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2000
Volume 21, Issue 1
  • ISSN: 1574-3624
  • E-ISSN: 2212-389X

Abstract

Introduction

Toll-Like Receptor 4 (TLR4) is vital for the innate immune system as it recognizes a wide array of pathogens, such as bacteria, fungi, and viruses. TLR4 activates downstream signaling pathways upon recognizing microbial components, triggering and regulating the immune response. With improvements in genomic technologies, it has become possible to identify Single-Nucleotide Polymorphisms (SNPs) in genes coding for immune receptors, such as TLR4. These genetic differences may affect the way TLR4 reacts to various pathogens and thus the intensity and outcome of immune responses. It is essential to have a comprehensive understanding of SNPs associated with TLR4 to assess individual susceptibility to infection and inform personalized medicine strategies.

Methods

Multiple scientific literature review databases were utilized to examine TLR4 SNPs and their roles in pathogen recognition, immune signaling, and disease outcomes. These studies elaborated the role of TLR4 polymorphisms in various forms of infections involving bacteria, fungi, and viruses.

Results

Some polymorphisms in the TLR4 gene, including rs4986790 [Asp299Gly] and rs4986791 [Thr399Ile], have been associated with differing immune responses and increased susceptibility to septic shock, candidiasis, tuberculosis, and viral infections. This inhibition of TLR4 signaling by the mutant alleles augments some arms of immune response while inhibiting others, which in turn affects the severity of the infection and the response to treatment.

Discussion

This review focuses on the identification and examination of SNPs in TLR4 and their association with infectious diseases caused by pathogens. The review also examines the impact of these SNPs on TLR4 signaling pathways and the immune response. Polymorphisms in the TLR4 gene, including rs4986790 [Asp299Gly] and rs4986791 [Thr399Ile], have been associated with differing immune responses and increased susceptibility to septic shock, candidiasis, tuberculosis, and viral infections.

Conclusion

Recognition of TLR4 SNPs would provide information on susceptibility to various infections and immune modulation. Current knowledge of genetic variations will lead to the identification of biomarkers for infectious diseases, and consequently, patient-specific treatment and vaccine generation targeted toward specific genotypes in precision medicine, particularly in immunology.

