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These outcomes are largely driven by an excessive yet ineffective neuroinflammatory response. Although pneumococci express multiple virulence factors that enable immune evasion, how these factors modulate phagocytic responses in the central nervous system remains unclear. Here, we identify neuraminidase A (NanA) as a critical regulator of phagocytic activation in microglia and macrophages. Using murine and human microglia and RAW 264.7 macrophages, we show that NanA deficiency increases bacterial adhesion, indicating enhanced immune recognition, but paradoxically promotes intracellular bacterial survival. Despite elevated expression of the phagocytic marker CD68, microglia infected with NanA-deficient pneumococci fail to efficiently eliminate intracellular bacteria, as evidenced by unchanged levels of the lysosomal enzyme cathepsin 3 compared with NanA-expressing strains. Treatment with recombinant NanA restored phagocytic activation and significantly enhanced clearance of NanA-deficient bacteria. This effect was dependent on NanA sialidase activity, as enzymatically inactive NanA failed to restore immune sensing. Notably, this immunomodulatory function was specific to the secreted form of NanA produced by the invasive TIGR4 strain and was not observed with membrane-anchored NanA from D39-derived mutants. Together, these findings reveal an unexpected role for NanA in promoting effective innate immune activation and bacterial clearance, highlighting its potential as a therapeutic target for pneumococcal meningitis and invasive pneumococcal disease.<\/jats:p>","DOI":"10.1093\/immadv\/ltag002","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T12:39:14Z","timestamp":1770295154000},"source":"Crossref","is-referenced-by-count":2,"title":["Neuraminidase A controls pneumococcal recognition and fate: deficiency enhances immune sensing and intracellular survival, while treatment promotes phagocytic clearance."],"prefix":"10.1093","volume":"6","author":[{"given":"Kristine","family":"Farmen","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Karolinska Institutet, Biomedicum , Solna ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Yfanti","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Karolinska Institutet, Biomedicum , Solna ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabienne","family":"Geers","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Karolinska Institutet, Biomedicum , Solna ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Hollenbeck","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Karolinska Institutet, Biomedicum , Solna ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Tofi\u00f1o Vian","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Karolinska Institutet, Biomedicum , Solna ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas P","family":"Kohler","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Infection Biology, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald , Greifswald ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Hammerschmidt","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Infection Biology, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald , Greifswald ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5249-9120","authenticated-orcid":false,"given":"Federico","family":"Iovino","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, 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