Regulation of Human Neutrophil Responses to Candida albicans by Carcinoembryonic

22 Invasive candidiasis, mainly caused by the pathogen Candida albicans, is an important health-care23 associated fungal infection that results in mortality rates as high as 40%. Neutrophils are the first 24 line of defense during Candida infections. They can launch various killing mechanisms and release 25 cytokines to attract further immune cells to the site of infection. These responses are closely 26 controlled, since they can also result in severe tissue/organ damage. We hypothesized that the 27 regulation of C. albicans-specific neutrophil functions by the immunoregulatory C. albicans 28 receptors CEACAM1, CEACAM3, and CEACAM6 are involved in the immune pathology of 29 candidemia. Here, we analyzed the effects of specific antibodies targeting the three CEACAM 30 receptors on C. albicans-induced neutrophil responses. We show that CEACAM6 ligation 31 significantly enhanced the immediate response to C. albicans, as shown by the increased 32 CXCL8/IL-8 degranulation. By assessing the transcriptional responses, we found that CEACAM6 33 ligation and to some extent CEACAM1 ligation, but not CEACAM3 ligation led to an altered gene 34 regulation of the C. albicans-stimulated neutrophils. Differentially expressed genes were analyzed 35 with different bioinformatic methods for the affected cellular processes and signaling pathways 36 including dynamic simulations of signaling cascades. We verified predicted alterations with regard 37 to IL-1β/IL-6 expression and apoptosis induction after C. albicans stimulation. Taken together, we 38 could demonstrate for the first time that CEACAM receptors have an important and differential 39 impact in regulating C. albicans-induced immune functions in human neutrophils. In particular, 40 CEACAM6 ligation modulated neutrophil apoptosis and cytokine release in responses to 41