rs5743618 — TLR1 I602S

Coding variant replacing isoleucine with serine at TLR1 position 602, disrupting a transmembrane trafficking motif and preventing TLR1 from reaching the cell surface — reducing TLR1/TLR2 heterodimer signaling in response to bacterial triacylated lipopeptides

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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.

Genotype Interpretations

What each possible genotype means for this variant.

AC Partial TLR1 Surface Expression Intermediate

Reduced TLR1 cell-surface expression with intermediate triacylated lipopeptide signaling

The heterozygous state produces a partial phenotype: some TLR1 reaches the cell surface (from the I allele-encoded protein), while some is retained intracellularly (from the S allele-encoded protein). This intermediate surface expression means TLR1/TLR2 heterodimer signaling is partially preserved but reduced compared to AA homozygotes.

In the tuberculosis context, a Brazilian cohort (Amazonas state) found heterozygous individuals (TG in coding notation, equivalent to AC on plus strand) were overrepresented among multibacillary versus paucibacillary TB patients (OR 3.72), suggesting that partial TLR1 activity may facilitate the granulomatous response that characterizes more severe TB. This finding has not been consistently replicated across all studies and should be interpreted cautiously.

For Lyme arthritis risk, heterozygotes appear to have an intermediate phenotype between the high-risk AA group and the lower-risk CC group.

AA Full TLR1 Surface Expression High Risk

Full TLR1 cell-surface expression with robust TLR1/TLR2 signaling to bacterial triacylated lipopeptides

With full TLR1 surface expression, your monocytes, macrophages, and neutrophils mount strong cytokine responses (TNF-α, IL-6, IL-12) when encountering bacterial triacylated lipopeptides. Neutrophils with this genotype show enhanced priming including elevated ROS generation, MAPK phosphorylation, and cytokine secretion in response to Pam3CSK4.

The Lyme arthritis data is clinically relevant for individuals in tick-endemic areas: AA homozygotes fail to properly downregulate their Borrelia immune response even after antibiotic clearance, leading to persistent joint inflammation. Prompt antibiotic treatment early in Lyme disease course (before chronic activation sets in) is particularly important.

In the sepsis context, AA individuals appear to have more vigorous neutrophil priming responses that may both improve bacterial killing and amplify organ damage; data from a pediatric sepsis cohort showed prolonged PICU stays in AA homozygotes.

For TB, the relationship is nuanced — active TLR1 may contribute to immunopathology of severe disease in endemic settings, though standard TB prevention still applies.

CC Reduced Surface TLR1 Decreased

Absent cell-surface TLR1 expression with reduced triacylated lipopeptide signaling — the common form in Europeans

The complete absence of cell-surface TLR1 in 602S/602S individuals means TLR1/TLR2 heterodimers cannot assemble efficiently on the plasma membrane. In vitro, whole-blood from CC homozygotes produces markedly reduced TNF-α when stimulated with Pam3CSK4 (a synthetic triacylated lipopeptide), and monocytes fail to activate NF-κB through this pathway.

Despite this functional deficit, CC individuals appear largely healthy in low-endemic settings — the body compensates via TLR2/TLR6 (diacylated lipopeptides), TLR4 (LPS), and TLR9 (bacterial DNA). The reduced TLR1 signaling may even be protective against pathological immune responses in certain settings, as demonstrated by the strong leprosy-protective association (OR 0.31 for CC vs AA in Indian case-control studies).

One potential benefit: CC individuals in tick-endemic regions may be at lower risk for post-infectious Lyme arthritis, which appears to require overactive TLR1-mediated Borrelia responses.