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References

  1. VosT. LimS.S. AbbafatiC. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019.Lancet2020396102581204122210.1016/S0140‑6736(20)30925‑9 33069326
     [Google Scholar]
  2. AkiraS. TakedaK. KaishoT. Toll-like receptors: Critical proteins linking innate and acquired immunity.Nat. Immunol.20012867568010.1038/90609 11477402
     [Google Scholar]
  3. LiD. WuM. Pattern recognition receptors in health and diseases.Signal Transduct. Target. Ther.20216129110.1038/s41392‑021‑00687‑0 34344870
     [Google Scholar]
  4. LinY.T. VermaA. HodgkinsonC.P. Toll-like receptors and human disease: Lessons from single nucleotide polymorphisms.Curr. Genomics201213863364510.2174/138920212803759712 23730203
     [Google Scholar]
  5. SmithK.D. Toll-like receptors in kidney disease.Curr. Opin. Nephrol. Hypertens.200918318919610.1097/MNH.0b013e32832a1d5f 19352178
     [Google Scholar]
  6. OspeltC. GayS. TLRs and chronic inflammation.Int. J. Biochem. Cell Biol.201042449550510.1016/j.biocel.2009.10.010 19840864
     [Google Scholar]
  7. NeteaM.G. Van der GraafC. Van der MeerJ.W.M. KullbergB.J. Toll-like receptors and the host defense against microbial pathogens: Bringing specificity to the innate-immune system.J. Leukoc. Biol.200475574975510.1189/jlb.1103543 15075354
     [Google Scholar]
  8. O’NeillL.A.J. GolenbockD. BowieA.G. The history of toll-like receptors — redefining innate immunity.Nat. Rev. Immunol.201313645346010.1038/nri3446 23681101
     [Google Scholar]
  9. KawaiT. IkegawaM. OriD. AkiraS. Decoding toll-like receptors: Recent insights and perspectives in innate immunity.Immunity202457464967310.1016/j.immuni.2024.03.004 38599164
     [Google Scholar]
  10. NikolakopoulouC. WillmentJ.A. BrownG.D. C-type lectin receptors in antifungal immunity.Adv. Exp. Med. Biol.2020120413010.1007/978‑981‑15‑1580‑4_1 32152941
     [Google Scholar]
  11. HatinguaisR. WillmentJ.A. BrownG.D. PAMPs of the fungal cell wall and mammalian prrs.Curr. Top. Microbiol. Immunol.202042518722310.1007/82_2020_201 32180018
     [Google Scholar]
  12. ElettoD. MentucciF. VoliA. PetrellaA. PortaA. ToscoA. Helicobacter pylori pathogen-associated molecular patterns: Friends or foes?Int. J. Mol. Sci.2022237353110.3390/ijms23073531 35408892
     [Google Scholar]
  13. MogensenT.H. Pathogen recognition and inflammatory signaling in innate immune defenses.Clin. Microbiol. Rev.200922224027310.1128/CMR.00046‑08 19366914
     [Google Scholar]
  14. HuérfanoS. ŠrollerV. BruštíkováK. HorníkováL. ForstováJ. The interplay between viruses and host DNA sensors.Viruses202214466610.3390/v14040666 35458396
     [Google Scholar]
  15. AkiraS. UematsuS. TakeuchiO. Pathogen recognition and innate immunity.Cell2006124478380110.1016/j.cell.2006.02.015 16497588
     [Google Scholar]
  16. SotoJ.A. GálvezN.M.S. AndradeC.A. The role of dendritic cells during infections caused by highly prevalent viruses.Front. Immunol.202011151310.3389/fimmu.2020.01513 32765522
     [Google Scholar]
  17. DuanT. DuY. XingC. WangH.Y. WangR.F. Toll-like receptor signaling and its role in cell-mediated immunity.Front. Immunol.20221381277410.3389/fimmu.2022.812774 35309296
     [Google Scholar]
  18. El-ZayatS.R. SibaiiH. MannaaF.A. Toll-like receptors activation, signaling, and targeting: An overview.Bull. Natl. Res. Cent.201943118710.1186/s42269‑019‑0227‑2
     [Google Scholar]
  19. BiondoC. MidiriA. MessinaL. MyD88 and TLR2, but not TLR4, are required for host defense against Cryptococcus neoformans.Eur. J. Immunol.200535387087810.1002/eji.200425799 15714580
     [Google Scholar]
  20. YauchL.E. MansourM.K. ShohamS. RottmanJ.B. LevitzS.M. Involvement of CD14, toll-like receptors 2 and 4, and MyD88 in the host response to the fungal pathogen Cryptococcus neoformans in vivo.Infect. Immun.20047295373538210.1128/IAI.72.9.5373‑5382.2004 15322035
     [Google Scholar]
  21. NeteaM. FerwerdaG. van der GraafC. Van der MeerJ.W. KullbergB.J. Recognition of fungal pathogens by toll-like receptors.Curr. Pharm. Des.200612324195420110.2174/138161206778743538 17100622
     [Google Scholar]
  22. NeteaM.G. Van der GraafC.A.A. VonkA.G. VerschuerenI. Van der MeerJ.W.M. KullbergB.J. The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis.J. Infect. Dis.2002185101483148910.1086/340511 11992285
