{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T02:03:50Z","timestamp":1789697030699,"version":"4.0.1"},"posted":{"date-parts":[[2025,1,8]]},"group-title":"Microbiology","reference-count":118,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T00:00:00Z","timestamp":1736294400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["T32 GM007205"],"award-info":[{"award-number":["T32 GM007205"]}]},{"name":"National Institutes of Health","award":["R01GM138599"],"award-info":[{"award-number":["R01GM138599"]}]},{"name":"Stanford Bio-X Interdisciplinary Initiatives Seed Grants Program","award":["R10-9"],"award-info":[{"award-number":["R10-9"]}]},{"id":[{"id":"https:\/\/ror.org\/006w34k90","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,31]]},"abstract":"<jats:p>\n                  The spirochete\n                  <jats:italic>Borrelia burgdorferi<\/jats:italic>\n                  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\n                  <jats:italic>B. burgdorferi<\/jats:italic>\n                  peptidoglycan (PG\n                  <jats:sup>Bb<\/jats:sup>\n                  ) fragments within joint tissues may contribute to immunopathogenesis pre- and post-antibiotic treatment. In live\n                  <jats:italic>B. burgdorferi<\/jats:italic>\n                  cells, the outer membrane shields the polymeric PG\n                  <jats:sup>Bb<\/jats:sup>\n                  sacculus from exposure to the immune system. However, unlike most diderm bacteria,\n                  <jats:italic>B. burgdorferi<\/jats:italic>\n                  releases PG\n                  <jats:sup>Bb<\/jats:sup>\n                  turnover products into its environment due to the absence of recycling activity. In this study, we identified the released PG\n                  <jats:sup>Bb<\/jats:sup>\n                  fragments using a mass spectrometry-based approach. By characterizing the L,D-carboxypeptidase activity of\n                  <jats:italic>B. burgdorferi<\/jats:italic>\n                  protein BB0605 (renamed DacA), we found that PG\n                  <jats:sup>Bb<\/jats:sup>\n                  turnover largely occurs at sites of PG\n                  <jats:sup>Bb<\/jats:sup>\n                  synthesis. In parallel, we demonstrated that the lytic transglycosylase activity associated with BB0259 (renamed MltS) releases PG\n                  <jats:sup>Bb<\/jats:sup>\n                  fragments with 1,6-anhydro bond on their\n                  <jats:italic>N<\/jats:italic>\n                  -acetylmuramyl residues. Stimulation of human cell lines with various synthetic PG\n                  <jats:sup>Bb<\/jats:sup>\n                  fragments revealed that 1,6-anhydromuramyl-containing PG\n                  <jats:sup>Bb<\/jats:sup>\n                  fragments are poor inducers of a NOD2-dependent immune response relative to their hydrated counterparts found in the polymeric PG\n                  <jats:sup>Bb<\/jats:sup>\n                  isolated from dead bacteria. We also showed that the activity of the human\n                  <jats:italic>N<\/jats:italic>\n                  -acetylmuramyl-L-alanine amidase PGLYRP2, which reduces the immunogenicity of PG\n                  <jats:sup>Bb<\/jats:sup>\n                  material, is low in joint (synovial) fluids relative to serum. Altogether, our findings suggest that MltS activity helps\n                  <jats:italic>B. burgdorferi<\/jats:italic>\n                  evade PG-based immune detection by NOD2 during growth despite shedding PG\n                  <jats:sup>Bb<\/jats:sup>\n                  fragments and that PG\n                  <jats:sup>Bb<\/jats:sup>\n                  -induced immunopathology likely results from host sensing of PG\n                  <jats:sup>Bb<\/jats:sup>\n                  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.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Author summary<\/jats:title>\n                  <jats:p>\n                    During bacterial infection, the presence of peptidoglycan\u2013 a polymeric element of bacterial cell walls\u2013triggers a host inflammatory response. Although generally protective during acute phases, inflammation, when chronic, can contribute to disease development. Recent work has suggested that the persistence of pro-inflammatory peptidoglycan derived from the Lyme disease spirochete\n                    <jats:italic>Borrelia burgdorferi<\/jats:italic>\n                    in joints may contribute to persistent arthritis in some patients despite appropriate antibiotic therapy. Interestingly,\n                    <jats:italic>B. burgdorferi<\/jats:italic>\n                    sheds peptidoglycan turnover products into the environment during growth. Here, we show that these shed products from live spirochetes are poor effectors of an immune response by the human NOD2 immune receptor due to the formation of an anhydro bond on the\n                    <jats:italic>N<\/jats:italic>\n                    -acetyl-muramic residue during peptidoglycan hydrolysis by a\n                    <jats:italic>B. burgdorferi<\/jats:italic>\n                    lytic transglycosylase. We also show that human\n                    <jats:italic>N<\/jats:italic>\n                    -acetylmuramyl-L-alanine amidase activity, which abrogates the NOD2-dependent response to the immunogenic peptidoglycan isolated from lysed\n                    <jats:italic>B. burgdorferi<\/jats:italic>\n                    cells, is low in human joint fluids relative to serum. Based on our findings, we propose that immunopathogenesis by peptidoglycan material more likely derives from lysed spirochetes (killed by an immune attack or antibiotics) than live ones and that the level of human peptidoglycan hydrolytic enzymes across tissues and individuals influences susceptibility to chronic inflammation.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.01.08.631998","type":"posted-content","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T03:45:29Z","timestamp":1736394329000},"source":"Crossref","is-referenced-by-count":4,"title":["Bacterial and host enzymes modulate the inflammatory response produced by the peptidoglycan of the Lyme disease agent"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6585-0506","authenticated-orcid":false,"given":"Joshua W.","family":"McCausland","sequence":"first","affiliation":[{"name":"Sarafan ChEM-H Institute, Stanford University, Stanford, CA, USA"},{"name":"Department of Biology, Stanford University, Stanford, CA, USA"},{"name":"Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8273-5830","authenticated-orcid":false,"given":"Zachary A.","family":"Kloos","sequence":"additional","affiliation":[{"name":"Microbiology Program, Yale University, West Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8631-4075","authenticated-orcid":false,"given":"Irnov","family":"Irnov","sequence":"additional","affiliation":[{"name":"Sarafan ChEM-H Institute, Stanford University, Stanford, CA, USA"},{"name":"Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2781-4675","authenticated-orcid":false,"given":"Nicole D.","family":"Sonnert","sequence":"additional","affiliation":[{"name":"Microbiology Program, Yale University, West Haven, Connecticut, USA"},{"name":"Department of Immunology, Yale University School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhui","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Delaware, Neward, DE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Putnick","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Delaware, Neward, DE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5482-6551","authenticated-orcid":false,"given":"Elizabeth A.","family":"Mueller","sequence":"additional","affiliation":[{"name":"Sarafan ChEM-H Institute, Stanford University, Stanford, CA, USA"},{"name":"Department of Biology, Stanford University, Stanford, CA, USA"},{"name":"Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5268-9853","authenticated-orcid":false,"given":"Allen C.","family":"Steere","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7262-9455","authenticated-orcid":false,"given":"Noah W.","family":"Palm","sequence":"additional","affiliation":[{"name":"Department of Immunology, Yale University School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0586-2879","authenticated-orcid":false,"given":"Catherine L.","family":"Grimes","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Delaware, Neward, DE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0980-5334","authenticated-orcid":false,"given":"Christine","family":"Jacobs-Wagner","sequence":"additional","affiliation":[{"name":"Sarafan ChEM-H Institute, Stanford University, Stanford, CA, USA"},{"name":"Department of Biology, Stanford University, Stanford, CA, USA"},{"name":"Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091718450852000_2025.01.08.631998v2.1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm7306a1"},{"key":"2026091718450852000_2025.01.08.631998v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.idc.2015.02.010"},{"key":"2026091718450852000_2025.01.08.631998v2.3","doi-asserted-by":"crossref","unstructured":"Mead PS , Schwartz A. 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