Purpose: Single nucleotide gene polymorphisms (SNP) within pattern recognition receptor (PRR) genes have recently been associated with the incidence and outcome of infections and SNPs within Toll-like receptor (TLR) genes (e.g. TLR1, TLR4 and TLR6) have been associated with susceptibility to invasive aspergillosis (IA) in patients after allogeneic stem cell transplantation (allo-SCT). However some studies show confl icting results. To investigate the association between SNPs of PRR genes in donors and recipients and the incidence of IA in our patients, we performed SNP analysis for TLR2, TLR4, TLR5, TLR9 and NOD2/CARD15. Experimental Design: We analyzed 334 patients undergoing allo-SCT for an association of SNPs within TLR2, TLR4, TLR5, TLR9 and NOD2/CARD15 genes with susceptibility to IA. 105 patients developed proven/probable IA after allo-SCT whereas 229 patients did not (controls). SNPs were determined by Taqman allelic discrimination test. For an animal model of fungal infection female TLR5+/+ and TLR5-/- mice were infected with 5 x 10 6 Aspergillus fumigatus conidia i.v. and survival was monitored for 21 days. All studies were approved by the local ethics committees and samples were obtained after informed consent. Results: No association was found for donor SNPs and the risk of IA. Analyzing recipient SNPs, we found a signifi cant difference in genotype and allele frequencies between controls and patients developing IA with a higher frequency of the mutated S25 T allele in patients with IA compared to controls (16% versus 5%; P=0.0029) when only the recipient had the TLR5-Stop SNP. The recipient TLR5-Stop SNP was an independent risk factor for IA after allo-SCT. A similar correlation between TLR5 defi ciency and enhanced susceptibility to Aspergillus fumigatus could be observed in the animal model of fungal infection. Whereas 8 of 9 (89 %) TLR5-/- mice died within 16 days after infection with Aspergillus conidia, only 3 of 10 (30 %) TLR5+/+ mice succumbed to infection during the observation period of 21 days (P=0.009). Conclusion: For the fi rst time we provide evidence that TLR5 is involved in the host defense to fungal infection. Our data suggest that the TLR5-Stop SNP in the recipient might serve as a prognostic factor for the development of IA after allo-SCT and that SNP determination could guide antifungal prophylaxis strategies.
Full conference title:
Annual Meeting of the EBMT, 37th
- EBMT 37th (2011)