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

Esther Klaile,Peter F Zipfel,Ilse D Jacobsen,Tilman E Klassert,Tien D Nguyen,Mario M Müller,Hortense Slevogt,Cristina Zubiría-Barrera,Adrian Durotin,Saskia Brehme,Sabina Feer,Sven Rudolphi,Magdalena Stock,Bernhard B Singer

doi:10.3389/fmicb.2019.02703

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.

Highlights

Since our in vitro data obtained from a human intestinal epithelial cell model show that the lack of Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) prevents a normal mucosal response to C. albicans (Klaile et al, 2017), we studied the influence of human CEACAM1 in a transgenic gain-of-function mouse strain (Gu et al, 2010)
I.e., the presence or absence of a specific receptor like Dectin-1, NLRP6, or TLR5 can influence the microbiome and the gut homeostasis and host responses (Iliev et al, 2012; Marietta et al, 2015), we hypothesized that the expression of human CEACAM1 on the intestinal epithelial mucosa may influence their response to fungal ligands and the homeostasis of the gut mycobiota
Our recent in vitro studies show that the interaction of human CEACAM1 with C. albicans is necessary for the CXCL-8 release in an intestinal epithelial cell model (Klaile et al, 2017)

Summary

Introduction

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is recognized as an important immuno-regulatory receptor in the host response to infections with bacteria that are colonizing human mucosal surfaces such as Helicobacter pylori, Neisseria meningitidis, Neisseria gonorrhoeae, Moraxella catarrhalis, and Fusobacterium spp. (Gray-Owen and Blumberg, 2006; Slevogt et al, 2008; Klaile et al, 2013; Tchoupa et al, 2014; Javaheri et al, 2016; Horst et al, 2018a; Helfrich and Singer, 2019). The highly conserved N-terminal variable Ig-like domain is recognized in a species-specific manner by bacterial, fungal, and viral pathogens (Gray-Owen and Blumberg, 2006; Klaile et al, 2017; Horst et al, 2018a; Helfrich and Singer, 2019). The long cytoplasmic domain comprises two immuno-receptor tyrosine receptor-based inhibition motifs (ITIM) that allow an isoform-specific signal transduction (Gray-Owen and Blumberg, 2006). While lacking the tyrosine-containing motifs, the short isoforms have several serine phosphorylation motifs, and the ratio between long and short isoforms is known to affect cellular responses regulated by CEACAM1 (Singer et al, 2002; Müller et al, 2009; Dankner et al, 2017; Horst et al, 2018a; Helfrich and Singer, 2019)

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Conclusion