Forward genetic approaches for elucidation of novel regulators of Lyme arthritis severity

Abstract

Patients experiencing natural infection with Borrelia burgdorferi display a spectrum of associated symptoms and severity, strongly implicating the impact of genetically determined host factors in the pathogenesis of Lyme disease. Herein, we provide a summary of the host genetic factors that have been demonstrated to influence the severity and chronicity of Lyme arthritis symptoms, and a review of the resources available, current progress, and added value of a forward genetic approach for identification of novel genetic regulators.

Generality of Post-Antimicrobial Treatment Persistence of Borrelia burgdorferi Strains N40 and B31 in Genetically Susceptible and Resistant Mouse Strains

“…C3H/HeJ mice are susceptible to infection by Gram-negative bacteria as a result of spontaneous mutation in the Tlr4 gene (89). It has been demonstrated that C3H mice develop more severe arthritis and carditis following B. burgdorferi infection than B6 mice (90). B6 mice harbor tissue spirochete burdens equivalent to those of C3H mice, become persistently infected, and have normal macrophage function (89).…”

β-Glucuronidase, a Regulator of Lyme Arthritis Severity, Modulates Lysosomal Trafficking and MMP-9 Secretion in Response to Inflammatory Stimuli

“…We previously identified an increased extracellular GAG deposition, visualized histochemically with Alcian blue staining, and localized inflammation following B. burgdorferi infection in severely Gusb deficient mice on a B6 genetic background ( Gusb Null ) and several Gusb hypomorphic strains (6, 10). The previously described runted growth and spontaneous rheumatologic abnormalities of Gusb Null mice suggest that the presence of excess partially degraded GAGs may be responsible for a shared disease process underlying both pathologies (11).…”

Lyme disease: recent advances and perspectives

“…Pratt and Brown review the role of eicosanoids as important mediators of arthritis (Pratt and Brown, 2014 ). Also, Bramwell et al review the challenges of genome wide association studies for studying complex genetic traits in humans and the power of forward genetic approaches in model animals leading to the identification of genetic loci responsible for arthritis severity phenotypes (Bramwell et al, 2014 ). Finally, in a research paper, Belperron et al present data that implicate the FcRY receptor as an important contributor to acute phase Lyme arthritis (Belperron et al, 2014 ).…”