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Among these, <jats:italic>Listeria monocytogenes<\/jats:italic> (<jats:italic>Lm<\/jats:italic>) stands out as a key pathogen, responsible for often fatal neurolisteriosis in humans and cattle. Emerging evidence highlights the distinct roles played by microglia, the resident macrophages of the CNS, and infiltrating monocyte-derived macrophages (MDM) during neuroinflammation. Using bovine models, we investigated the interactions between these two macrophage populations and <jats:italic>Lm<\/jats:italic> during infection. Our results show that <jats:italic>Lm<\/jats:italic> thrives in the cytosol of microglia, driving productive infection and facilitating bacterial spread. In contrast, MDM effectively sequesters <jats:italic>Lm<\/jats:italic> within the phagolysosomal system, limiting its replication and inducing a viable but non-culturable (VBNC) state without completely eliminating the pathogen. Listeriolysin O contributes to the dichotomy of <jats:italic>Lm<\/jats:italic> fate, determining whether <jats:italic>Lm<\/jats:italic> escapes into the cytosol or transitions to the VBNC state. These findings underscore the complexity of <jats:italic>Lm<\/jats:italic>-host dynamics in neurolisteriosis, emphasizing the distinct yet complementary roles of microglia and MDM in shaping CNS infection. By elucidating these mechanisms, our study offers new perspectives on the neurolisteriosis pathogenesis and opens avenues for innovative therapeutic approaches to combat bacterial neuroinfections.<\/jats:p>","DOI":"10.1007\/s00401-025-02900-8","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T12:10:08Z","timestamp":1750075808000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Divergent host\u2013pathogen interactions in neurolisteriosis: cytosolic replication vs. phagosomal dormancy of\u00a0Listeria monocytogenes\u00a0in CNS macrophages"],"prefix":"10.1007","volume":"149","author":[{"given":"Leticia","family":"Tavares-Gomes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margherita","family":"Polidori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camille","family":"Monney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00e9raldine","family":"Neuhaus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatriz","family":"Vidondo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guillaume","family":"Witz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Hemphill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Oevermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,6,16]]},"reference":[{"key":"2900_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.plasmid.2015.05.003","volume":"81","author":"H Abdelhamed","year":"2015","unstructured":"Abdelhamed H, Lawrence ML, Karsi A (2015) A novel suicide plasmid for efficient gene mutation in Listeria monocytogenes. 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