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PG is a microbe-associated molecular pattern (MAMP) and two of its major pattern recognition receptors in human cells are nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1 and NOD2, respectively). It has been proposed that this unique morphological feature is evidence of pathoadaptation by the microbe, permitting PG-dependent cell division while also reducing the bacterium\u2019s recognition by innate immune receptors.\n                  <jats:italic>Chlamydia trachomatis<\/jats:italic>\n                  -infected cells activate NOD1 signaling within 8-12 hours of exposure to the bacterium, roughly coinciding with the microbe\u2019s transition from its infectious to replicative forms. Here we report that, unlike NOD1 signaling,\n                  <jats:italic>Chlamydia<\/jats:italic>\n                  -induced NOD2 signaling does not occur until later in the pathogen\u2019s developmental cycle. Both\n                  <jats:italic>C. trachomatis<\/jats:italic>\n                  and the related murine pathogen\n                  <jats:italic>Chlamydia muridarum<\/jats:italic>\n                  signal late in infection in HEK293 reporter cell lines expressing either human or murine-derived NOD2 receptors. NOD2 signaling can be modulated by disruption of the chlamydial amidase enzyme, AmiA\n                  <jats:sub>CT<\/jats:sub>\n                  , interrupting the microbe\u2019s developmental cycle, and treatment with inhibitors of lipooligosaccharide or peptidoglycan biosynthesis \/ assembly. These results mirror prior observations with Chlamydia-induced TLR9 signaling, leading us to hypothesize that Chlamydia-induced NOD2 signaling results from lytic events that occur sporadically during the transition between the pathogen\u2019s developmental forms. Given our finding that pre-treating cells with NOD2-stimulatory ligands reduces chlamydial inclusion size and delays the developmental cycle, we hypothesize that the microbe preferentially degrades its PG during development to reduce the generation of NOD2 ligands.\n                <\/jats:p>","DOI":"10.1101\/2025.05.28.656691","type":"posted-content","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T17:30:16Z","timestamp":1748626216000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>Chlamydia trachomatis<\/i>\n                  restricts signaling through NOD2 until late in the pathogen\u2019s developmental cycle"],"prefix":"10.64898","author":[{"given":"Grace","family":"Overman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Loeckener","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Williford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aissata","family":"Diallo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josie","family":"Blair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Henrichfreise","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3028-8474","authenticated-orcid":false,"given":"George W.","family":"Liechti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025100709150871000_2025.05.28.656691v2.1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0143304"},{"key":"2025100709150871000_2025.05.28.656691v2.2","unstructured":"Organization, W. 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