Investigation of the Function of Candida albicans Als3 by Heterologous Expression in Candida glabrata

Abstract

ABSTRACTDuring hematogenously disseminated infection, blood-borneCandida albicansinvades the endothelial cell lining of the vasculature to invade the deep tissues. Although theC. albicansAls3 invasin is critical for invasion and damage of endothelial cellsin vitro, aC. albicans als3Δ/Δ mutant has normal virulence in the mouse model of disseminated infection. We hypothesized that the contribution of Als3 to virulence is obscured by the presence of additionalC. albicansinvasins. To elucidate thein vivofunction of Als3, we heterologously expressedC. albicans ALS3inCandida glabrata, a yeast that lacks a closeALS3ortholog and has low virulence in mice. We found that following intravenous inoculation into mice, theALS3-expressing strain preferentially trafficked to the brain, where it induced significantly elevated levels of myeloperoxidase, tumor necrosis factor, monocyte chemoattractant protein 1, and gamma interferon. Also, theALS3-expressing strain had enhanced adherence to and invasion of human brain microvascular endothelial cellsin vitro, demonstrating a potential mechanism forALS3-mediated neurotropism. In addition, upon initiation of infection, theALS3-expressing strain had increased trafficking to the cortex of the kidneys. With prolonged infection, this strain persisted in the kidneys at significantly higher levels than the control strain but did not induce an elevated inflammatory response. Finally, theALS3-expressing strain had increased resistance to neutrophil killingin vitro. These results indicate that during disseminated infection, Als3 mediates initial trafficking to the brain and renal cortex and contributes to fungal persistence in the kidneys.