title: Toll-like receptor 4 Asp299Gly/Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection.
abstract: Toll-like receptor (TLR)-4 is an important pattern recognition receptor for Candida albicans, playing a role in innate host defense. We investigated whether there is an association between the TLR4 Asp299Gly or TLR4 Thr399Ile polymorphism, and the occurrence of Candida bloodstream infection. We performed a case-control study, involving 43 patients with a Candida bloodstream infection and 166 healthy individuals. TLR4 Asp299Gly and Thr399Ile polymorphisms were assessed, as well as cytokine production after stimulation of peripheral blood mononuclear cells (PBMC) with Candida albicans. We observed that the prevalence of TLR4 Asp299Gly polymorphism was found to be higher in patients with Candida bloodstream infection than in controls (26% versus 10%; OR 3.0; 95%CI 1.3-6.9). All patients bearing the Asp299Gly polymorphism were also positive for the Thr399Ile allele, a linkage well described in literature. IL-10 production was higher in C. albicans-stimulated PBMC from volunteers bearing the TLR4 Asp299Gly polymorphism, and a similar tendency was observed in TLR4 Asp299Gly heterozygous patients who had recovered from candidemia. These findings show that the TLR4 Asp299Gly/Thr399Ile polymorphisms are associated with an increased susceptibility to Candida bloodstream infections, and an increased production of IL-10 is probably involved in this effect.
authors.affiliation: Department of Internal Medicine (463), Radboud University Nijmegen Medical Center, PO BOX 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Chantal A A
authors.initials: CA
authors.lastname: Van der Graaf
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Servaas A
authors.initials: SA
authors.lastname: Morré
authors.forename: Martin
authors.initials: M
authors.lastname: Den Heijer
authors.forename: Paul E
authors.initials: PE
authors.lastname: Verweij
authors.forename: Jos W M
authors.initials: JW
authors.lastname: Van der Meer
authors.forename: Bart Jan
authors.initials: BJ
authors.lastname: Kullberg
mesh_terms: D019943:Amino Acid Substitution; D002176:Candida albicans; D002177:Candidiasis / Q000235:genetics*; D016022:Case-Control Studies; D016207:Cytokines / Q000096:biosynthesis; D016469:Fungemia / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000382:microbiology; D011110:Polymorphism, Genetic; D012307:Risk Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: D016207:Cytokines; D051197:Toll-Like Receptor 4; D016753:Interleukin-10