Neisseria gonorrhoeae causes the
sexually transmitted disease gonorrhea exclusively in humans and uses multiple strategies to infect, including acquisition of host
sialic acids that cap and mask lipooligosaccharide termini, while restricting complement activation. We hypothesized that gonococci selectively target human anti-inflammatory
sialic acid-recognizing
Siglec receptors on innate immune cells to blunt host responses and that pro-inflammatory
Siglecs and
SIGLEC pseudogene polymorphisms represent host evolutionary adaptations to counteract this interaction. N. gonorrhoeae can indeed engage multiple human but not chimpanzee CD33rSiglecs expressed on innate immune cells and in the genitourinary tract--including Siglec-11 (inhibitory) and Siglec-16 (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-specific manner. Lastly, we studied the distribution of null
SIGLEC polymorphisms in a Namibian cohort with a high prevalence of
gonorrhea and found that uninfected women preferentially harbor functional SIGLEC16 alleles encoding an activating immune receptor. These results contribute to the understanding of the human specificity of N. gonorrhoeae and how it evolved to evade the human immune defense.