TLR5 stop codon polymorphism is associated with invasive aspergillosis after allogeneic stem cell transplantation

Ref ID: 18603

Author:

M. Grube (1), J. Löf64258; er (2), M. Mezger (2), B. Krüger (3),
B. Echtenacher (1), P. Hoffmann (1), M. Edinger (1), H. Einsele (2),
R. Andreesen (1), E. Holler (1)

Author address:

(1)University Hospital (Regensburg, DE); (2)University of
Würzburg (Würzburg, DE); (3)University Hospital (Mannheim,
DE)

Full conference title:

Annual Meeting of the EBMT, 37th

Abstract:

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.

Abstract Number: O191

Conference Year: 2011

Link to conference website: NULL

New link: NULL

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