Highlights
- •People with keratitis were compared to controls to determine whether they had changes to genes encoding Toll-like receptors (TLRs).
- •Several single nucleotide polymorphisms in TLRs 2, 4 and 5 were significantly different between the cases and controls.
- •These differences may relate to susceptibility towards keratitis during contact lens wear.
Abstract
Objective
To investigate differences in SNPs in TLR genes between people who had keratitis and controls in an Indian population.
Methods
145 cases of keratitis and 189 matched controls were recruited. DNA was extracted
from peripheral blood. Single nucleotide polymorphisms (SNP) in TLR2 (n = 6), TLR4 (n = 15), TLR5 (n = 13) and TLR9 (n = 10) were analysed. The risk of developing keratitis was assessed based on allele,
genotype and haplotype associations.
Results
For all cases of keratitis, the TLR4 SNP rs4986791 TC genotype frequency was significantly higher in cases (p = 0.006,
OR = 1.96, 95 % CI 1.19–3.2). Including cases of only microbial keratitis (MK) revealed
that genotypes in TLR2 SNP rs5743706 TA (p = 0.0001; OR = 8.61; 95 % CI 2.59–28.56)), TLR4 SNP s4986791 TC (p = 0.002; OR = 2.65; 95 % CI 1.39–5.07) were significantly more
common for MK, whereas the TLR5 SNP rs2241096 A allele (p = 0.00316, OR = 0.42, 95
% CI 0.2−0.9286) and GA genotype (p = 0.016; OR = 0.45; 95 % CI 0.23−0.86) was significantly
less common in MK cases. The TLR2 SNP rs5743706 genotype TA was significantly less common in the sterile keratitis
(SK) group (p = 0.004, OR = 0.43, 95 %CI 0.24−0.77). Haplotype analysis of MK compared
to controls showed that TLR2 AT was more common in controls (p = 0.003); TLR4 ACAC was more common in cases (p = 0.004); TLR5 TGGCA was more common in controls (p = 0.001).
Conclusion
The present study revealed multiple associations between variants across TLR genes, which may have implications for understanding the underlying host factors,
risk of developing keratitis and molecular pathogenesis in keratitis.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Contact Lens and Anterior EyeAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Incidence of contact-lens-associated microbial keratitis and its related morbidity.Lancet. 1999; 354: 181-185
- Risk factors and causative organisms in microbial keratitis.Cornea. 2008; 27: 22-27
- Microbial analyses of contact lens-associated microbial keratitis.Optom Vis Sci. 2014; 91: 47-53
- Epidemiology and aetiological diagnosis of corneal ulceration in Madurai, south India.Br J Ophthalmol. 1997; 81: 965-971
- Bacteria commonly isolated from keratitis specimens retain antibiotic susceptibility to fluoroquinolones and gentamicin plus cephalothin.Clin Exp Ophthalmol. 2006; 34: 44-50
- Contact lens-induced peripheral ulcers with extended wear of disposable hydrogel lenses: histopathologic observations on the nature and type of corneal infiltrate.Cornea. 1999; 18: 538-543
- Contact lens induced peripheral ulcers during hydrogel contact lens wear.CLAO J. 1998; 24: 145-151
- Colonization of hydrogel lenses with Streptococcus pneumoniae: risk of development of corneal infiltrates.Cornea. 1999; 18: 289-295
- Isolation of Staphylococcus aureus from a contact lens at the time of a contact lens-induced peripheral ulcer: case report.Cornea. 2000; 19: 116-120
- Gram-negative bacteria can induce contact lens related acute red eye (CLARE) responses.CLAO J. 1996; 22: 47-52
- Clinical characterization of corneal infiltrative events observed with soft contact lens wear.Cornea. 2003; 22: 435-442
- Haemophilus influenzae adherent to contact lenses associated with production of acute ocular inflammation.J Clin Microbiol. 1996; 34: 2426-2431
- Bacterial colonization of disposable soft contact lenses is greater during corneal infiltrative events than during asymptomatic extended lens wear.J Clin Microbiol. 2000; 38: 4420-4424
- Rethinking contact lens associated keratitis.Clin Exp Optom. 2006; 89: 280-298
- Common and rare variants in multifactorial susceptibility to common diseases.Nat Genet. 2008; 40: 695-701
- Common vs. rare allele hypotheses for complex diseases.Curr Opin Genet Dev. 2009; 19: 212-219
- Uncovering the roles of rare variants in common disease through whole-genome sequencing.Nat Rev Genet. 2010; 11: 415-425
- IL-10 promotor haplotypes associated with susceptibility to and severity of bacterial corneal ulcers.Exp Eye Res. 2009; 88: 1124-1128
- Association of single nucleotide polymorphisms of interleukins-1beta, -6, and -12B with contact lens keratitis susceptibility and severity.Ophthalmology. 2012; 119: 1320-1327
- Immune defense single nucleotide polymorphisms and recruitment strategies associated with contact lens keratitis.Ophthalmology. 2012; 119: 1997-2002
- Association study of single nucleotide polymorphisms in IL-10 and IL-17 genes with the severity of microbial keratitis.Cont Lens Anterior Eye. 2019; 42: 658-661
- Structure and function of Toll receptors and their ligands.Annu Rev Biochem. 2007; 76: 141-165
- Toll-like receptors.Annu Rev Immunol. 2003; 21: 335-376
- Recognition of Corynebacterium pseudodiphtheriticum by Toll-like receptors and up-regulation of antimicrobial peptides in human corneal epithelial cells.Virulence. 2015; 6: 716-721
- Host response and bacterial virulence factor expression in Pseudomonas aeruginosa and Streptococcus pneumoniae corneal ulcers.PLoS One. 2013; 8e64867
