# Role of human innate immune mutations in loss of tolerance to Borrelia burgdorferi

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2020 · $612,118

## Abstract

The majority of symptoms of Lyme disease are due to the host immune response to the organism, Borrelia
burgdorferi, and resolve over time, even without antibiotic treatment. In its natural host, little or no reaction to
infection can be seen despite the fact that the organism persists for life. In humans and inbred mice (which do
develop immune responses to the organism), inflammation is thought to be initiated by receptors of the innate
immune system. In vitro, loss of innate, pathogen-sensing receptors that recognize B. burgdorferi such as toll-
like receptor 2 (TLR2) results in a decrease inflammatory response. However, in vivo studies of animals
deficient in these receptors or their adaptor molecules do not show reduced inflammation and in many cases
show increased inflammation. Recently, in humans, a single nucleotide polymorphism (SNP) in the tlr1 gene
that results in loss of expression of the receptor on the cell surface was found to be associated with increased
inflammation and symptoms. This suggests that after the initial stimulus, a major role for these innate immune
molecules is in dampening inflammation. One major difference between in vitro studies and the in vivo
infections is that the in vitro experiments are typically conducted by measuring responses minutes to hours
after exposure to the organism. We have evidence that more prolonged exposures in vitro result in the
development of innate immune “tolerance” to stimulation by B. burgdorferi.
 In this proposal, we will study the role of the tlr1-1805GG SNP in disrupting innate immune tolerance,
thereby leading to excessive inflammatory responses. The 1805GG SNP results in a loss of localization to the
cell surface but does not affect the activity of the receptor. Therefore, in Aim 1, we will first determine the
effects of the SNP on specific, localization-dependent signaling pathways and downstream cytokine
responses. We have previously shown that the TLR1/TLR2 ligand Pam3CSK4 can initiate signaling from both
intracellular and cell surface locations although the signals are different in each location. It is likely that the tlr1-
1805GG SNP continues to signal endosomally. We will track movements of the receptors and ligands as well
as compare a tlr1 deletion to the tlr1-1805GG SNP. In Aim 2, we will assess the role of the tlr1-1805GG SNP
on macrophage reprogramming leading to loss of innate immune tolerance to B. burgdorferi. We will focus on
understanding its effects on macrophage polarization, cell death and the role of glucose metabolism. Finally, in
Aim 3, using isogenic B. burgdorferi isolates that do or do not initiate tolerance, we will identify the role of
specific components of the organism in moderating macrophage reprograming and loss of tolerance.
 We believe that B. burgdorferi infection, where there is prolonged infection with minimal evidence of
inflammation over time, is an excellent model to understand how the immune system can control responses to
invasive bacteri...

## Key facts

- **NIH application ID:** 10072980
- **Project number:** 1R01AI150157-01A1
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Linden T Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $612,118
- **Award type:** 1
- **Project period:** 2020-09-08 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072980

## Citation

> US National Institutes of Health, RePORTER application 10072980, Role of human innate immune mutations in loss of tolerance to Borrelia burgdorferi (1R01AI150157-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10072980. Licensed CC0.

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