Genetic and mechanistic analyses of type I interferon-driven lyme arthritis

B6 and C3H mice develop opposite Lyme arthritis phenotypes in response to the same Borrelia burgdorferi infection, providing a unique opportunity to use unbiased genetic approaches to identify host genes modulating pathogenic responses. Previously, gene expression profiling in joint tissue revealed a robust type I IFN profile in C3H mice that was formally linked to arthritis severity through IFNAR1 mAb blockade and genetic ablation. Independently, forward genetics identified a QTL, termed Borrelia burgdorferi arthritis-associated locus 1 (Bbaa1), which regulates Lyme arthritis severity and includes the type I IFN gene cluster. Here, interval specific congenic lines on B6 and C3H backgrounds were generated to mechanistically analyze the role of Bbaa1 as a regulator of Lyme arthritis severity. B6 mice congenic for the C3H Bbaa1 allele (B6.C3-Bbaa1) developed more severe Lyme arthritis than parental B6, which was correctable by IFNAR1 mAb blockade. Bbaa1 also regulated the magnitude of interferon-stimulated gene expression in BMDMs. Extensive analysis on phagocytic uptake, bacterial sensing and trafficking pathways, and IFN-responsive states further established that genes within Bbaa1 intrinsically control the differential IFN response. B6.C3-Bbaa1 mice also developed more severe K/BÃ-N serum transfer arthritis through dysregulated type I IFN, establishing shared pathological processes in models of Lyme and rheumatoid arthritis. Refined, interval specific recombinant congenic lines further highlighted thecontribution of C3H type I IFN genes to Lyme arthritis. Specific mAb blockade identified IFN-β (and not IFN-α) as the proarthritogenic type I IFN in B6.C3-Bbaa1 mice, and IFN-β was solely responsible for interferon-stimulated gene expression and feed-forward amplification in BMDMs. Reciprocal radiation chimeras between B6.C3-Bbaa1 and B6 mice illuminated a critical “pass off” in joint tissue, where radiation-sensitive cells initiate arthritis (likely through internalization-dependent initiation of IFN-β) and radiation-resistant joint resident cells choreograph arthritis development through myostatin upregulation. Together, these findings suggest tantalizing new options for therapeutic intervention in Lyme arthritic patients: (1) blockade of IFN-β to only partially suppress the antiviral response, and (2) blockade of myostatin to correct dysregulated inflammation without interfering with conventional inflammatory pathways.