- Modulation of immune signaling, bacterial clearance, and corneal integrity by toll-like receptors during streptococcus pneumoniae keratitis.Curr Eye Res. 2013; 38: 1036-1048
- Signaling mediated by toll-like receptor 5 sensing of Pseudomonas aeruginosa flagellin influences IL-1beta and IL-18 production by primary fibroblasts derived from the human cornea.Front Cell Infect Microbiol. 2017; 7: 130
- Understanding early TLR signaling through the Myddosome.J Leukoc Biol. 2019; 105: 339-351
- MyD88 contribution to ocular surface homeostasis.PLoS One. 2017; 12e0182153
- Innate immune regulation of Serratia marcescens-induced corneal inflammation and infection.Invest Ophthalmol Vis Sci. 2012; 53: 7382-7388
- A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection.Infect Immun. 2000; 68: 6398-6401
- Arg753Gln polymorphism of the human toll-like receptor-2 gene in children with recurrent febrile infections.Biochem Genet. 2007; 45: 507-514
- Cytokine and cytokine receptor gene polymorphisms and their functionality.Cytokine Growth Factor Rev. 2009; 20: 43-59
- TLR5 as an anti-inflammatory target and modifier gene in cystic fibrosis.J Immunol. 2010; 185: 7731-7738
- Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. Ethnic groups and exploratory case-control disease association studies.Genomics. 2003; 81: 85-91
- Comprehensive genetic assessment of a functional TLR9 promoter polymorphism: no replicable association with asthma or asthma-related phenotypes.BMC Med Genet. 2011; 12: 26
- Strategies for processing and quality control of Illumina genotyping arrays.Brief Bioinform. 2018; 19: 765-775
- Power and sample size calculations. A review and computer program.Control Clin Trials. 1990; 11: 116-128
- A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers: update of the SHEsis (http://analysis.bio-x.cn).Cell Res. 2009; 19: 519-523
- Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2.J Biol Chem. 1999; 274: 17406-17409
- Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2.Science. 1999; 285: 736-739
- Intracellularly expressed TLR2s and TLR4s contribution to an immunosilent environment at the ocular mucosal epithelium.J Immunol. 2004; 173: 3337-3347
- TLR2 activation in corneal stromal cells by Staphylococcus aureus-induced keratitis.APMIS. 2015; 123: 163-168
- Peptidoglycan and muramyl dipeptide from Staphylococcus aureus induce the expression of VEGF-A in human limbal fibroblasts with the participation of TLR2-NFkappaB and NOD2-EGFR.Graefes Arch Clin Exp Ophthalmol. 2013; 251: 53-62
- Expression of toll-like receptors in human limbal and conjunctival epithelial cells.Mol Vis. 2007; 13: 813-822
- Innate immune response of corneal epithelial cells to Staphylococcus aureus infection: role of peptidoglycan in stimulating proinflammatory cytokine secretion.Invest Ophthalmol Vis Sci. 2004; 45: 3513-3522
- Cutting edge: a toll-like receptor 2 polymorphism that is associated with lepromatous leprosy is unable to mediate mycobacterial signaling.J Immunol. 2003; 170: 3451-3454
- The relationship between toll like receptor 4 gene rs4986790 and rs4986791 polymorphisms and sepsis susceptibility: a meta-analysis.Sci Rep. 2016; 6: 38947
- Correlations between TLR polymorphisms and inflammatory bowel disease: a meta-analysis of 49 case-control studies.Immunol Res. 2019; 67: 142-150
- Polymorphisms in TLR4 and TNFA and risk of mycobacterium tuberculosis infection and development of active disease in contacts of tuberculosis cases in Brazil: a prospective cohort study.Clin Infect Dis. 2019; 69: 1027-1035
- Genetic variants of TLR4 and TLR9 are risk factors for chronic Helicobacter pylori infection in South Indian Tamils.Hum Immunol. 2017; 78: 216-220
- Toll-like receptor 5-mediated corneal epithelial inflammatory responses to Pseudomonas aeruginosa flagellin.Invest Ophthalmol Vis Sci. 2003; 44: 4247-4254
- Flagellin suppresses the inflammatory response and enhances bacterial clearance in a murine model of Pseudomonas aeruginosa keratitis.Infect Immun. 2008; 76: 89-96
- A toll-like receptor recognizes bacterial DNA.Nature. 2000; 408: 740-745
- Analysis of Pseudomonas aeruginosa corneal infection using an oligonucleotide microarray.Invest Ophthalmol Vis Sci. 2003; 44: 3409-3416
- Silencing Toll-like receptor-9 in Pseudomonas aeruginosa keratitis.Invest Ophthalmol Vis Sci. 2005; 46: 4209-4216
- Cutting edge: role of Toll-like receptor 9 in CpG DNA-induced activation of human cells.J Immunol. 2001; 167 (3555-8)
- Pseudomonas aeruginosa invasion of and multiplication within corneal epithelial cells in vitro.Infect Immun. 1995; 63: 4072-4077
- Internalization of Staphylococcus aureus by human corneal epithelial cells: role of bacterial fibronectin-binding protein and host cell factors.Infect Immun. 2002; 70: 4697-4700
- Toll-like receptor 4 promoter polymorphisms: common TLR4 variants may protect against severe urinary tract infection.PLoS One. 2010; 5e10734
- Association of TLR2 and TLR4 gene single nucleotide polymorphisms with Fungal Keratitis in Chinese Han population.Curr Eye Res. 2014; 39: 47-52
Article info
Publication history
Published online: July 25, 2020
Accepted:
July 14,
2020
Received in revised form:
July 13,
2020
Received:
January 30,
2020
Identification
Copyright
© 2020 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.
