Candida albicans Ras1 Inactivation Increases Resistance to Phagosomal Killing by Human Neutrophils

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Abstract
Host phagocytic cells are crucial players in initial defense against Candida albicans infection. C. albicans utilizes MAP Kinases and Ras1 stress response signaling pathways to protect itself from killing by immune cells. In this study we tested the importance of these pathways on C. albicans phagocytosis by neutrophils and subsequent phagosomal survival. Phagocytosis was influenced by C. albicans morphology, so that hyphal length > 10 μm reduced the phagocytic index (PI) by 2-3 fold in human neutrophils. Primary human neutrophils killed 81% of phagocytosed C. albicans, while primary mouse neutrophils killed 63% yeast. We found that both C. albicans Cek1 and Hog1 pathways were required for survival of phagocytosed yeast, whereas deletion of C. albicans RAS1 resulted in an 84% increase in survival within neutrophils compared to WT. The absence of Ras1 did not alter ROS production by C. albicans, however phagocytosed C. albicans Δ/Δras1 cells reduced ROS release by neutrophils by 86%. Moreover, C. albicans Δ/Δras1 cells had increased resistance to hydrogen peroxide as a result of high levels of catalase activity. This phenotype was specific to Ras1, since these effects were not observed in the absence of its partner Cyr1 or with its downstream target Efg1. In addition, C. albicans Δ/Δras1 cells had a significantly increased resistance to non-oxidative killing by human neutrophil peptide 1 (HNP-1) that was reversed by restoring cellular cAMP levels. These data show that C. albicans Ras1 inactivation leads to fungal resistance to both oxidative and non-oxidative mechanisms of neutrophil phagosomal killing.
Funding Information
  • National Institute of Dental and Craniofacial Research (R01DE010641, R01DE022720)
  • National Institute of Dental and Craniofacial Research (R03DE025062)
  • Comisión Nacional de Investigación Científica y Tecnológica (72150173)

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