The unusual peptidoglycan cell wall of Borrelia burgdorferi and it’s role in Lyme disease pathogenesis

Abstract Borrelia burgdorferi — the Lyme disease agent — does not produce typical bacterial proinflammatory compounds, so the genesis of Lyme arthritis (LA) is largely unknown. To better understand this manifestation, we’ve begun investigating B. burgdorferi peptidoglycan (PG). PG is a large polymer that protects bacteria from various stressors. While most double-membraned bacteria recycle PG fragments during cell wall turnover, B. burgdorferi lack this pathway, instead releasing ~45% of their total PG into their host per generation. Released PG can interact with the immune system as a pathogen associated molecular pattern (PAMP). To that end, we discovered PG lingers in the synovial fluid of LA patients and PG, alone, can cause arthritis in a mouse model. Virtually all bacteria produce PG, but the chemical composition of B. burgdorferi PG is unlike any previously described. We hypothesize the unique chemical structure of B. burgdorferi PG, coupled with shedding, impact host immune responses, and contribute to cell wall half-life and LA pathogenesis. To study this relationship, we developed an in vivo imaging system to track the real-time biodistribution of B. burgdorferi PG in mice. Our results suggest certain organs act as reservoirs, retaining material well after arthritis resolution. Apart from half-life, transcriptomic studies reveal that B. burgdorferi PG induces unique immunological responses in human PBMCs, that appear to be dictated by PG chemistry. Our findings provide a fundamental basis for understanding the complex interplay between a unique PAMP and a host, in addition to deciphering the role of the B. burgdorferi cell wall in Lyme disease pathogenesis, results that may lead to new therapeutic approaches to alleviate LA symptoms. Supported by grants from NIH (R21 AI159800), USDA (VA-160113), the Steven & Alexandra Cohen Foundation, and the Bay Area Lyme Foundation