The Early Transcriptional Response of Human Granulocytes to Infection withCandida albicansIs Not Essential for Killing but Reflects Cellular Communications

Abstract

Candida albicans is a polymorphic opportunistic fungus that can cause life-threatening systemic infections following hematogenous dissemination in patients susceptible to nosocomial infection. Neutrophils form part of the innate immune response, which is the first line of defense against microbes and is particularly important in C. albicans infections. To compare the transcriptional response of leukocytes exposed to C. albicans, we investigated the expression of key cytokine genes in polymorphonuclear and mononuclear leukocytes after incubation with C. albicans for 1 h. Isolated mononuclear cells expressed high levels of genes encoding proinflammatory signaling molecules, whereas neutrophils exhibited much lower levels, similar to those observed in whole blood. The global transcriptional profile of neutrophils was examined by using an immunology-biased human microarray to determine whether different morphological forms or the viability of C. albicans altered the transcriptome. Hyphal cells appeared to have the broadest effect, although the most strongly induced genes were regulated independently of morphology or viability. These genes were involved in proinflammatory cell-cell signaling, cell signal transduction, and cell growth. Generally, genes encoding known components of neutrophil granules showed no upregulation at this time point; however, lactoferrin, a wellknown candidacidal peptide, was secreted by neutrophils. Addition to inhibitors of RNA or protein de novo synthesis did not influence the killing activity within 30 min. These results support the general notion that neutrophils do not require gene transcription to mount an immediate and direct attack against microbes. However, neutrophils exposed to C. albicans express genes involved in communication with other immune cells.

Analysis ofPRA1and Its Relationship toCandida albicans- Macrophage Interactions

“…The interaction between the fungal pathogen Candida albicans and cells of the innate immune system is associated with significant changes in gene expression in both fungal and mammalian cells (24,26,35,46,69). We used microarray analysis to investigate the transcriptional consequences of the engulfment of cells of the SC5314 strain of C. albicans by both primary macrophages (BMDM) and the macrophage line RAW 264.7.…”

Lactoferrin Acts as an Alarmin to Promote the Recruitment and Activation of APCs and Antigen-Specific Immune Responses

“…This is particularly noticeable in blood, where lactoferrin concentration can be as low as 0.5ϳ1 g/ml under normal conditions, but increases to 200 g/ml with systemic bacterial infection (6,7). Recent reports indicate that lactoferrin expression in both neutrophils and epithelial cells can be induced (8,9).…”

New Insights in Medical Mycology

“…The fact that both quantitative and qualitative defects of neutrophils are associated with an undue susceptibility to major disseminated fungal infections points to the important role that neutrophils play in the protective immunity to fungal diseases (Romani, 2004a;Fradin et al, 2006). Their functions may well go beyond microbicidal activity, and also include an immunoregulatory role in adaptive immunity (Romani et al, 1996).…”

“…A number of studies have utilised host DNA microarrays to examine transcriptional changes occurring when host cells interact with C. albicans or with C. albicansderived cell wall components Ishibashi et al, 2004;McLaren et al, 2004;Kim et al, 2005;Fradin et al, 2006). These studies have been performed for a human monocytic cell line , blood cells (Ishibashi et al, 2004;McLaren et al, 2004;Kim et al, 2005;Fradin et al, 2006), cell line-derived granulocytes , and dendritic cells .…”