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We hypothesized that gonococci selectively target human anti\u2010inflammatory sialic acid\u2010recognizing Siglec receptors on innate immune cells to blunt host responses and that pro\u2010inflammatory Siglecs and <jats:italic>SIGLEC<\/jats:italic> pseudogene polymorphisms represent host evolutionary adaptations to counteract this interaction. <jats:italic>N.\u00a0gonorrhoeae<\/jats:italic> can indeed engage multiple human but not chimpanzee CD33rSiglecs expressed on innate immune cells and in the genitourinary tract\u2013\u2013including Siglec\u201011 (inhibitory) and Siglec\u201016 (activating), which we detected for the first time on human cervical epithelium. Surprisingly, in addition to LOS sialic acid, we found that gonococcal porin (PorB) mediated binding to multiple Siglecs. PorB also bound preferentially to human Siglecs and not chimpanzee orthologs, modulating host immune reactions in a human\u2010specific manner. Lastly, we studied the distribution of null <jats:italic>SIGLEC <\/jats:italic>polymorphisms in a Namibian cohort with a high prevalence of gonorrhea and found that uninfected women preferentially harbor functional <jats:italic>SIGLEC16<\/jats:italic> alleles encoding an activating immune receptor. These results contribute to the understanding of the human specificity of <jats:italic>N.\u00a0gonorrhoeae <\/jats:italic>and how it evolved to evade the human immune defense.<\/jats:p>","DOI":"10.1111\/eva.12744","type":"journal-article","created":{"date-parts":[[2018,12,4]],"date-time":"2018-12-04T12:39:05Z","timestamp":1543927145000},"page":"337-349","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Evolution of the exclusively human pathogen <i>Neisseria gonorrhoeae<\/i>: Human\u2010specific engagement of immunoregulatory Siglecs"],"prefix":"10.1111","volume":"12","author":[{"given":"Corinna S.","family":"Landig","sequence":"first","affiliation":[{"name":"Glycobiology Research and Training Center University of California, San Diego La Jolla California"},{"name":"Department of Cellular and Molecular Medicine University of California, San Diego La Jolla California"},{"name":"Department of Medicine University of 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