# Molecular Genetics of Lyme Arthritis

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $387,178

## Abstract

PROJECT SUMMARY / ABSTRACT
Lyme disease is caused by the tick borne spirochete Borrelia burgdorferi and there are estimated to be
300,000 cases/year in the US. It is associated with a spectrum of clinical symptoms of varying severities,
ranging from localized skin lesion to disseminated infection including secondary skin lesions, arthritis,
neuropathies, and carditis. It is apparent that genetically regulated responses of the host contribute to the
severity of symptoms. We have taken a forward genetics approach to identify allelic genes that determine the
difference in Lyme arthritis between the severely arthritic C3H mouse and the mildly arthritic C57BL/6 (B6)
mouse. This analysis has identified Quantitative Trait Loci on several chromosomes, including the Bbaa1 locus
on Chr 4, which encompasses the Type I IFN gene cluster. Congenic mouse lines in which the C3H Bbaa1
allele was introgressed onto the B6 background (B6.C3H-Bbaa1) confirmed the presence of a genetic element
in this locus that regulates arthritis through expression of IFNβ, a Type I IFN. As the C3H and B6 IFNβ genes
lack polymorphisms, any expression differences must be regulated by a linked genetic element. Advanced,
interval specific recombinant congenic lines (ISRCL) have narrowed the physical region associated with Bbaa1
to 2.2 Mbp and identified the Cyclin Dependent Kinase Inhibitory gene, Cdkn2a, as a candidate regulator of
IFNβ expression and determinant of the severity of Lyme arthritis. A variety of experiments demonstrated that
the Bbaa1 impact on IFNβ expression was manifest through B. burgdorferi stimulation of myeloid cells, but that
an additional, downstream mediator of arthritis required distinct activation of resident cells of the joint tissues.
Independent studies characterized the arthritis-inducing activity of IFNβ as myostatin (MSTN). MSTN is well
characterize as modulating skeletal muscle development, but has also been implicated in chronic disease and
inflammation. We will utilize the B6.C3-Bbaa1 ISRCLs to characterize the mechanism by which products of the
Cdkn2a locus regulate IFNβ production in myeloid cells, and, in turn, the mechanism by which the downstream
effector MSTN modulates Lyme arthritis development. We propose a combination of lineage-specific
expression analysis, silencing of gene expression, development of targeted KO mice, and the use of small
molecule inhibitors in order to define the complex interactions involved in Lyme arthritis development. Our
findings may provide insight into other pathologies driven by Type I IFN, which could also implicate unexpected
pathways involving Cdkn2a and MTSN.

## Key facts

- **NIH application ID:** 10754232
- **Project number:** 5R01AR043521-30
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Janis J. Weis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $387,178
- **Award type:** 5
- **Project period:** 2020-01-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754232

## Citation

> US National Institutes of Health, RePORTER application 10754232, Molecular Genetics of Lyme Arthritis (5R01AR043521-30). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10754232. Licensed CC0.

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