Review
Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease

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Summary

Toll-like receptors (TLRs) play an important part in the innate immune recognition of invading microorganisms, initiating sufficient immune responses. Growing amounts of data suggest that the ability of certain individuals to respond properly to TLR ligands may be impaired by single nucleotide polymorphisms (SNPs) within TLR genes, resulting in an altered susceptibility to, or course of, infectious or inflammatory disease. Most studies have focused on two cosegregating SNPs—Asp299Gly and Thr399Ile—within the gene encoding TLR4, the receptor for bacterial lipopolysaccharide. These SNPs are present in approximately 10% of white individuals, and have been found to be positively correlated with several infectious diseases. However, these SNPs seem to protect from atherosclerosis and related diseases, which is reviewed in this article also. Meanwhile, SNPs of genes encoding other TLRs—eg, TLR2, which recognises a wide variety of microbial ligands—have been reported, and preliminary studies indicate an impact on susceptibility to infectious and inflammatory diseases as well. This review summarises and discusses the results obtained, and draws conclusions from these data.

Section snippets

Toll-like receptors and innate immunity

Innate immune responses to pathogens are mainly orchestrated by monocytes/macrophages, granulocytes, and dendritic cells, which act as a first line of defence against invading microorganisms.7 Discrimination of non-self from self is achieved by numerous host proteins equipped with the ability to recognise structures, or molecular patterns, present on foreign organisms.8 One major family of proteins are the Toll-like receptors (TLRs), also referred to as pattern recognition receptors (PRRs).9, 10

Polymorphisms of PRRs involved in immune recognition

Genetic polymorphisms—for the most part, single nucleotide polymorphisms (SNPs)—are common variants within a population that are found at a frequency of over 1%. SNPs may alter the aminoacid sequence (non-synonymous SNPs), affect promoter characteristics, or may be completely “silent”. Mutations do not occur randomly within the genome, but rather depend on the particular genomic region, as well as on selective pressure.36 Thus, one might expect that genes encoding for proteins involved in

CD14, LBP, MD2, and NOD2

Two SNPs have been identified within the promoter region of CD14, and there is evidence that one of them—Cys159Thr—is related to the incidence and mortality of septic shock.33 Several papers reported the importance of these SNPs for cardiovascular diseases as well, possibly reflecting the inflammatory nature of atherosclerosis pathology, which will be discussed later in the context of TLR4 SNPs.40 LBP is a key regulator of lipopolysaccharide toxicity, as high concentrations have been found to

The Asp299Gly and Thr399Ile SNPs of TLR4 and their potential impact on the incidence of infectious disease

Several studies suggest that, after inhaling lipopolysaccharide, individuals exhibit a strong asthma-like reaction.57, 58 Furthermore, allergic asthmatics display a stronger reaction to inhaled lipopolysaccharide compared with healthy individuals.59 However, some people lack this reaction to an experimental lipopolysaccharide challenge, and a yet unknown genetic predisposition was postulated.60 In 2001, Arbour and colleagues described two cosegregating polymorphisms of the human TLR4

Association of the Asp299Gly allele with atherosclerosis and related diseases

Although, generally, atherosclerosis is not considered to be an infectious disease, there is a large body of genetic data pointing to an involvement of TLR4—in particular, the Asp299Gly allele—in atherosclerosis development. Whether microbial stimuli, such as chlamydia, are triggering TLR4, or endogenous mediators—eg, oxidised lipids or heat-shock proteins—have a pathogenic role is still controversial and discussion of this issue is covered elsewhere.84, 85 Two studies with knock-out mice

The Asp299Gly and Thr399Ile SNPs of TLR4 and other diseases

Studies have suggested an association of the Asp299Gly allele with premature birth,95 which is frequently the result of infections. Crohn's disease is also linked to local inflammation, and one study found a correlation with the frequent TLR4 SNPs.96 A study investigating asthma found no association of TLR4 variants with the incidence of this disease; however, Asp299Gly was found to be significantly correlated with severity of disease (p=0·003).97 The TLR4 Asp299Gly variant was shown to be

Objections to the potential relevance of TLR4 SNPs

Although there is some evidence that the Asp299Gly and Thr399Ile alleles influence susceptibility to infectious diseases and carotid atherosclerosis, the question of whether these SNPs really have an impact on human health is still much debated. Doubts on the relevance of the frequent TLR4 SNPs were raised by a study investigating a large population (n=924) of people diagnosed with meningococcal meningitis. Among these people, the occurrence of the Asp299Gly allele was comparable with a large

Rare SNPs of TLR4

Under the assumption that a genetic variation that causes negative effects should not spread within a population, studies were done to investigate the potential presence of multiple, less frequent polymorphisms within the TLR4 gene. Smirnova and colleagues sequenced the TLR4 gene in human beings and mice, and comparative analysis revealed that, in both species, the extracellular region and the C-terminal end—bearing the TIR domain—are highly variable.105 A study done by the same group confirmed

SNPs of other TLRs

Protocols have been developed to allow for easy typing of polymorphisms of other TLRs with light cycler and similar techniques.108 In 2000, Lorenz and co-workers reported a novel non-synonymous SNP within a conserved part of the C-terminal region of human TLR2 (Arg753Gln, figure 2B).109 As shown for the Asp299Gly and Thr399Ile SNPs in TLR4,61 this polymorphism led to a decreased activation of transfected HEK293 cells by TLR2 ligands in vitro.109 However, although the original study investigated

Conclusions

Taking into account both epidemiological studies and genomic analyses, there is no doubt that genetic variations influence the frequency and course of infectious diseases. The most substantial data have been collected for malaria, where red-blood-cell disorders protect against infection,1, 2, 3 or for Crohn's disease, where a frameshift mutation in the NOD2 gene acts as a strong risk factor.36 Strong evidence for the role of inflammation triggered by the innate immune system in Crohn's disease

Search strategy and selection criteria

Data for this review were identified by searches of the National Library of Medicine (NLM) via PubMed and references from relevant articles. Numerous articles were identified through searches of the extensive files of the authors. Typical search terms included the following: “Toll-like”, “TLR”, “SNP”, “polymorphism”, “genetics”, and “infectious diseases”. English and German language papers were reviewed.

Conflicts of interest

We declare that we have no conflicts of interest.

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