Genetic mechanisms contributing to IFNβ regulation of Lyme Arthritis: involvement of the Borrelia burgdorferi arthritis associated locus 1 (Bbaa1)

Abstract Lyme disease shows a spectrum of clinical disorders in patients that are infected with the tick borne spirochete Borrelia burgdorferi. Studies have shown that C3H mice develop severe arthritis while C57BL/6 (B6) mice display mild arthritis when infected with the same isolate of B. burgdorferi. In order to study the role of the host genetics in regulating the severity of Lyme arthritis development, we used forward genetics and identified a genetic region, Bbaa1, that includes the Type I IFN cluster on Chr4. We further developed congenic mice isolating the C3H allele of Bbaa1 onto the background of B6 mice and determined that Bbaa1 regulates arthritis severity by upregulating Type I IFN. Antibody blocking revealed IFNβ, but not IFNα, as the key effector that drives severe Lyme arthritis. Because there are no SNPs between the C3H and B6 IFNβ genes, we hypothesized that other genetic factors in the Bbaa1 locus regulate the differential expression of IFNβ and Lyme arthritis severity. RNA silencing was used to identify candidate genes within Bbaa1 that regulate IFNβ expression in myeloid cells. Cdkn2a was identified as a strong regulator of IFNβ expression. Although Cdkn2a encodes two proteins, p16 and ARF, only the silencing of Arf resulted in the suppression of IFNβ expression. Additionally, the overexpression of ARF led to enhancement of IFNβ. We propose that ARF regulates IFNβ by two pathways involving the proteins p53 and BCL6. Indeed, blocking of BCL6 by a small molecule inhibitor induced IFNβ activation in the joint tissue of B6 mice and enhanced the severity of Lyme arthritis. Future work will focus on the impact of the two pathways on IFNβ expression and arthritis severity in mice.