The intraspecies diversity of C. albicans triggers qualitatively and temporally distinct host responses that determine the balance between commensalism and pathogenicity.

The host immune status is critical for preventing opportunistic infections with Candida albicans. Whether the natural fungal diversity that exists between C. albicans isolates also influences disease development remains unclear. Here, we used an experimental model of oral infection to probe the host response to diverse C. albicans isolates in vivo and found dramatic differences in their ability to persist in the oral mucosa, which inversely correlated with the degree and kinetics of immune activation in the host. Strikingly, the requirement of interleukin (IL)-17 signaling for fungal control was conserved between isolates, including isolates with delayed induction of IL-17. This underscores the relevance of IL-17 immunity in mucosal defense against C. albicans. In contrast, the accumulation of neutrophils and induction of inflammation in the infected tissue was strictly strain dependent. The dichotomy of the inflammatory neutrophil response was linked to the capacity of fungal strains to cause cellular damage and release of alarmins from the epithelium. The epithelium thus translates differences in the fungus into qualitatively distinct host responses. Altogether, this study provides a comprehensive understanding of the antifungal response in the oral mucosa and demonstrates the relevance of evaluating intraspecies differences for the outcome of fungal-host interactions in vivo.

Never in neutral: a systems biology and evolutionary perspective on how aneuploidy contributes to human diseases.

Whereas germline-inherited whole-chromosome aneuploidy has long been known to cause miscarriages and developmental abnormalities, somatically acquired aneuploidies have been observed in cancer cells and more recently also in cells of the normal liver and brain. Furthermore, aneuploidy is being increasingly reported in clinical isolates of pathogenic microbes such as fungi and parasites. Whereas many efforts have been devoted to the dissection of the molecular mechanisms that lead to aneuploidy, we have only recently started to investigate how aneuploidy alters the phenotypic makeup of a cell. Here we review recent evidence supporting the idea that aneuploidy is a large-effect mutation that introduces large changes in the cellular phenome. From a systems biology perspective, this can be explained by the extensive changes that aneuploidy brings about in both the transcriptome and the proteome of a cell. We further provide an evolutionary perspective on how aneuploidy-induced phenotypic variation may contribute to the exacerbation of human pathologies such as cancer and infectious diseases, by conferring selectable traits such as increased virulence and drug resistance.

Inducible IL-2 production by dendritic cells revealed by global gene expression analysis.

Dendritic cells (DCs) are strong activators of primary T cell responses. Their priming ability is acquired upon encounter with maturation stimuli. To identify the genes that are differentially expressed upon maturation induced by exposure to Gram-negative bacteria, a kinetic study of DC gene expression was done with microarrays representing 11,000 genes and ESTs (expressed sequence tags). Approximately 3000 differentially expressed transcripts were identified. We found that functional interleukin 2 (IL-2) mRNA, which gave rise to IL-2 production, was transiently up-regulated at early time-points after bacterial encounter. In contrast, macrophages did not produce IL-2 upon bacterial stimulation. Thus, IL-2 is an additional key cytokine that confers unique T cell stimulatory capacity to DCs.