White-opaque switching is one of the most enigmatic features of Candida albicans
. Switching occurs, on average, every 103
generations, and the white and opaque forms are each heritable for many generations- until a new switching event occurs. It has been proposed that the heritability of the two states is based on a self-perpetuating feedback loop which is excited in the opaque state but which remains broken in the white state 
. Regardless of the exact mechanism, the phenomenon appears to be epigenetic, that is, switching from the white form to the opaque form and back occurs without any changes in the primary DNA sequence of the Candida
Despite having identical genomes, white and opaque cells show enormous phenotypic differences. The two types of cells are easily distinguished under the microscope and each gives rise to a specific type of colony easily distinguished by the naked eye [for reviews see 2]
. The two types of cells appear to favor different niches in the host: opaque cells are more suited to skin infection, while white cells appear more stable in a systemic mode of infection 
. The two types of cells also differ in their mating behavior; while opaque cells of opposite mating types readily mate, white cells do not. Indeed, white-opaque switching is itself controlled by the mating type locus- a
and α cells can undergo switching but a
/α cells cannot. Finally, approximately 400 genes are differentially regulated between white and opaque cells; although a few of these genes make conceptual sense (for example some mating genes are upregulated in opaque cells), most do not and, instead, point to our incomplete understanding of the fundamental differences between these two types of cells [for reviews see 24]
In the present study, we examined whether white and opaque cells differ in the extent to which they are phagocytosed by cells derived from the innate immune system. We chose this property because phagocytosis of microorganisms is an especially important component of the immune response 
. We show that two distinct cell lines derived from the innate immune system, D. melanogaster
S2 cells and M. musculus
RAW cells, phagocytose white C. albicans
cells much more efficiently than they do opaque cells. This difference is seen in both the percentage of S2 or RAW cells that have phagocytosed at least one C. albicans
and by the average number of C. albicans
phagocytosed per S2 or RAW cell. These results are statistically highly significant and repeated in multiple assays in multiple strain backgrounds carried out over a period of six months. Experiments carried out with mixed white and opaque C. albicans
populations produced similar results: from this mixture, S2 and RAW cells both selectively phagocytosed white cells. Taken together, these results suggest that the difference in phagocytosis is due to an intrinsic difference between white and opaque cells. For example, the mixed population experiments show that white cells do not secrete a signal that stimulates phagocytosis of opaque cells. This result is consistent with the results seen by Behnsen et al.
2007 where the efficient phagocytosis of Aspergillus fumigatus
did not result in an increase of C. albicans
phagocytosis by polymorphonuclear neutrophils in conditions unfavorable to C. albicans
. It is worth pointing out that while opsonization of C. albicans
cells prior to exposure to macrophages would be expected to change the overall rate of phagocytosis, it is not clear whether the distinction between white and opaque cells would be increased or decreased.
Although this is the first study to examine phagocytosis of white and opaque cells, it is among several to indicate a differential response of the innate immune system to white and opaque cells. As described in the introduction, opaque cells are more sensitive than whites to oxidative stress and white cells, but not opaque cells, secrete a chemoattractant for leukocytes. Although it may be years before we understand the molecular basis of any of the differences in the way the host deals with white versus opaque cells, it is tempting to imagine that white-opaque switching in C. albicans plays a role conceptually similar to the many switching systems in bacteria, one of whose roles is to present the immune system with multiple “identities.” Although many bacterial pathogens typically use programmed DNA rearrangements to generate these differences, C. albicans- a eukaryote- has evolved an epigenetic mechanism that may serve the same basic function.