Unaltered Fungal Burden and Lethality in Human CEACAM1-Transgenic Mice During Candida albicans Dissemination and Systemic Infection

Abstract

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, CD66a) is a receptor for Candida albicans. It is crucial for the immune response of intestinal epithelial cells to this opportunistic pathogen. Moreover, CEACAM1 is of importance for the mucosal colonization by different bacterial pathogens. We therefore studied the influence of the human CEACAM1 receptor in human CEACAM1-transgenic mice on the C. albicans colonization and infection utilizing a colonization/dissemination and a systemic infection mouse model. Our results showed no alterations in the host response between the transgenic mice and the wild-type littermates to the C. albicans infections. Both mouse strains showed comparable C. albicans colonization and mycobiota, similar fungal burdens in various organs, and a similar survival in the systemic infection model. Interestingly, some of the mice treated with anti-bacterial antibiotics (to prepare them for C. albicans colonization via oral infection) also showed a strong reduction in endogenous fungi instead of the normally observed increase in fungal numbers. This was independent of the expression of human CEACAM1. In the systemic infection model, the human CEACAM1 expression was differentially regulated in the kidneys and livers of Candida-infected transgenic mice. Notably, in the kidneys, a total loss of the largest human CEACAM1 isoform was observed. However, the overwhelming immune response induced in the systemic infection model likely covered any CEACAM1-specific effects in the transgenic animals. In vitro studies using bone marrow-derived neutrophils from both mouse strains also revealed no differences in their reaction to C. albicans. In conclusion, in contrast to bacterial pathogens interacting with CEACAM1 on different mucosal surfaces, the human CEACAM1-transgenic mice did not reveal a role of human CEACAM1 in the in vivo candidiasis models used here. Further studies and different approaches will be needed to reveal a putative role of CEACAM1 in the host response to C. albicans.

Antibody ligation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), CEACAM3, and CEACAM6, differentially enhance the cytokine release of human neutrophils in responses toCandida albicans

“…2A). In accordance with our findings that the CEACAM family receptors are not critical for C. albicans adhesion to different epithelial cell lines (12) and CEACAM1-transgenic mouse neutrophils (42), neutrophil binding to fungal cells was not affected by antibody-mediated CEACAM ligation in two different donors ( Fig. 2A).…”

“…We next analyzed the influence of the three CEACAM1/3/6-targeting antibodies on different cellular functions elicited directly upon the engagement of the neutrophil by the fungal pathogen. First, we tested if the antibodies affected C. albicans binding to neutrophil cell surfaces (S1 Fig) . In accordance with our findings that the CEACAM family receptors are not critical for C. albicans adhesion to different epithelial cell lines (12) and CEACAM1-transgenic mouse neutrophils (39), neutrophil binding to fungal cells was not affected by antibody-mediated CEACAM ligation in two different donors (S1 Fig) . A major killing mechanism employed by neutrophils is the oxidative burst. We therefore tested the production of reactive oxygen species (ROS) under the different antibody treatments in the presence or absence of C. albicans stimulation in two different donors (S2 Fig) . While ROS production by C. albicans stimulation was clearly detected, none of the three antibodies used for ligation changed neither the basic ROS levels in absence of C. albicans nor the C. albicans-induced ROS levels after infection (S2 Fig) . To test for effects of the antibody treatments on the overall efficiency of fungal killing by the neutrophils, we next analyzed the number of surviving fungal cells after 30 min co-incubation with the neutrophils.…”

Immunization against Invasive Candidiasis is the Exigency of the Decade

“…The major victims of the invasive fungal attack the skin, heart, brain, and respiratory organs [21,22]. Candida spp.…”