TLR1 and TLR6 Polymorphisms Are Associated with Susceptibility to Invasive Aspergillosis after Allogeneic Stem Cell Transplantation
ABSTRACT Toll-like receptors (TLRs) transmit signals in response to Aspergillus fumigatus conidia and hyphae. In this preliminary study, we examined the association between single nucleotide polymorphisms (SNPs) in TLR1, TLR4, and TLR6 genes and development of invasive aspergillosis (IA) in 127 allogeneic hematopoietic stem cell transplant recipients consisting of 22 patients with IA and 105 unaffected control subjects. The following SNPs and their pairwise interactions were considered in the model: TLR1 (239G > C, 743A > G, 914A > T, 1805G > T), TLR4 (896A > G, 1196C > T), and TLR6 (359T > C, 745C > T, 764C > T). No association was found between donor SNP and the risk of IA. Analysis of recipient SNP data showed that the presence of TLR1 239G > C (Arg80 > Thr) or the presence of both TLR1 743A > G (Asn248 > Ser) and TLR6 745C > T (Ser249 > Pro) is associated with IA (odds ratio = 1.30, 95% confidence interval = 1.13 to 1.50; P < .001). Further analyses using a prospective cohort may enable us to identify TLR polymorphisms associated with the susceptibility to IA within a defined interval among immunocompromised patients.
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- "Another study in Germany found a weak association of the TLR6 Ser249Pro SNP and asthma, however this association was lost after Bonferroni correction . In single studies the TLR6 Ser249Pro SNP has been linked with susceptibility to infection with aspergillosis  and women homozygous for the 249Ser allele were found to have thinner left ventricular posterior walls as well as possessing monocytes responding weakly to the TLR6 ligand zymosan . "
ABSTRACT: Toll-like receptors (TLRs), a large group of proteins which recognize various pathogen-associated molecular patterns, are critical for the normal function of the innate immune system. Following their discovery many single nucleotide polymorphisms within TLRs and components of their signaling machinery have been discovered and subsequently implicated in a wide range of human diseases including atherosclerosis, sepsis, asthma, and immunodeficiency. This review discusses the effect of genetic variation on TLR function and how they may precipitate disease.Current Genomics 12/2012; 13(8):633-45. DOI:10.2174/138920212803759712 · 2.87 Impact Factor
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- "Gene SNPs or haplotypes Effect Disease Outcome References TLR1 R80T, N248S, I602S Reduced cytokine production by PBMCs in vitro Invasive aspergillosis, C. albicans systemic infections Susceptibility Kesh et al., 2005; Plantinga et al., 2012 TLR3 +95C/A Failure to activate CD8 + T-cell response Invasive aspergillosis Susceptibility Carvalho et al., 2012b L412F Decreased TLR3 functionality Chronic mucocutaneous candidiasis Susceptibility Nahum et al., 2011 TLR4 D299G/T399I Predicted to impair ligand binding Invasive aspergillosis, A. fumigatus, CCPA, C. albicans systemic infections Susceptibility Van Der Graaf et al., 2006; Bochud et al., 2008; Carvalho et al., 2008; De Boer et al., 2011 TLR6 S249P Unknown Invasive aspergillosis Susceptibility Kesh et al., 2005 TLR9 T-1237C "
ABSTRACT: Hundred-thousands of fungal species are present in our environment, including normal colonizers that constitute part of the human microbiota. The homeostasis of host-fungus interactions encompasses efficient fungal sensing, tolerance at mucosal surfaces, as well as antifungal defenses. Decrease in host immune fitness or increase in fungal burden may favor pathologies, ranging from superficial mucocutaneous diseases to invasive life-threatening fungal infections. Toll-like receptors (TLRs) are essential players in this balance, due to their ability to control both inflammatory and anti-inflammatory processes upon recognition of fungal-specific pathogen-associated molecular patterns (PAMPs). Certain members of the TLR family participate to the initial recognition of fungal PAMPs on the cell surface, as well as inside phagosomes of innate immune cells. Active signaling cascades in phagocytes ultimately enable fungus clearance and the release of cytokines that shape and instruct other innate immune cells and the adaptive immune system. Some TLRs cooperate with other pattern recognition receptors (PRRs) (e.g., C-type lectins and Galectins), thus allowing for a tailored immune response. The spatio-temporal and physiological contributions of individual TLRs in fungal infections remains ill-defined, although in humans, TLR gene polymorphisms have been linked to increased susceptibility to fungal infections. This review focuses entirely on the role of TLRs that control the host susceptibility to environmental fungi (e.g., Aspergillus, Cryptoccocus, and Coccidoides), as well as to the most frequent human fungal pathogens represented by the commensal Candida species. The emerging roles of TLRs in modulating host tolerance to fungi, and the strategies that evolved in some of these fungi to evade or use TLR recognition to their advantage will also be discussed, as well as their potential suitability as targets in vaccine therapies.Frontiers in Cellular and Infection Microbiology 11/2012; 2:142. DOI:10.3389/fcimb.2012.00142 · 2.62 Impact Factor
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- "Nevertheless, we cannot assume that TLR1 or TLR6 polymorphisms that lead to alteration in receptor function are impacting TLR2 recognition and activation. There is evidence that TLR1 and TLR6 polymorphism do exist in humans that affect responses to infectious diseases (especially mycobacteria ; Kesh et al., 2005; Bhide et al., 2009; Shey et al., 2010). However, for sake of clarity, this review will not address TLR1 or TLR6 polymorphisms and will only focus on TLR2 polymorphisms. "
ABSTRACT: Toll-like receptors (TLRs) are recognition molecules for multiple pathogens, including bacteria, viruses, fungi, and parasites. TLR2 forms heterodimers with TLR1 and TLR6, which is the initial step in a cascade of events leading to significant innate immune responses, development of adaptive immunity to pathogens and protection from immune sequelae related to infection with these pathogens. This review will discuss the current status of TLR2 mediated immune responses by recognition of pathogen-associated molecular patterns (PAMPS) on these organisms. We will emphasize both canonical and non-canonical responses to TLR2 ligands with emphasis on whether the inflammation induced by these responses contributes to the disease state or to protection from diseases.Frontiers in Immunology 04/2012; 3:79. DOI:10.3389/fimmu.2012.00079