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

Blood - Tập 116 - Trang 5394-5402 - 2010
Cristina Cunha1, Mauro Di Ianni2, Silvia Bozza1, Gloria Giovannini1, Silvia Zagarella1, Teresa Zelante1, Carmen D'Angelo1, Antonio Pierini2, Lucia Pitzurra1, Franca Falzetti2, Alessandra Carotti2, Katia Perruccio2, Jean-Paul Latgé3, Fernando Rodrigues4, Andrea Velardi2, Franco Aversa2, Luigina Romani1, Agostinho Carvalho1,4
1Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy
2Division of Hematology and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
3Unité des Aspergillus, Institut Pasteur, Paris, France
4Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal

Tóm tắt

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-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.

Tài liệu tham khảo

Marr, 2002, Aspergillosis: pathogenesis, clinical manifestations, and therapy., Infect Dis Clin North Am, 16, 875, 10.1016/S0891-5520(02)00035-1 Romani, 2010, Immunology of Aspergillus and Aspergillosis: the story so far., Aspergillosis: From Diagnosis to Prevention, ed 1, 33 Romani, 2008, Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease., Nature, 451, 211, 10.1038/nature06471 Bonifazi, 2010, Intranasally delivered siRNA targeting PI3K/Akt/mTOR inflammatory pathways protects from aspergillosis., Mucosal Immunol, 3, 193, 10.1038/mi.2009.130 Mezger, 2008, Proinflammatory response of immature human dendritic cells is mediated by dectin-1 after exposure to Aspergillus fumigatus germ tubes., J Infect Dis, 197, 924, 10.1086/528694 Osorio, 2008, DC activated via dectin-1 convert Treg into IL-17 producers., Eur J Immunol, 38, 3274, 10.1002/eji.200838950 Reid, 2009, Pattern recognition: recent insights from Dectin-1., Curr Opin Immunol, 21, 30, 10.1016/j.coi.2009.01.003 Werner, 2009, Requisite role for the dectin-1 beta-glucan receptor in pulmonary defense against Aspergillus fumigatus., J Immunol, 182, 4938, 10.4049/jimmunol.0804250 Bozza, 2009, Immune sensing of Aspergillus fumigatus proteins, glycolipids, and polysaccharides and the impact on Th immunity and vaccination., J Immunol, 183, 2407, 10.4049/jimmunol.0900961 Chai, 2010, Anti-Aspergillus human host defence relies on type 1 T helper (Th1), rather than type 17 T helper (Th17), cellular immunity., Immunology, 130, 46, 10.1111/j.1365-2567.2009.03211.x Gringhuis, 2009, Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-kappaB activation through Raf-1 and Syk., Nat Immunol, 10, 203, 10.1038/ni.1692 Puccetti, 2007, IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-kappaB activation., Nat Rev Immunol, 7, 817, 10.1038/nri2163 Plantinga, 2009, Early stop polymorphism in human DECTIN-1 is associated with increased Candida colonization in hematopoietic stem cell transplant recipients., Clin Infect Dis, 49, 724, 10.1086/604714 Ferwerda, 2009, Human dectin-1 deficiency and mucocutaneous fungal infections., N Engl J Med, 361, 1760, 10.1056/NEJMoa0901053 Aversa, 1998, Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype., N Engl J Med, 339, 1186, 10.1056/NEJM199810223391702 Girmenia, 2009, Prophylaxis and treatment of invasive fungal diseases in allogeneic stem cell transplantation: results of a consensus process by Gruppo Italiano Trapianto di Midollo Osseo (GITMO)., Clin Infect Dis, 49, 1226, 10.1086/605665 De Pauw, 2008, Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group., Clin Infect Dis, 46, 1813, 10.1086/588660 Carvalho, 2007, Study of disease-relevant polymorphisms in the TLR4 and TLR9 genes: a novel method applied to the analysis of the Portuguese population., Mol Cell Probes, 21, 316, 10.1016/j.mcp.2007.03.005 Heinsbroek, 2006, Expression of functionally different dectin-1 isoforms by murine macrophages., J Immunol, 176, 5513, 10.4049/jimmunol.176.9.5513 Aimanianda, 2009, Surface hydrophobin prevents immune recognition of airborne fungal spores., Nature, 460, 1117, 10.1038/nature08264 Romani, 2006, Thymosin