Identification of Serum Bridging Molecules that Mediate Human Endothelial Cell Invasion byCandidaspecies

AbstractDuring hematogenously disseminated candidiasis, blood borne fungi must invade the endothelial cells that line the blood vessels to infect the deep tissues. AlthoughCandida albicans, which forms hyphae, readily invades endothelial cells, other medically important species ofCandidaare poorly invasive in standard in vitro assays. Here, we show thatCandida glabrata, Candida tropicalis, Candida parapsilosis, andCandida kruseican bind to vitronectin and high molecular weight kininogen present in human serum. Acting as bridging molecules, vitronectin and kininogen bind to αv integrins and the globular C1q receptor (gC1qR), inducing human endothelial cells to endocytose the fungus. This mechanism of endothelial cell invasion is poorly supported by mouse endothelial cells, but can be restored when mouse endothelial cells are engineered to express human gC1qR or αv integrin. Overall, these data indicate that bridging molecule-mediated endocytosis is a common pathogenic strategy used by many medically importantCandida spp. to invade human vascular endothelial cells.SignificanceThe invasion of vascular endothelial cells is a key step in the pathogenesis of hematogenously disseminated candidiasis. How species ofCandidaother thanC. albicansinvade endothelial cells is poorly understood because these fungi are weakly invasive in serum-free media. Here, we demonstrate thatC. glabrataand otherCandidaspp. bind to the serum proteins kininogen and vitronectin, which act as bridging molecules and mediate the adherence and endocytosis of the organisms by endothelial cells. These serum proteins induce endocytosis when they interact with the globular C1q receptor and αv integrins on human, but not mouse endothelial cells. Thus, bridging molecule-mediated endocytosis is a common mechanism by which medically importantCandidaspp. invade human endothelial cells.