ORIGINAL RESEARCH article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Toll-like Receptor 1 single nucleotide polymorphism is associated with impaired innate immune tolerance and dysregulated inflammatory responses to Borrelia burgdorferi in Lyme disease
Provisionally accepted
Morgan A Williams1*
Sergio A. Hernandez1Sheila L. Arvikar2Katherine B. Sulka1
Franc Strle3Christopher C. Wells1
Tanja Petnicki-Ocwieja1
Allen C Steere2Klemen Strle1- 1Tufts University School of Medicine, Boston, United States
- 2Massachusetts General Hospital Division of Rheumatology Allergy & Immunology, Boston, United States
- 3Department of Infectious Diseases, Univerzitetni klinicni center Ljubljana, Ljubljana, Slovenia
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Abstract Introduction: Clinical presentation of Lyme disease is largely due to host immune response to infection. Previously, we identified a variant (1805GG) in the TLR1 gene, a key immune sensor for Borrelia burgdorferi, which was associated with excessive inflammation and severe disease. Herein we examined the mechanism by which this variant leads to dysregulated immunity. Methods: We found that patients with post-infectious LA, a condition characterized by marked persistent synovitis in joints, have a higher frequency of TLR1-1805GG compared to those whose arthritis resolves with antibiotics. To explore the possibility that this genotype-phenotype association was due to excessive inflammation we then tested the functional impact of TLR1-1805GG on inflammatory responses and immune tolerance in PBMCs with or without this SNP and in THP-1 cell lines lacking TLR1. Results: In response to B. burgdorferi stimulation, PBMCs with TLR1-1805GG had greater transcriptional upregulation of ~1200 immune-related genes and significantly higher cytokine levels in supernatants compared to cells without this variant. Moreover, repeat B. burgdorferi stimulation, which mimics tolerogenic conditions during the infection, failed to induce innate immune tolerance in PBMCs with TLR1-1805GG, or in THP-1 cells lacking TLR1, resulting in seemingly unabated immune activation consistent with marked inflammation in LA joints. Conclusions: These results suggest that excessive inflammation in patients with TLR1-1805GG variant appears to be due to immune dysregulation and inability to induce immune tolerance. The findings help explain how early events during the infection may contribute to sustained immune activation after antibiotics and point to the role of TLR1 signaling in immune regulation.
Keywords: Lyme Disease, Borrelia burgdorferi, Toll-Like Receptors, innate immune tolerance, Inflammation, Lyme Arthritis, Innate immunology
Received: 23 Sep 2025; Accepted: 23 Oct 2025.
Copyright: © 2025 Williams, Hernandez, Arvikar, Sulka, Strle, Wells, Petnicki-Ocwieja, Steere and Strle. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Morgan A Williams, morgan.williams@tufts.edu
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