Toll-like receptor cascade and gene polymorphism in host–pathogen interaction in Lyme disease

Figures & data

Table 1 Characteristics of the Toll-like receptors and their gene polymorphism-related infectious diseases

TLR	Immune-cell expression	Ligands	Pathogen-associated molecular patterns	Disease-related SNPs	SNP-linked infectious disease
TLR1	Cell surface of monocytes, macrophages, dendritic cells, and B-cells	Multiple triacyl lipopeptides Heat-shock proteins High-mobility group proteins Proteoglycans	Triacylated lipoproteins Peptidoglycans Lipopolysaccharides	Asn248Ser Ile602Ser Arg80Thr G-7202Aa	Sepsis Leprosy Candidemia Lyme disease
TLR2	Cell surface of monocytes, macrophages, dendritic cells, and B-cells	Multiple triacyl lipopeptides Heat-shock proteins High-mobility group proteins Proteoglycans Lipoteichoic acid β-Glucan	Diacylated lipoproteins Triacylated lipoproteins Peptidoglycans Lipopolysaccharides	Arg677Trp Arg753Gln Arg395Stop Ser249Pro	Leprosy Tuberculosis Lyme disease Urinary tract infection Staphylococcal infection
TLR3	Endosomes of B-cells, T-cells, natural killer cells, dendritic cells, neutrophils, and mast cells	mRNA tRNA	dsRNA (poly[I:C]) tRNA siRNA	Asn284Ile Tyr307Asp Leu412Phe Pro554Ser Ser737Thr	HIV infection Herpes simplex encephalitis
TLR4	Cell surface and endosomes of monocytes, macrophages, myeloid dendritic cells, mast cells, intestinal epithelium, and B lymphocytes	Lipopolysaccharide Heat-shock proteins Opioid drugs Fibrinogen Proteoglycans Nickel Fibronectin Tenascin C	Glycolipid lipopolysaccharides Paclitaxel	Asp299Gly Thr399Ile	Risk of infection
TLR5	Cell surface of monocytes, macrophages, dendritic cells, and intestinal epithelium	Bacterial flagellin Profilin	Flagellin	Arg392Stop	Pneumonia Systemic lupus erythematosus Lyme disease (probable)
TLR6	Cell surface of monocytes, macrophages, dendritic cells, and B-cells	Multiple triacyl lipopeptides Heat-shock proteins High-mobility group proteins Proteoglycans Lipoteichoic acid β-Glucan	Mycoplasma Diacylated lipoproteins Triacylated lipoproteins Peptidoglycans Lipopolysaccharides	Ser249Pro	Aspergillosis infection Lyme disease (probable)
TLR7	Endosomes of monocytes, macrophages, plasmacytoid dendritic cells, and B-cells	ssRNA Imidazoquinoline Bropirimine	ssRNA Imidazoquinolines Guanosine analogs	Gln11Leu	Hepatitis C infection HIV infection Systemic lupus erythematosus
TLR8	Endosomes of monocytes, macrophages, dendritic cells, and mast cells	Small synthetic compounds ssRNA Phagocytized bacterial RNA	ssRNA Imidazoquinolines	Met1Val	Hepatitis C infection Congo hemorrhagic fever Tuberculosis
TLR9	Endosomes of monocytes, macrophages, plasmacytoid dendritic cells, B-cells, and T-cells	Unmethylated CpG oligodeoxynucleotide DNA	Bacteria DNA viruses	Pro99Leu Pro545Pro T-1237Cb G1174Ab	Cerebral malaria Lupus nephritis
TLR10	Endosomes of monocytes, macrophages, and dendritic cells	Remains the only TLR without a defined ligand	Profilin-like proteins (probable)	Pro344Pro Iso775Val	Influenza viral infection (probable)

Notes:

a 5′-Flanking region;

b transition substitution, intronic SNPs. Data from Takeda et al,¹⁶ Beutler,¹⁷ and Lin et al.³²

Abbreviations: TLR, Toll-like receptor; SNP, single-nucleotide polymorphism; mRNA, messenger RNA; tRNA, transfer RNA; dsRNA, double-stranded RNA; siRNA, small interfering RNA; ssRNA, single-stranded RNA.

