunol.165.3.1541
Source: PubMed


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.

15 Reads
  • Source
    • "Many infectious microorganisms induced expression of chemokines and adhesion molecules in human endothelial cells. Studies of the gene expression in primary HUVEC revealed that C. neoformans had the ability to interfere with inflammatory signaling in human endothelial cells, and suggested that C. neoformans may later induce leukocyte activation and trafficking in the infected host (HUVEC) [15, 16]. Our results also showed that expression of interferon-related genes and MHC group genes are changed during C. neoformans infection. "
    [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.
    BioMed Research International 02/2008; 2008(1):375620. DOI:10.1155/2008/375620 · 2.71 Impact Factor
  • Source
    • "Endothelial cells were detached from tissue culture plates by incubating in HEDTA for 5 min at 37 8C. Then, the cells were fixed in 4% paraformaladehyde in PBS for 30 min at 4 8C and labeled with an anti-ICAM-1 mAb following the manufacturer's recommendations (1 mg) [4]. Goat-anti mouse IgG-FITC (1:500 dilution) was added prior to flow cytometric analysis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: During sepsis, endothelial cells are both a source and target of pro-inflammatory cytokines (e.g. IL-1alpha, IL-1beta, TNFalpha and others), which may be detrimental to vascular homeostasis. Our laboratory has demonstrated that Haemophilus somnus, a gram-negative pathogen of cattle that causes sepsis and vasculitis, and its lipooligosaccharide (LOS) induce caspases-3, -8 and -9 activation, and apoptosis of endothelial cells in vitro. In this study, we provide evidence that H. somnus LOS increases IL-1alpha and IL-1beta mRNA expression, and caspase-1 activation in endothelial cells. Addition of a caspase-1 inhibitor (YVAD), or incubation in a high extracellular potassium buffer (150 mM), reduced caspase-1 activation and significantly enhanced H. somnus LOS-mediated caspase-3 activation. Likewise, blocking the IL-1 type 1 receptor by addition of IL-receptor antagonist (IL-1ra) significantly enhanced LOS-mediated caspase-3 activation. Conversely, addition of exogenous recombinant bovine IL-1beta (100 ng/mL) to endothelial cells diminished LOS-mediated apoptosis. IL-1beta has been reported previously to protect numerous cell types from apoptosis by activating PI3 kinase/p-Akt signaling pathways. Addition of selective PI3 kinase inhibitors (e.g. wortmannin and LY294002) significantly enhanced LOS-mediated caspase-3 activation. Exposure of endothelial cells to IL-1beta or LOS increased pAkt protein as assessed by western blot. Overall, these results suggest that signaling through the IL-1 type 1 receptor diminishes H. somnus LOS-mediated apoptosis.
    Microbial Pathogenesis 11/2005; 39(4):121-30. DOI:10.1016/j.micpath.2005.07.001 · 1.79 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Enhanced prostaglandin production during fungal infection could be an important factor in promoting fungal colonization and chronic infection. Host cells are one source of prostaglandins; however, another potential source of prostaglandins is the fungal pathogen itself. Our objective was to determine if the pathogenic yeastsCryptococcus neoformans and Candida albicansproduce prostaglandins and, if so, to begin to define the role of these bioactive lipids in yeast biology and disease pathogenesis. C. neoformans and C. albicans both secreted prostaglandins de novo or via conversion of exogenous arachidonic acid. Treatment with cyclooxygenase inhibitors dramatically reduced the viability of the yeast and the production of prostaglandins, suggesting that an essential cyclooxygenase like enzyme may be responsible for fungal prostaglandin production. A PGE series lipid was purified from both C. albicans and C. neoformans and was biologically active on both fungal and mammalian cells. Fungal PGEx and synthetic PGE2 enhanced the yeast-to-hypha transition in C. albicans. Furthermore, in mammalian cells, fungal PGEx down-modulated chemokine production, tumor necrosis factor alpha production, and splenocyte proliferation while up-regulating interleukin 10 production. These are all activities previously documented for mammalian PGE2. Thus, eicosanoids are produced by pathogenic fungi, are critical for growth of the fungi, and can modulate host immune functions. The discovery that pathogenic fungi produce and respond to immunomodulatory eicosanoids reveals a virulence mechanism that has potentially great implications for understanding the mechanisms of chronic fungal infection, immune deviation, and fungi as disease cofactors.
    Infection and Immunity 06/2001; 69(5):2957-63. DOI:10.1128/IAI.69.5.2957-2963.2001 · 3.73 Impact Factor
Show more


15 Reads
Available from