     [Google Scholar]
  23. DubourdeauM. AthmanR. BalloyV. Aspergillus fumigatus induces innate immune responses in alveolar macrophages through the MAPK pathway independently of TLR2 and TLR4.J. Immunol.200617763994400110.4049/jimmunol.177.6.3994 16951362
     [Google Scholar]
  24. MeierA. KirschningC.J. NikolausT. WagnerH. HeesemannJ. EbelF. Toll-like receptor (TLR) 2 and TLR4 are essential for Aspergillus-induced activation of murine macrophages.Cell. Microbiol.20035856157010.1046/j.1462‑5822.2003.00301.x 12864815
     [Google Scholar]
  25. NeteaM.G. GowN.A. MunroC.A. Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and toll-like receptors.J. Clin. Invest.200611661642165010.1172/JCI27114 16710478
     [Google Scholar]
  26. VaureC.Ã. LiuY. A comparative review of toll-like receptor 4 expression and functionality in different animal species.Front. Immunol.2014531610.3389/fimmu.2014.00316 25071777
     [Google Scholar]
  27. AhmadA. ImranM. AhsanH. Biomarkers as biomedical bioindicators: Approaches and techniques for the detection, analysis, and validation of novel biomarkers of diseases.Pharmaceutics2023156163010.3390/pharmaceutics15061630
     [Google Scholar]
  28. SitinjakB.D.P. MurdayaN. RachmanT.A. ZakiyahN. BarlianaM.I. The potential of single nucleotide polymorphisms (SNPs) as biomarkers and their association with the increased risk of coronary heart disease: A systematic review.Vasc. Health Risk Manag.20231928930110.2147/VHRM.S405039 37179817
     [Google Scholar]
  29. FerwerdaB. McCallM.B.B. VerheijenK. Functional consequences of toll-like receptor 4 polymorphisms.Mol. Med.2008145-634635210.2119/2007‑00135.Ferwerda 18231573
     [Google Scholar]
  30. NagaiY. GarrettK.P. OhtaS. Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment.Immunity200624680181210.1016/j.immuni.2006.04.008 16782035
     [Google Scholar]
  31. KimH.M. ParkB.S. KimJ.I. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran.Cell2007130590691710.1016/j.cell.2007.08.002 17803912
     [Google Scholar]
  32. SchumannR.R. LeongS.R. FlaggsG.W. Structure and function of lipopolysaccharide binding protein.Science199024949751429143110.1126/science.2402637 2402637
     [Google Scholar]
  33. ParkB.S. SongD.H. KimH.M. ChoiB.S. LeeH. LeeJ.O. The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex.Nature200945872421191119510.1038/nature07830 19252480
     [Google Scholar]
  34. BartonG.M. MedzhitovR. Toll-like receptor signaling pathways.Science200330056251524152510.1126/science.1085536 12791976
     [Google Scholar]
  35. ZanoniI. OstuniR. MarekL.R. CD14 controls the LPS-induced endocytosis of Toll-like receptor 4.Cell2011147486888010.1016/j.cell.2011.09.051 22078883
     [Google Scholar]
  36. NahidM.A. PauleyK.M. SatohM. ChanE.K.L. miR-146a is critical for endotoxin-induced tolerance: Implication in innate immunity.J. Biol. Chem.200928450345903459910.1074/jbc.M109.056317 19840932
     [Google Scholar]
  37. O’NeillL.A. SheedyF.J. McCoyC.E. MicroRNAs: The fine-tuners of toll-like receptor signalling.Nat. Rev. Immunol.201111316317510.1038/nri2957 21331081
     [Google Scholar]
  38. SchurrJ.R. YoungE. ByrneP. SteeleC. ShellitoJ.E. KollsJ.K. Central role of toll-like receptor 4 signaling and host defense in experimental pneumonia caused by Gram-negative bacteria.Infect. Immun.200573153254510.1128/IAI.73.1.532‑545.2005 15618193
     [Google Scholar]
  39. MolteniM. GemmaS. RossettiC. The role of toll-like receptor 4 in infectious and noninfectious inflammation.Mediators Inflamm.201620161910.1155/2016/6978936 27293318
     [Google Scholar]
  40. AutonA. AbecasisG.R. AltshulerD.M. A global reference for human genetic variation.Nature20155267571687410.1038/nature15393 26432245
     [Google Scholar]
  41. LeeJ.E. ChoiJ.H. LeeJ.H. LeeM.G. Gene SNPs and mutations in clinical genetic testing: Haplotype-based testing and analysis.Mutat. Res.20055731-219520410.1016/j.mrfmmm.2004.08.018 15829248
     [Google Scholar]
  42. ShindeS.D. SatputeD.P. BeheraS.K. KumarD. Computational biology of BRCA2 in male breast cancer, through prediction of probable nsSNPs, and hit identification.ACS Omega2022734304473046110.1021/acsomega.2c03851 36061650
     [Google Scholar]