Table 2 Impact of TLR1 T1805G (Ile602Ser) and TLR2 A2258G (Arg753Gln) alleles on late-stage Lyme disease

Gene	SNP	Findingsa
TLR1	T1805G (Ile602Ser)		Control	Erythema migrans	Antibiotic-responsive arthritis	Antibiotic-refractory arthritis
		n	505	71	76	101
		Frequency (%)	50	51	47	62
		ORb				1.9c
		P				<0.05
TLR2	A2258G (Arg753Gln)		Matched control	Stage Id	Stage II	Stage III
		n	155	27	40	88
		Frequency (%)	13.5	0	17.5	2.3
		OR (95% CI)				0.15^e (0.03–0.65)
		P				0.003

Notes:

a Only statistically significant P-values reported;

b 95% CI was not clearly mentioned in the original article;⁷²

c versus erythema migrans group;

d stage I, early localized Lyme disease (1–4 weeks); stage II, early disseminated infection (1–4 months); stage III, late persistent Lyme disease (eg, Lyme arthritis); ^eversus matched control group. Data from Strle et al⁷² and Schröder et al.⁸⁶

Abbreviations: SNP, single-nucleotide polymorphism; OR, odds ratio; CI, confidence interval.

Table 3 Summary of TLR-gene polymorphisms’ functional significance in Lyme disease and their role in host–pathogen interactions

TLR	SNP	Functional significance
TLR1	Arg80Thr Asn248Ser Ile602Ser	• Lower cytokine production in PBMCs homozygous for the three SNPs after Pam3 Cys exposure • Live Borrelia burgdorferi led to lower IL-1β synthesis in cells homozygous for Arg80Thr • Significantly lower IL-1β production in cells with TLR1 Asn248Ser and Ser602Ile following exposure to live B. burgdorferi • Induction with Pam3 Cys lipopeptide and live pathogen led to a lower production of IFNγ • Significant differences in the synthesis of IL-6, IL-8, TNFα, and IL-10 after Pam3 Cys and B. burgdorferi stimulation • Patients with erythema migrans more likely to have symptoms and elevated serum levels of IL-6, CXCL9, and CXCL10 • Patients with antibiotic-refractory arthritis exhibited high IL-6, CXCL9, and CXCL10 compared to erythema migrans or patients with antibiotic-responsive Lyme arthritis
TLR2	Arg753Gln	• Decreased synthesis of TNFα and IFNγ following exposure to B. burgdorferi lysates in human kidney embryo epithelial HEK293 cells • No significant difference in cytokines/chemokines was observed in PBMCs from patients with Lyme arthritis from basal levels after exposure to B. burgdorferi
TLR5	Arg395Stop	• No significant difference in cytokines/chemokines observed from basal levels after exposure to B. burgdorferi
TLR6	Ser249Pro	• No significant difference in IL-1β, IL-6, IL-8, IL-10, or TNFα cytokine levels upon FSL1 exposure • Stimulation with live B. burgdorferi inhibited IL-1β, IL-6, and IL-8 synthesis • No effect on IFNγ or IL-17 compared to wild type

Note: Data from Strle et al,⁷² Schröder et al,⁸⁶ and Oosting et al.⁹⁷

Abbreviations: SNP, single-nucleotide polymorphism; PBMCs, peripheral blood mononuclear cells.

TakedaKAkiraSTLR signaling pathwaysSemin Immunol20041613914751757

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BeutlerBInnate immunity: an overviewMol Immunol2004401284585914698223

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LinYTVermaAHodgkinsonCPToll-like receptors and human disease: lessons from single nucleotide polymorphismsCurr Genomics201213863364523730203

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StrleKShinJJGlicksteinLJSteereACAssociation of a Toll-like receptor 1 polymorphism with heightened Th1 inflammatory responses and antibiotic-refractory Lyme arthritisArthritis Rheum20126451497150722246581

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SchröderNWDiterichIZinkeAHeterozygous Arg753Gln polymorphism of human TLR-2 impairs immune activation by Borrelia burgdorferi and protects from late stage Lyme diseaseJ Immunol200517542534254016081826

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OostingMTer HofstedeHSturmPTLR1/TLR2 heterodimers play an important role in the recognition of Borrelia spirochetesPLoS One2011610e2599821998742

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