Release of a Potent Polymorphonuclear Leukocyte Chemoattractant Is Regulated by White-Opaque Switching inCandida albicans

Abstract

Previous studies employing transmembrane assays suggested that Candida albicans and related species, as well as Saccharomyces cerevisiae, release chemoattractants for human polymorphonuclear leukocytes (PMNs). Because transmembrane assays do not definitively distinguish between chemokinesis and chemotaxis, singlecell chemotaxis assays were used to confirm these findings and test whether mating-type or white-opaque switching affects the release of attractant. Our results demonstrate that C. albicans, C. dubliniensis, C. tropicalis, C. parapsilosis, and C. glabrata release bona fide chemoattractants for PMNs. S. cerevisiae, however, releases a chemokinetic factor but not a chemoattractant. Characterization of the C. albicans chemoattractant revealed that it is a peptide of approximately 1 kDa. Whereas the mating type of C. albicans did not affect the release of chemoattractant, switching did. White-phase cells released chemoattractant, but opaque-phase cells did not. Since the opaque phase of C. albicans represents the mating-competent phenotype, it may be that opaque-phase cells selectively suppress the release of chemoattractant to facilitate mating.Polymorphonuclear leukocytes (PMNs) represent the first line of defense in combating microbial infections. By sensing chemoattractants, PMNs migrate toward sites of infection. In vitro, PMNs orient and chemotax up spatial gradients of formyl methyl peptides (11,(53)(54)(55), which are released by bacteria. These peptides bind to a receptor on the surface of PMNs (26, 31). The receptor-mediated signal is transduced through regulatory cascades that control the actin cytoskeleton in order to polarize and direct the movement of the PMNs toward the site of infection (6, 18, 52). The spatial, and possibly temporal, patterns of receptor occupancy dictate orientation and subsequent chemotaxis (11,12).The process of PMN chemotaxis may play a role in controlling the levels of Candida spp. carriage in the commensal state, as well as in clearing yeast from sites of infection (10, 34). The attraction of PMNs to sites of infection may also contribute to the inflammatory response associated with vaginitis and other forms of mucosal candidiasis. Immunocompromised individuals are far more prone to mucosal candidiasis and candidemias (3), supporting the suggestion that the cellular immune response plays a role in suppressing such infections. The attraction of PMNs to sites of fungal infection may be mediated by an attractant either released by the colonizing yeast cells or released by human cells activated by the yeast. Interestingly, however, in animal models of vaginitis and in human cases of vaginitis the frequent absence of PMNs has been noted (10). The absence of PMNs at the site of a fungal infection may be due either to unresponsive PMNs or to the failure by the colonizing yeast to release a chemoattractant. The release of PMN chemoattractants by colonizing yeast and the responsiveness of PMNs to such chemoattractants, therefore, warrant careful scrutiny as they relate to yeast...

Stress-Induced Phenotypic Switching inCandida albicans

“…Studies have shown that white and opaque cells show marked differences in their relationship with the host, as exemplified by differences in both tissue specificity and in interactions with immune cells. For example, white cells are phagocytosed more efficiently than opaque cells by macrophages, and white cells, but not opaque cells, secrete a chemoattractant for leukocytes (Geiger et al, 2004;Lohse and Johnson, 2008). The current work shows that white-toopaque switching rates are modulated in response to multiple forms of cell stress, perhaps conferring a selective advantage during hostile conditions.…”

“…In particular, strains exhibit an increased tendency to switch to opaque in response to oxidative stress, and this could potentiate escape from the immune system. Host neutrophils often target microbial invaders by release of oxidants, and thus the ability to sense these agents and switch to an alternative form could promote survival, particularly given that host cells differentially sense white and opaque cells (Kolotila and Diamond, 1990;Geiger et al, 2004;Lohse and Johnson, 2008). In addition, increased switching to opaque may provide a benefit during colonization and infection of specific host niches.…”

“…White and opaque cells have also been shown to differ in their interaction with immune cells. White cells secrete a chemoattractant for leukocytes, whereas opaque cells do not (Geiger et al, 2004). In addition, white and opaque cells are differentially phagocytosed by macrophages, suggesting that white-opaque switching may be an adaptive mechanism to help C. albicans cells escape the attention of the host immune system (Lohse and Johnson, 2008).…”

Thoughts on Quorum Sensing and Fungal Dimorphism

“…Distinct morphologies elicit different responses by the host immune system. Both white and opaque cells are known to attract leukocytes to the site of infection, but only white cells produce and secrete a small molecular weight chemoattractant that draws the leukocyte directly towards the white cell (Geiger et al 2004). Lohse and Johnson (2008) took this knowledge a step further by showing that not only were leukocytes more attracted to white cells than opaque cells, but because of the presence of a chemoattractant produced by the white cells, mouse macrophages engulfed white C. albicans cells much more efficiently than they did opaque cells (Lohse and Johnson 2008).…”

Crystal structure of the WOPR-DNA complex and implications for Wor1 function in white-opaque switching of Candida albicans

“…Important to its pathogenesis and commensalism is its ability to switch between different morphological forms [2][3][4]. C. albicans can switch between two distinct cell types, white and opaque, which have different properties including cell shape, colonial morphology, metabolic preference, mating ability, gene expression pattern, and host tissue preference [5][6][7][8][9]. White-opaque switching is controlled through expression of a master regulator, Wor1 (whiteopaque switching regulator 1), which is highly upregulated in opaque cells and is required for both the transition to and maintenance of the opaque cell type [10][11][12][13].…”