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

Abstract

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-␥ and interleukin-10 (IL-10), in addition to IL-1␤, 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. (Blood. 2010;116(24):5394-5402) IntroductionAspergillus spp are ubiquitous in nature, and the spectrum of diseases they cause is myriad, including saprophytic colonization of preexisting cavities (aspergilloma), allergic asthma, hypersensitivity pneumonitis, allergic bronchopulmonary aspergillosis occurring as a complication of bronchial asthma or cystic fibrosis, and disseminated disease associated with high mortality rates in patients with hematologic malignancies and recipients of solid organs and stem cell transplantations. 1 Immunocompetent and nonatopic subjects are relatively resistant to infections, and disease occurs in the setting of host damage. 2 The association of persistent inflammation with intractable infection is common in nonneutropenic patients after hematopoietic stem cell transplantation (HSCT) as well as in allergic fungal diseases. 2 The current understanding of the pathophysiology underlying Aspergillus infection and disease highlights a truly bipolar nature of the inflammatory process in infection. Early inflammation prevents or limits infection, but an uncontrolled response may eventually oppose disease eradication. This condition is crucially exemplified in mice with chronic granulomatous disease, in which an intrinsic, genetically determined failure to control inflammation to sterile fungal components determines the animals' inability to resolve an actual infection with A fumigatus. 3 A main implication of these findings is that, at least in specific clinical settings, it is an exag...

Aspergillosis and stem cell transplantation: An overview of experimental pathogenesis studies

“…Dectin-1 deficient mice transplanted with stem cells from donors deficient in dectin-1 exhibit the highest susceptibility to IA, while wild-type mice transplanted with dectin-1 deficient stem cells do not exhibit increased susceptibility to infection. 98 These findings suggest that expression of dectin-1 by non-haematopoietic cells may also play an important role in mediating protection against IA during HSCT.…”

“…95,96 Immunocompetent mice deficient in dectin-1 are more susceptible to A. fumigatus infection. [97][98][99] In an experimental HSCT mouse model investigators observed that dectin-1 deficient mice are more susceptible to IA than wild-type mice following transplantation with wild-type stem cells. Dectin-1 deficient mice transplanted with stem cells from donors deficient in dectin-1 exhibit the highest susceptibility to IA, while wild-type mice transplanted with dectin-1 deficient stem cells do not exhibit increased susceptibility to infection.…”

“…HSCT patients who received allogeneic stem cells with TLR1, TLR4, TLR6 and dectin-1 polymorphisms have significantly increased susceptibility to IA. 98,[109][110][111] One of the best studied of these mutations is the dectin-1 Y238X polymorphism, which results in the production of a truncated dectin-1 protein that is unable to localize to the cell membrane and mediate fungal recognition. 98 The presence of this mutation in HSCT donors or recipients is associated with a significantly increased susceptibility to IA.…”

Immunotherapy for opportunistic infections: Current status and future perspectives

“…64 For instance, patients with genetic variants of Dectin-1 or DC-SIGN were reported to have a significantly increased risk of invasive fungal infections. 65,66 Several studies using mouse models support the idea that Th1 cells play an important role in the control of Aspergillus. Censi et al reported that treatment of immunocompetent mice with Aspergillus crude culture filtrate antigens resulted in the development of protective Th1 memory responses, mediated by antigen-specific CD4 C T cells producing IFN-g and IL-2.…”

Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection

“…For example, Aspergillus preexposed to caspofungin can unmask β-glucan residues in the cell wall of fungi and enhance antifungal activity mediated by neutrophils (31). Engineering a T-cell response to Aspergillus hyphae also may overcome congenital impairment of the innate immune system, as with the Dectin-1 Y238X polymorphism (48). This mutation is associated with diminished Dectin-1 receptor activity, increased susceptibility to IFI among recipients of HSCT (48), and loss of TLR4-mediated signals during hyphal germination, thereby contributing to the evasion of immune recognition by Aspergillus (49).…”