  43. DabhiB. MistryK.N. In silico analysis of single nucleotide polymorphism (SNP) in human TNF-α gene.Meta Gene2014258659510.1016/j.mgene.2014.07.005 25606441
     [Google Scholar]
  44. KellyJ.N. BarrS.D. In silico analysis of functional single nucleotide polymorphisms in the human TRIM22 gene.PLoS One20149710143610.1371/journal.pone.0101436 24983760
     [Google Scholar]
  45. ThakurR. ShankarJ. In silico analysis revealed high-risk single nucleotide polymorphisms in human pentraxin-3 gene and their impact on innate immune response against microbial pathogens.Front. Microbiol.2016719210.3389/fmicb.2016.00192 26941719
     [Google Scholar]
  46. ThakurR. ShankarJ. Comprehensive in-silico analysis of high-risk non-synonymous snps in dectin-1 gene of human and their impact on protein structure.Curr. Pharmacogenomics Person. Med.201815214415510.2174/1875692116666180115142706
     [Google Scholar]
  47. FukusakiT. OharaN. HaraY. YoshimuraA. YoshiuraK. Evidence for association between a Toll‐like receptor 4 gene polymorphism and moderate/severe periodontitis in the Japanese population.J. Periodontal Res.200742654154510.1111/j.1600‑0765.2007.00979.x 17956467
     [Google Scholar]
  48. MansurA. GrubenL. PopovA.F. The regulatory toll-like receptor 4 genetic polymorphism rs11536889 is associated with renal, coagulation and hepatic organ failure in sepsis patients.J. Transl. Med.201412117710.1186/1479‑5876‑12‑177 24950711
     [Google Scholar]
  49. SatoK. YoshimuraA. KanekoT. A single nucleotide polymorphism in 3′-untranslated region contributes to the regulation of Toll-like receptor 4 translation.J. Biol. Chem.201228730251632517210.1074/jbc.M111.338426 22661708
     [Google Scholar]
  50. PapadopoulosA.I. FerwerdaB. AntoniadouA. Association of toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms with increased infection risk in patients with advanced HIV-1 infection.Clin. Infect. Dis.201051224224710.1086/653607 20521908
     [Google Scholar]
  51. GowinE. Świątek-KościelnaB. KałużnaE. Analysis of TLR2, TLR4, and TLR9 single nucleotide polymorphisms in children with bacterial meningitis and their healthy family members.Int. J. Infect. Dis.201760232810.1016/j.ijid.2017.04.024 28487240
     [Google Scholar]
  52. SilvaM.J.A. SantanaD.S. de OliveiraL.G. MonteiroE.O.L. LimaL.N.G.C. The relationship between 896A/G (rs4986790) polymorphism of TLR4 and infectious diseases: A meta-analysis.Front. Genet.202213104572510.3389/fgene.2022.1045725 36506333
     [Google Scholar]
  53. EspositoS. ZampieroA. PugniL. Genetic polymorphisms and sepsis in premature neonates.PLoS One20149710124810.1371/journal.pone.0101248 25000179
     [Google Scholar]
  54. AriffA. SongY. AguilarR. Genetic variants of TLR4, including the novel variant, rs5030719, and related genes are associated with susceptibility to clinical malaria in African children.Malar. J.202322117710.1186/s12936‑023‑04549‑8 37287037
     [Google Scholar]
  55. GentileA. FulgioneA. AuzinoB. In vivo biological validation of in silico analysis: A novel approach for predicting the effects of TLR4 exon 3 polymorphisms on brucellosis.Infect. Genet. Evol.202411810555210.1016/j.meegid.2024.105552 38218390
     [Google Scholar]
  56. ArbourN.C. LorenzE. SchutteB.C. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans.Nat. Genet.200025218719110.1038/76048 10835634
     [Google Scholar]
  57. von AulockS. SchröderN.W.J. GueinziusK. Heterozygous toll-like receptor 4 polymorphism does not influence lipopolysaccharide-induced cytokine release in human whole blood.J. Infect. Dis.2003188693894310.1086/378095 12964127
     [Google Scholar]
  58. ErridgeC. StewartJ. PoxtonI.R. Monocytes heterozygous for the Asp299Gly and Thr399Ile mutations in the Toll-like receptor 4 gene show no deficit in lipopolysaccharide signalling.J. Exp. Med.2003197121787179110.1084/jem.20022078 12796470
     [Google Scholar]
  59. BellocchioS. MorettiS. PerruccioK. TLRs govern neutrophil activity in aspergillosis.J. Immunol.2004173127406741510.4049/jimmunol.173.12.7406 15585866
     [Google Scholar]
  60. BochudP.Y. ChienJ.W. MarrK.A. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation.N. Engl. J. Med.2008359171766177710.1056/NEJMoa0802629 18946062
     [Google Scholar]
