Early stop polymorphism in human DECTIN-1 is associated with increased candida colonization in hematopoietic stem cell transplant recipients.
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.
Plantinga
Theo S
TS
Departments of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
van der Velden
Walter J F M
WJ
Ferwerda
Bart
B
van Spriel
Annemiek B
AB
Adema
Gosse
G
Feuth
Ton
T
Donnelly
J Peter
JP
Brown
Gordon D
GD
Kullberg
Bart-Jan
BJ
Blijlevens
Nicole M A
NM
Netea
Mihai G
MG
D000293:Adolescent; D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000627:therapeutic use; D002175:Candida / Q000254:growth & development*; D002177:Candidiasis / Q000188:drug therapy / Q000209:etiology* / Q000276:immunology; D005260:Female; D015725:Fluconazole / Q000627:therapeutic use; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D016867:Immunocompromised Host / Q000235:genetics*; D037181:Lectins, C-Type; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009894:Opportunistic Infections / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D055815:Young Adult; D000099181:Dectin-1
D000935:Antifungal Agents; D015725:Fluconazole; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000099181:Dectin-1