Genetic Variation in Pattern Recognition Receptors: Functional Consequences and Susceptibility to Infectious Disease

Jaeger, Martin; Stappers, Mark H. T.; Joosten, Leo A. B.; Gyssens, Inge C.; Netea, Mihai G.

doi:10.2217/fmb.15.37

Cited by 22 publications

(12 citation statements)

References 195 publications

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“…In addition, polymorphisms of TLR1 N248S have been associated with differences in severity of malaria infections [23]. Similarly, TLR 6 P249S was previously associated with susceptibility to tuberculosis, aspergillosis and malaria [20]. Altogether, these previous findings and ours suggest functional immunophenotypes for TLR1 N248S and TLR6 P249S for infectious diseases.…”

Section: Discussionsupporting

confidence: 81%

“…Both this tolerance and the TLR1 N248S polymorphism, resulting in lower IL-6 production, could contribute to larger DFI lesions [19]. Interestingly, TLR1 N248S was previously shown to be associated with increased susceptibility to different infectious diseases including cSSSIs, tuberculosis, leprosy, aspergillosis, candidemia [20], Q fever [21], and malaria [22]. In addition, polymorphisms of TLR1 N248S have been associated with differences in severity of malaria infections [23].…”

Section: Discussionmentioning

confidence: 99%

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Lesion size is associated with genetic polymorphisms in TLR1, TLR6, and TIRAP genes in patients with major abscesses and diabetic foot infections

Monnier

Kremer

Stappers

et al. 2019

Eur J Clin Microbiol Infect Dis

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Lesion size is associated with genetic polymorphisms in TLR1, TLR6, and TIRAP genes in patients with major abscesses and diabetic foot infections The Author(s) 2019Genetic variation in Toll-like receptors (TLRs) has previously been associated with susceptibility to complicated skin and skin structure infections (cSSSIs). The aim of this study was to investigate associations between the severity of cSSSIs, i.e., major abscesses and diabetic foot infections (DFIs), and a set of genetic polymorphisms in the Toll-like receptor pathway. A total of 121 patients with major abscesses and 132 with DFIs participating in a randomized clinical trial were genotyped for 13 nonsynonymous single-nucleotide polymorphisms (SNPs) in genes coding for TLRs and the signaling adaptor molecule TIRAP. Infection severity was defined by lesion size at clinical presentation for both types of infections. The PEDIS infection score was also used to define severity of DFIs. Linear regression models were used to study factors independently associated with severity. In patients with large abscesses, hetero-or homozygosity for the allelic variant TLR6 (P249S) was associated with significantly smaller lesions while homozygosity for the allelic variant TLR1 (R80T) was associated with significantly larger lesions. PRRs genes were not significantly associated with PEDIS. However, patients with DFI hetero-or homozygous for the allelic variant TLR1 (S248N) had significantly larger lesions. Polymorphisms in TLR1 and TLR6 influence the severity of cSSSIs as assessed by the lesion size of major abscesses and DFIs. ClinicalTrial.gov Identifier: NCT 00402727

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Lesion size is associated with genetic polymorphisms in TLR1, TLR6, and TIRAP genes in patients with major abscesses and diabetic foot infections

Monnier

Kremer

Stappers

et al. 2019

Eur J Clin Microbiol Infect Dis

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“…The innate immune system displays a remarkable homology of various innate immune molecules, including pattern recognition receptors (PRR) such as toll-like receptors (TLRs), which either recognize pathogen-associated microbial patterns (PAMP) or endogenous damage-associated molecular patterns (DAMP) (94–96). The common feature of these innate immune receptors is that they are germline-encoded and are considered highly conserved, with limited single-nucleotide polymorphisms (SNPs) in humans (97, 98). Innate cells with PRR expression are capable of mounting rapid effector responses independently of clonal expansion.…”

Section: Highly Conserved Antigen-presenting Moleculesmentioning

confidence: 99%

Targeting Innate-Like T Cells in Tuberculosis

Huang

2016

Front. Immunol.