  61. de BoerM.G.J. JolinkH. HalkesC.J.M. Influence of polymorphisms in innate immunity genes on susceptibility to invasive aspergillosis after stem cell transplantation.PLoS One2011641840310.1371/journal.pone.0018403 21483748
     [Google Scholar]
  62. ChenZ. ZhaoN. DaiY. ChenZ. Correlation between TLR4 gene polymorphism and severe enterovirus 71 infection.J. Infect. Chemother.202026101015102010.1016/j.jiac.2020.05.004
     [Google Scholar]
  63. ZacherC. SchönfelderK. RohnH. SiffertW. MöhlendickB. The single nucleotide polymorphism rs4986790 (c.896A>G) in the gene TLR4 as a protective factor in corona virus disease 2019 (COVID-19).Front. Immunol.202415135519310.3389/fimmu.2024.1355193 38433829
     [Google Scholar]
  64. TahaS.I. ShataA.K. BaioumyS.A. Toll-like receptor 4 polymorphisms (896A/G and 1196C/T) as an indicator of COVID-19 severity in a convenience sample of egyptian patients.J. Inflamm. Res.2021146293630310.2147/JIR.S343246 34866927
     [Google Scholar]
  65. BakarosE. VoulgaridiI. PaliatsaV. Innate immune gene polymorphisms and COVID-19 prognosis.Viruses2023159178410.3390/v15091784 37766191
     [Google Scholar]
  66. AL-EitanL AlmomaniFA Al-KhatibSM AljamalHA Al-QusamiMN AljamalRA Association of toll-like receptor 4, 5 and 10 polymorphisms with Helicobacter pylori-positive peptic ulcer disease in a center in Jordan.Ann. Saudi Med.202141420621510.5144/0256‑4947.2021.206 34420402
     [Google Scholar]
  67. EedE.M. HawashY.A. KhalifaA.S. Association of toll-like receptors 2, 4, 9 and 10 genes polymorphisms and Helicobacter pylori-related gastric diseases in Saudi patients.Indian J. Med. Microbiol.20203819410010.4103/ijmm.IJMM_20_164 32719215
     [Google Scholar]
  68. MuheremuA. JiangJ. YakufuM. AiliA. LiL. LuoZ. Relationship between tool-like receptor 4 gene polymorphism and the susceptibility to pulmonary tuberculosis.Am. J. Transl. Res.202214638933903 35836860
     [Google Scholar]
  69. ChenX. WangK. YaoQ. PengL. WeiL. The relationship between the rs4986791 variant of the TLR4 gene and the severity of bronchial asthma in children.Asian Pac. J. Allergy Immunol.2024422159164 34246209
     [Google Scholar]
  70. TeräsjärviJ.T. ToivonenL. VuononvirtaJ. MertsolaJ. PeltolaV. HeQ. TLR4 polymorphism, nasopharyngeal bacterial colonization, and the development of childhood asthma: A prospective birth-cohort study in finnish children.Genes202011776810.3390/genes11070768 32650475
     [Google Scholar]
  71. TenhuE. TeräsjärviJ. CruzeiroM.L. Gene polymorphisms of TLR4 and TLR9 and Haemophilus influenzae meningitis in Angolan children.Genes2020119109910.3390/genes11091099 32967147
     [Google Scholar]
  72. ShiJ. HeL. TaoR. TLR4 polymorphisms as potential predictors of atopic dermatitis in Chinese Han children.J. Clin. Lab. Anal.20223652438510.1002/jcla.24385 35349724
     [Google Scholar]
  73. HoldG.L. BerryS. SaundersK.A. The TLR4 D299G and T399I SNPs are constitutively active to up-regulate expression of Trif-dependent genes.PLoS One201491111146010.1371/journal.pone.0111460 25365308
     [Google Scholar]
  74. JabłońskaA. StudzińskaM. SzenbornL. TLR4 896A/G and TLR9 1174G/A polymorphisms are associated with the risk of infectious mononucleosis.Sci. Rep.20201011315410.1038/s41598‑020‑70129‑4 32753695
     [Google Scholar]
  75. PandeyN.O. ChauhanA.V. RaithathaN.S. Association of TLR4 and TLR9 polymorphisms and haplotypes with cervical cancer susceptibility.Sci. Rep.201991972910.1038/s41598‑019‑46077‑z 31278284
     [Google Scholar]
  76. ShankarJ. ThakurR. ClemonsK.V. StevensD.A. Interplay of cytokines and chemokines in Aspergillosis.J. Fungi202410425110.3390/jof10040251 38667922
     [Google Scholar]
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Exploring Toll-like Receptor-4 Associated Single Nucleotide Polymorphisms and Susceptibility to Microbial Infections
Current Signal Transduction Therapy 21, E15743624386717 (2026); https://doi.org/10.2174/0115743624386717250804053842
/content/journals/cst/10.2174/0115743624386717250804053842
/content/journals/cst/10.2174/0115743624386717250804053842
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  • Article Type:     Review Article
Keyword(s): cytokines; microbial infections; pathogen-associated molecular patterns; pathogens; single-nucleotide polymorphisms; Toll-like receptor 4

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