{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T17:15:39Z","timestamp":1787764539875,"version":"build-2784847793"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013324","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000}}],"reference-count":113,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T00:00:00Z","timestamp":1751846400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"James D. Jamieson and Family M.D.-Ph.D. Scholarship Fund"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM007205"],"award-info":[{"award-number":["GM007205"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Stanford Bio-X Interdisciplinary Initiatives Seed Grants Program","award":["R10-9"],"award-info":[{"award-number":["R10-9"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM138599"],"award-info":[{"award-number":["R01GM138599"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Younger Family"},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>The spirochete <jats:italic>Borrelia burgdorferi<\/jats:italic> causes Lyme disease. In some patients, an excessive, dysregulated proinflammatory immune response can develop in joints leading to persistent arthritis even after antibiotic therapy. In such patients, persistence of antigenic <jats:italic>B. burgdorferi<\/jats:italic> peptidoglycan (PG<jats:sup>Bb<\/jats:sup>) fragments within joint tissues may contribute to immunopathogenesis pre- and post-antibiotic treatment. In live <jats:italic>B. burgdorferi<\/jats:italic> cells, the outer membrane shields the polymeric PG<jats:sup>Bb<\/jats:sup> sacculus from exposure to the immune system. However, unlike most diderm bacteria, <jats:italic>B. burgdorferi<\/jats:italic> releases PG<jats:sup>Bb<\/jats:sup> turnover products into its environment due to the absence of recycling activity. In this study, we identified the released PG<jats:sup>Bb<\/jats:sup> fragments using a mass spectrometry-based approach. By characterizing the <jats:sc>l<\/jats:sc>,<jats:sc>d<\/jats:sc>-carboxypeptidase activity of <jats:italic>B. burgdorferi<\/jats:italic> protein BB0605 (renamed DacA), we found that PG<jats:sup>Bb<\/jats:sup> turnover largely occurs at sites of PG<jats:sup>Bb<\/jats:sup> synthesis. In parallel, we demonstrated that the lytic transglycosylase activity associated with BB0259 (renamed MltS) releases PG<jats:sup>Bb<\/jats:sup> fragments with 1,6-anhydro bond on their <jats:italic>N<\/jats:italic>-acetylmuramyl residues. Stimulation of human cell lines with various synthetic PG<jats:sup>Bb<\/jats:sup> fragments revealed that 1,6-anhydromuramyl-containing PG<jats:sup>Bb<\/jats:sup> fragments are poor inducers of a NOD2-dependent immune response relative to their hydrated counterparts found in the polymeric PG<jats:sup>Bb<\/jats:sup> isolated from dead bacteria. We also showed that the activity of the human <jats:italic>N<\/jats:italic>-acetylmuramyl-<jats:sc>l<\/jats:sc>-alanine amidase PGLYRP2, which reduces the immunogenicity of PG<jats:sup>Bb<\/jats:sup> material, is low in joint (synovial) fluids relative to serum. Altogether, our findings suggest that MltS activity helps <jats:italic>B. burgdorferi<\/jats:italic> evade PG-based immune detection by NOD2 during growth despite shedding PG<jats:sup>Bb<\/jats:sup> fragments and that PG<jats:sup>Bb<\/jats:sup>-induced immunopathology likely results from host sensing of PG<jats:sup>Bb<\/jats:sup> material from dead (lysed) spirochetes. Additionally, our results suggest the possibility that natural variation in PGLYRP2 activity may contribute to differences in susceptibility to PG-induced inflammation across tissues and individuals.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013324","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T14:20:07Z","timestamp":1751898007000},"page":"e1013324","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Bacterial and host enzymes modulate the pro-inflammatory response elicited by the peptidoglycan of Lyme disease agent Borrelia burgdorferi"],"prefix":"10.1371","volume":"21","author":[{"given":"Joshua W.","family":"McCausland","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary 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