Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity.
The C-type lectin receptor Dectin-1 plays a pivotal role in antifungal immunity. In this study, the recently characterized human DECTIN1 Y238X early stop codon polymorphism leading to diminished Dectin-1 receptor activity was studied in relation to invasive aspergillosis susceptibility and severity in patients receiving hematopoietic stem cell transplantation. We found that the presence of the DECTIN1 Y238X polymorphism in either donors or recipients of hematopoietic stem cell transplantation increased susceptibility to aspergillosis, with the risk being highest when the polymorphism was present simultaneously in both donors and recipients (adjusted hazard ratio = 3.9; P = .005). Functionally, the Y238X polymorphism impaired the production of interferon-γ and interleukin-10 (IL-10), in addition to IL-1β, IL-6, and IL-17A, by human peripheral mononuclear cells and Dectin-1 on human epithelial cells contributed to fungal recognition. Mechanistically, studies on preclinical models of infection in intact or bone marrow-transplanted Dectin-1 knockout mice revealed that protection from infection requires a distinct, yet complementary, role of both donor and recipient Dectin-1. This study discloses Dectin-1 deficiency as a novel susceptibility factor for aspergillosis in high-risk patients and identifies a previously unsuspected role for Dectin-1 in antifungal immunity that is the ability to control both resistance and tolerance to the fungus contingent on hematopoietic/nonhematopoietic compartmentalization.
Cunha
Cristina
C
Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
Di Ianni
Mauro
M
Bozza
Silvia
S
Giovannini
Gloria
G
Zagarella
Silvia
S
Zelante
Teresa
T
D'Angelo
Carmen
C
Pierini
Antonio
A
Pitzurra
Lucia
L
Falzetti
Franca
F
Carotti
Alessandra
A
Perruccio
Katia
K
Latgé
Jean-Paul
JP
Rodrigues
Fernando
F
Velardi
Andrea
A
Aversa
Franco
F
Romani
Luigina
L
Carvalho
Agostinho
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001228:Aspergillosis / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D002648:Child; D016207:Cytokines / Q000096:biosynthesis; D004198:Disease Susceptibility / Q000209:etiology*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D005658:Fungi / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D037181:Lectins, C-Type; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology*; D011110:Polymorphism, Genetic / Q000276:immunology*; D055815:Young Adult; D000099181:Dectin-1
D016207:Cytokines; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000099181:Dectin-1