rs5743618 — TLR1 I602S

TLR1 I602S — When a Receptor Stays Off the Surface

Bacteria don't invade quietly. The moment a triacylated lipopeptide from a mycobacterium, spirochete, or gram-positive organism reaches your innate immune cells, it should trigger a rapid response — but only if Toll-Like Receptor 1 (TLR1)¹¹ Toll-Like Receptor 1 (TLR1)
TLR1 is a pattern-recognition receptor that forms heterodimers with TLR2 to detect bacterial triacylated lipopeptides such as those from Mycobacterium tuberculosis and M. leprae has reached the cell surface. The rs5743618 I602S variant (c.2079T>G, historically labeled 1805T>G) disrupts a transmembrane trafficking motif at the boundary between TLR1's transmembrane and intracellular domains, trapping the receptor inside the cell rather than displaying it on the surface.

The evolutionary history of this variant is striking. The serine-602 (S) allele, which impairs TLR1 surface expression, shows clear signatures of positive selection²² clear signatures of positive selection
iHS and XP-EHH statistics in the 1000 Genomes populations in European populations and is found in approximately 75% of Europeans — making intact (isoleucine-602) TLR1 the minority form in Europe. The allele is far less common in African (~25%) and East Asian (~2%) populations, suggesting it was selected for in environments where dampening TLR1 signaling conferred a survival advantage, possibly by reducing immunopathology from chronic bacterial and mycobacterial exposure.

The Mechanism

TLR1 and TLR2 form obligate heterodimers to recognize bacterial triacylated lipopeptides (tri-acyl LP)³³ bacterial triacylated lipopeptides (tri-acyl LP)
lipoproteins with three fatty acid chains found on mycobacteria, borreliae, and gram-positive bacteria — structurally distinct from the diacylated lipopeptides recognized by TLR2/TLR6 heterodimers. When TLR1/TLR2 binds its ligand, the intracellular TIR domains recruit MAL and MyD88 and activate NF-κB, producing TNF-α, IL-6, IL-12, and other pro-inflammatory cytokines essential for bacterial killing.

The I602S substitution places a serine — a hydroxyl-bearing, polar amino acid — at position 602 in the transmembrane domain, where the hydrophobic isoleucine is required for proper folding and export. The result: TLR1 protein is produced normally but retained intracellularly⁴⁴ retained intracellularly
individuals homozygous for 602S completely lack cell-surface TLR1 while retaining normal intracellular TLR1 protein levels. Without surface expression, TLR1/TLR2 heterodimers cannot form efficiently, and NF-κB activation by triacylated lipopeptides is severely blunted⁵⁵ NF-κB activation by triacylated lipopeptides is severely blunted
whole-blood TNF-α production after Pam3CSK4 stimulation is markedly reduced in 602S homozygotes.

A key mechanistic nuance: this variant exclusively disrupts TLR1-dependent signaling. TLR2/TLR6 heterodimer signaling (recognizing diacylated lipopeptides) is unaffected. This means the immune system is selectively blunted for one arm of bacterial lipopeptide recognition while the other remains intact.

The Evidence

Leprosy provided the first strong human association. Johnson et al. (2007) showed the 602S allele protects against clinical leprosy⁶⁶ protects against clinical leprosy
OR 0.48 in Turkish case-control, with 602S homozygotes predominantly in the healthy control group. A larger Indian case-control replication across two cities (New Delhi and Kolkata) confirmed this with a combined P = 5.7×10⁻⁸, OR = 0.31⁷⁷ combined P = 5.7×10⁻⁸, OR = 0.31
one of the strongest associations ever reported for an innate immune variant and an infectious disease. The paradox: reduced TLR1 signaling protects against leprosy by limiting mycobacteria-driven tissue damage and the Th1 immunopathology that drives the severe lepromatous form.

Tuberculosis shows the inverse. When TLR1 is active (602I/A allele), it helps defend against mycobacteria. A Han Chinese pediatric study⁸⁸ Han Chinese pediatric study
206 TB cases and 201 healthy controls found the A (602I) allele associated with increased TB risk (OR 2.40, 95%CI 1.41–4.07, P = 0.0009). A separate Brazilian cohort (Amazonas state) found that heterozygous 1805TG individuals were overrepresented among multibacillary vs paucibacillary TB⁹⁹ heterozygous 1805TG individuals were overrepresented among multibacillary vs paucibacillary TB
OR 3.72 for multibacillary disease — consistent with heightened TLR1 signaling driving the granulomatous response and immune pathology of more severe disease. These findings are not entirely consistent across all meta-analyses, suggesting population-specific and disease-stage-specific effects.

Sepsis reveals an additional dimension. In the intensive care setting, the 602I (A allele) confers enhanced neutrophil priming by Pam3CSK4¹⁰¹⁰ neutrophil priming by Pam3CSK4
TLR2/1 agonist: elevated ROS generation, MAPK phosphorylation, integrin activation, and cytokine secretion. In a pediatric sepsis cohort, children homozygous for the 602I genotype had a prolonged PICU length of stay, suggesting that overly active TLR1-mediated neutrophil responses may amplify organ damage in sepsis.

Post-infectious Lyme arthritis is the most recently described association. A 2025 study found that patients with TLR1 1805GG (602I/602I)¹¹¹¹ TLR1 1805GG (602I/602I)
the AA genotype on plus strand were significantly overrepresented among patients who developed persistent post-infectious Lyme arthritis after antibiotic treatment. In PBMCs with this genotype, repeated Borrelia burgdorferi stimulation failed to induce innate immune tolerance — resulting in unabated cytokine production even after bacterial clearance — consistent with the sustained joint inflammation seen in this condition.

Practical Implications

This variant sits at a meaningful evolutionary trade-off: the 602S allele (reduced TLR1 surface expression) was positively selected in European populations — likely because a dampened TLR1/TLR2 response reduces immunopathology in chronic mycobacterial exposure. But this selection came with a cost: less effective early bacterial clearance in some infection contexts, particularly for individuals who are AA (602I/602I) or have one active copy (AC), who face an inverted risk landscape.

For users carrying the A allele (602I, full TLR1 surface expression): the practical significance depends heavily on exposure context. In low-leprosy environments, having intact TLR1 is generally an asset for bacterial defense. The Lyme arthritis finding deserves attention for those in tick-endemic regions.

For CC (602S/602S) users: TLR1 surface expression is absent, reducing bacterial triacylated lipopeptide recognition. In populations where leprosy and severe mycobacterial disease are rare, this is largely a neutral-to-protective state. Standard infection prevention measures apply.

Interactions

TLR1 forms obligate heterodimers with TLR2 (rs5743708) for triacylated lipopeptide recognition. The TLR2 R753Q variant independently impairs TLR2 signaling, and in a Colombian case-control study, the haplotype combining rs5743618, rs5743708 (TLR2 R753Q), and rs5743810 (TLR6 Ser249Pro) was associated with altered leprosy susceptibility — suggesting additive effects across the TLR1/2/6 trimer complex. Carriers of both TLR1 A allele (602I) and TLR2 A allele (753Q) would likely face compounded reductions in combined TLR1/TLR2 output via independent mechanisms.

TLR6 (rs5743810) pairs with TLR2 to recognize diacylated lipopeptides — the functional partner on the other side. TLR4 (rs4986790) handles gram-negative LPS independently. Innate immune profiling across TLR1, TLR2, TLR4, TLR6, and TLR9 variants provides the most complete picture of bacterial recognition capacity.