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

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Title Genetic and mechanistic analyses of type I interferon-driven lyme arthritis
Publication Type dissertation
School or College School of Medicine
Department Pathology
Author Paquette, Jacqueline Kaylah
Date 2017-08
Description 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.
Type Text
Publisher University of Utah
Subject MESH Borrelia burgdorferi; Borrelia Infections; Lyme Disease; Phenotype; Interferon Type I; Interferon-beta; Mice, Inbred Strains; Myostatin; Myeloid Cells; Chemokines; Arthralgia; Chronic Disease; Severity of Illness Index
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital version of Genetic and Mechanistic Analyses of Type I Interferon-Driven Lyme Arthritis
Rights Management Copyright © Jacqueline Kaylah Paquette 2017
Format application/pdf
Format Medium application/pdf
Source Original in Marriott Library Special Collections
ARK ark:/87278/s6546szs
Setname ir_etd
ID 1348633
Reference URL https://collections.lib.utah.edu/ark:/87278/s6546szs
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