Early Stop Polymorphism in Human DECTIN‐1 Is Associated with IncreasedCandidaColonization in Hematopoietic Stem Cell Transplant Recipients

Abstract

Background. Intensive treatment of hematological malignancies with hematopoietic stem cell transplantation (HSCT) is accompanied by a high incidence of opportunistic invasive fungal infection, but individual risk varies significantly. Dectin-1, a C-type lectin that recognizes 1,3-beta-glucans from fungal pathogens, including Candida species, is involved in the initiation of the immune response against fungi. Methods. Screening for the DECTIN-1 Y238X polymorphism within a group of 142 patients undergoing HSCT was correlated with Candida colonization and candidemia. Furthermore, functional studies were performed on the consequences of the polymorphism. Results. Patients bearing the Y238X polymorphism in the DECTIN-1 gene were more likely to be colonized with Candida species, compared with patients bearing wild-type DECTIN-1, necessitating more frequent use of fluconazole in the prevention of systemic Candida infection. Functional assays demonstrated a loss-of-function phenotype of the polymorphism, as shown by the decreased cytokine production by immune cells bearing this polymorphism. Conclusions. The Y238X polymorphism is associated with increased oral and gastrointestinal colonization with Candida species. This suggests a crucial role played by dectin-1 in the mucosal antifungal mechanisms in immunocompromised hosts. The finding that DECTIN-1 polymorphisms rendered HSCT recipients at increased risk for fungal complications may contribute to the selection of high-risk patients who should be considered for antifungal prophylaxis to prevent systemic candidiasis.

Dectin-1 isoforms contribute to distinct Th1/Th17 cell activation in mucosal candidiasis

“…15 Interestingly, the Y238X polymorphism had no associated risk with systemic candidiasis, likely due to unimpaired phagocytosis and the killing of C. albicans by host leukocytes. 15 Thus, in both humans and mice, 16 dectin-1 appears to be crucially involved in the control of mucosal candidiasis, while discrepant results have been observed for its role in systemic infection.…”

The Transmembrane Adaptor Protein SCIMP Facilitates Sustained Dectin-1 Signaling in Dendritic Cells

“…Dectin-1 is considered a major receptor for ␤-glucans and plays an important role in the defense against various species of pathogenic fungi in mice, including Candida albicans, Aspergillus fumigatus, and Pneumocystis carinii (7)(8)(9)(10)(11). The importance of dectin-1 for antifungal defense has also been demonstrated by studies of human patients with disrupted dectin-1 function who display increased mucosal colonization with Candida species and suffer from recurrent mucocutaneous fungal infections (12,13).…”

Dectin-1 Is Not Required for Controlling Candida albicans Colonization of the Gastrointestinal Tract

“…In vivo studies in mice have demonstrated that dectin-1 is vital for host defense in models of systemic candidiasis (26), although this can be fungal strain dependent (6,24). In humans, dectin-1 deficiency is associated with a predisposition to mucocutaneous candidiasis, as well as increased gastrointestinal (GI) colonization in immunocompromised individuals, highlighting the importance of this receptor in human mucosal defense (9,20).…”