Toll-like Receptor 4 Polymorphisms and Aspergillosis in Stem-cell Transplantation

Abstract & Commentary

By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert

Dr. Winslow serves as a consultant for Siemens Diagnostics, and is on the speaker's bureau for Boehringer-Ingelheim and GSK.

Synopsis: Twenty single-nucleotide polymorphisms (SNP's) were analyzed in the toll-like receptor 2 gene (TLR2), the toll-like receptor 3 gene (TLR3), the toll-like receptor 4 gene (TLR4), and the toll-like receptor 9 gene (TLR9) in 336 recipients of hematopoietic stem cell transplants (HSCTs) and their unrelated donors. Two donor TLR4 haplotypes (S3 and S4) were shown to be associated with increased risk of invasive aspergillosis.

Source: Bochud P-Y, et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med. 2008;359:1766-1777.

Single nucleotide polymorphisms were examined within TLR2, TLR3, TLR4, and TLR9 in a population of 336 HSCT recipients and their unrelated donors. Using multivariate Cox regression analysis, two donor TLR4 haplotypes were found to be associated with increased risk of developing invasive aspergillosis in the HSCT recipients. The S3 and S4 haplotypes were associated with an adjusted hazard ratio of 2.2 and 6.16, respectively. Donor positivity for CMV also appeared to increase the risk of development of invasive aspergillosis in the recipients. In a validation study of 103 HSCT recipients with invasive aspergillosis and 263 matched controls (which included both related and unrelated donors), the TLR4 S4 haplotype was confirmed to be associated with the development of invasive aspergillosis, with an odds ratio of 2.29 for related donors and 5.00 for unrelated donors.

Commentary

Toll-like receptors are transmembrane proteins on the surface of immune cells which detect microbe-associated molecular patterns from many organisms. They activate various transcription factors, leading to production of inflammatory cytokines and activation of adaptive immunity. Aspergillus species have been shown to activate TLR2 and TLR4. This study utilized the large population of HSCT patients treated at the Fred Hutchinson Cancer Center in Seattle to examine the frequencies of SNPs for four candidate TLR genes in both HSCT transplant recipients and their donors. The strong association demonstrated between the S3, and especially the S4, haplotype in donors and development of invasive aspergillosis in the recipients is a masterful demonstration of the significance of the innate immune system in host defense against an important pathogen. While it is a stretch to think that TLRs will become therapeutic targets anytime in the near future, the data presented in this paper are fascinating, and further illuminate our understanding of the delicate balance that defines the host/pathogen relationship.