alpha1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance., Blood, 108, 2265, 10.1182/blood-2006-02-004762 Veranth, 2004, Inflammatory cytokines and cell death in BEAS-2B lung cells treated with soil dust, lipopolysaccharide, and surface-modified particles., Toxicol Sci, 82, 88, 10.1093/toxsci/kfh248 Bonifazi, 2009, Balancing inflammation and tolerance in vivo through dendritic cells by the commensal Candida albicans., Mucosal Immunol, 2, 362, 10.1038/mi.2009.17 Gray, 1988, A class of K-sample tests for comparing the cumulative incidence of a competing risk., Ann Stat, 16, 1141, 10.1214/aos/1176350951 Scrucca, 2007, Competing risk analysis using R: an easy guide for clinicians., Bone Marrow Transplant, 40, 381, 10.1038/sj.bmt.1705727 Fine, 1999, A proportional hazards model for the subdistribution of a competing risk., J Am Stat Assoc, 94, 496, 10.1080/01621459.1999.10474144 Scrucca, 2010, Regression modeling of competing risk using R: an in depth guide for clinicians., Bone Marrow Transplant, 45, 1388, 10.1038/bmt.2009.359 Romani, 2006, Protective tolerance to fungi: the role of IL-10 and tryptophan catabolism., Trends Microbiol, 14, 183, 10.1016/j.tim.2006.02.003 Balloy, 2008, Aspergillus fumigatus-induced interleukin-8 synthesis by respiratory epithelial cells is controlled by the phosphatidylinositol 3-kinase, p38 MAPK, and ERK1/2 pathways and not by the toll-like receptor-MyD88 pathway., J Biol Chem, 283, 30513, 10.1074/jbc.M803149200 Lee, 2009, Dectin-1 is inducible and plays an essential role for mycobacteria-induced innate immune responses in airway epithelial cells., J Clin Immunol, 29, 795, 10.1007/s10875-009-9319-3 Bochud, 2007, Innate immunogenetics: a tool for exploring new frontiers of host defence., Lancet Infect Dis, 7, 531, 10.1016/S1473-3099(07)70185-8 Bochud, 2008, Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation., N Engl J Med, 359, 1766, 10.1056/NEJMoa0802629 Carvalho, 2009, Polymorphisms in Toll-like receptor genes and susceptibility to infections in allogeneic stem cell transplantation., Exp Hematol, 37, 1022, 10.1016/j.exphem.2009.06.004 Carvalho, 2008, Polymorphisms in toll-like receptor genes and susceptibility to pulmonary aspergillosis., J Infect Dis, 197, 618, 10.1086/526500 Kesh, 2005, TLR1 and TLR6 polymorphisms are associated with susceptibility to invasive aspergillosis after allogeneic stem cell transplantation., Ann N Y Acad Sci, 1062, 95, 10.1196/annals.1358.012 Mattila, 2008, Dectin-1 Fc targeting of aspergillus fumigatus beta-glucans augments innate defense against invasive pulmonary aspergillosis., Antimicrob Agents Chemother, 52, 1171, 10.1128/AAC.01274-07 de Vries, 2009, Genetic association analysis of the functional c. 714T → G polymorphism and mucosal expression of dectin-1 in inflammatory bowel disease., PLoS ONE, 4, e7818, 10.1371/journal.pone.0007818 Gribar, 2008, No longer an innocent bystander: epithelial toll-like receptor signaling in the development of mucosal inflammation., Mol Med, 14, 645, 10.2119/2008-00035.Gribar Desvignes, 2009, Interferon-gamma-responsive nonhematopoietic cells regulate the immune response to Mycobacterium tuberculosis., Immunity, 31, 974, 10.1016/j.immuni.2009.10.007 De Luca, Nonhematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO [published online ahead of print September 13.2010]., Cell Mol Immunol Paveglio, Airway epithelial indoleamine 2, 3-dioxygenase inhibits CD4+ T cells during Aspergillus fumigatus antigen exposure [published online ahead of print January 29, 2010]., Am J Respir Cell Mol Biol Plantinga, 2010, Functional consequences of DECTIN-1 early stop codon polymorphism Y238X in rheumatoid arthritis., Arthritis Res Ther, 12, R26, 10.1186/ar2933 Carvalho, Prognostic significance of genetic variants in the IL-23/Th17 pathway for the outcome of T cell-depleted allogeneic stem cell transplantation [published online ahead of print February 22, 2010]., Bone Marrow Transplant