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Peptide-specific conventional T cells have been major targets for designing most antimycobacterial vaccines. Immune responses mediated by conventional T cells exhibit a delayed onset upon primary infection and are highly variable in different human populations. In contrast, innate-like T cells quickly respond to pathogens and display effector functions without undergoing extensive clonal expansion. Specifically, the activation of innate-like T cells depends on the promiscuous interaction of highly conserved antigen-presenting molecules, non-peptidic antigens, and likely semi-invariant T cell receptors. In antimicrobial immune responses, mucosal-associated invariant T cells are activated by riboflavin precursor metabolites presented by major histocompatibility complex-related protein I, while lipid-specific T cells including natural killer T cells are activated by lipid metabolites presented by CD1 proteins. Multiple innate-like T cell subsets have been shown to be protective or responsive in mycobacterial infections. Through rapid cytokine secretion, innate-like T cells function in early defense and memory response, offering novel advantages over conventional T cells in the design of anti-tuberculosis strategies.

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“…In fact, SNPs that are or could be important for multiple human pathologies, such as cancer, diabetes, heart disease, schizophrenia, blood-pressure homeostasis, and autoimmune or metabolic diseases, have been identified [85][86][87][88][89][90][91]. Moreover, some described SNPs increase the human susceptibility to getting infected by viruses, bacteria or other pathogens [84,86,[92][93][94][95][96][97]. Advanced sequencing and bioinformatics technologies have allowed the identification of a large number of human SNPs whose information is accessible in the databases.…”

Section: Single Nucleotide Polymorphisms (Snps)mentioning

confidence: 99%

Host Single Nucleotide Polymorphisms Modulating Influenza A Virus Disease in Humans

Nogales¹,

DeDiego

2019

Pathogens

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A large number of human genes associated with viral infections contain single nucleotide polymorphisms (SNPs), which represent a genetic variation caused by the change of a single nucleotide in the DNA sequence. SNPs are located in coding or non-coding genomic regions and can affect gene expression or protein function by different mechanisms. Furthermore, they have been linked to multiple human diseases, highlighting their medical relevance. Therefore, the identification and analysis of this kind of polymorphisms in the human genome has gained high importance in the research community, and an increasing number of studies have been published during the last years. As a consequence of this exhaustive exploration, an association between the presence of some specific SNPs and the susceptibility or severity of many infectious diseases in some risk population groups has been found. In this review, we discuss the relevance of SNPs that are important to understand the pathology derived from influenza A virus (IAV) infections in humans and the susceptibility of some individuals to suffer more severe symptoms. We also discuss the importance of SNPs for IAV vaccine effectiveness. multiple mechanisms, although there are some differences between strains. For that genome plasticity, IAV take advantage of multiple strategies, such as alternative splicing, frameshift mechanisms, and overlapping open reading frames (ORFs) [7][8][9]. In addition, the coding capability of the viral genome is extended by encoding multifunctional proteins that act at different steps during virus infection. of synthetized vRNP, ensuring that the vRNPs are available for packaging [24]. Moreover, NEP has also other functions during IAV infection, contributing to viral budding and to regulate viral RNA synthesis. NS1 is a multifunctional protein and a key viral factor that counteracts the host antiviral responses. NS1 has been shown to inhibit the production of interferon (IFN), the activity and expression of multiple interferon-induced genes (ISG) and the processing and nuclear transport of host mRNAs causing cellular shut-off [25,26]. Segment 3 of IAV also encodes two proteins, the polymerase component PA and PA-X. PA is translated directly from the PA mRNA, whereas PA-X is translated using a +1 frameshift mechanism from the same open reading frame (ORF) [9]. Synergistically with NS1, PA-X is also able to block the cellular antiviral responses by inhibiting host protein expression. Moreover, the PA-X protein has been shown to modulate host inflammation, immune responses, apoptosis, and virus pathogenesis [25][26][27][28][29][30].

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Genetic Variation in Pattern Recognition Receptors: Functional Consequences and Susceptibility to Infectious Disease

Cited by 22 publications

References 195 publications

Lesion size is associated with genetic polymorphisms in TLR1, TLR6, and TIRAP genes in patients with major abscesses and diabetic foot infections

Lesion size is associated with genetic polymorphisms in TLR1, TLR6, and TIRAP genes in patients with major abscesses and diabetic foot infections

Targeting Innate-Like T Cells in Tuberculosis

Host Single Nucleotide Polymorphisms Modulating Influenza A Virus Disease in Humans

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