Klaile, E. | bioRxiv Science

bioRxiv2025

Expression of human CEACAMs promotes inflammation and organ damage during systemic Candida albicans infection in mice

Invasive candidiasis is a fungal infection characterized by a high mortality rate. CEACAM family receptors play a crucial role in regulating innate responses of both leukocytes and epithelia. Human CEACAM3, CEACAM5 and CEACAM6 receptors recognize C. albicans and are expressed in transgenic CEABAC10 mice. In a murine C. albicans infection model, CEABAC10 mice exhibited a shortened survival period attributed to an early cytokine storm, an exacerbated acute phase response, and heightened systemic inflammation compared to their wild-type littermates. The livers and kidneys of CEABAC10 mice displayed intensified purulent necrotizing inflammation, accompanied by increased infiltration of neutrophils and macrophages. Our in vivo and in vitro data indicated that the expression of CEACAM6 on monocytes of CEABAC10 mice caused the elevated cytokine levels and the subsequent exacerbation of the acute phase response upon C. albicans infection, resulting in decreased survival.

immunology↗

bioRxiv2021

Regulation of Human Neutrophil Responses to Candida albicans by Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (CEACAM1), CEACAM3 and CEACAM6

Invasive candidiasis, often caused by Candida albicans, is an important healthcare-associated fungal infection that results in a high mortality rate of up to 40%. Neutrophils are the first line of defense during Candida infections. They can initiate various killing mechanisms and release cytokines to attract further immune cells to the site of infection. These responses are tightly controlled, since they can also lead to severe tissue/organ damage. We hypothesized that the regulation of C. albicans-specific neutrophil functions by the immunoregulatory C. albicans receptors CEACAM1, CEACAM3, and CEACAM6 are involved in the immune pathology of candidemia. Here, we analyzed the effects of the specific antibodies B3-17, 308/3-3, and 1H7-4B, respectively, targeting the three CEACAM receptors on C. albicans-induced neutrophil responses. We show that ligation of CEACAM6 significantly enhanced the response to C. albicans, as evidenced by the increased CXCL8/IL-8 secretion. By assessing the transcriptional responses, we found that CEACAM6 ligation and to some extent CEACAM1 ligation, but not CEACAM3 ligation, resulted in altered gene regulation of the C. albicans-stimulated neutrophils. Genes that were differentially regulated by the different CEACAM-targeting antibodies were analyzed for affected cellular processes and signaling pathways using various bioinformatics methods, including integrated network analyses and dynamic simulations of signaling cascades. Predicted changes in cellular pathways and cellular functions included CEACAM-specific alterations in apoptosis and cytokine secretion. In particular, we verified predicted changes in IL-1{beta}/IL-6 expression in response to the antibody ligation of all three targeted CEACAMs and apoptosis induction by anti-CEACAM6 antibody treatment in presence of C. albicans stimulation. Specifically, CEACAM6 ligation by 1H7-4B enhanced neutrophil apoptosis and increased immediate and long-term cytokine release in responses to C. albicans. CEACAM1 ligation by B3-17 mainly enhanced the immediate secretion of pro-inflammatory cytokines, and CEACAM3 ligation by 308/3-3 increased the long-term release of pro-inflammatory cytokines. Taken together, we demonstrated for the first time that CEACAM receptors have an important and differential impact on the regulation of C. albicans-induced immune functions in human neutrophils.

immunology↗