Abstract
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.
Highlights
Gonorrhea is a sexually transmitted disease that poses a major global health problem, with about 78 million estimated infections worldwide in 2012 (Newman et al, 2015)
We explore the impact of sialic acid‐binding immuno‐ globulin superfamily lectins (Siglecs) polymorphisms in a population at high risk of gonorrhea
We focused on Siglecs 3, 5, 9, 11, 14, and 16, which are prominent ex‐ amples of Siglecs expressed by phagocytes and/or epithelial cells that are relevant to gonococcal infection in humans
Summary
Gonorrhea is a sexually transmitted disease that poses a major global health problem, with about 78 million estimated infections worldwide in 2012 (Newman et al, 2015) This disease is caused by Neisseria gonorrhoeae, a Gram‐negative bacterium that exclusively infects humans. Inhibitory effects are driven by ITIM motifs in Siglec intracellular domains, which recruit SHP phosphatases and quench pro‐inflammatory sig‐ naling cascades. This property is subverted by pathogens to control host immune responses and escape elimination. The adaptor pro‐ teins contain ITAM motifs that recruit Syk kinase, which induces a pro‐inflammatory signaling cascade (Lanier, 2009) It has been sug‐ gested that activating Siglecs represent evolutionary responses to microbes exploiting inhibitory Siglecs. We explore the impact of Siglec polymorphisms in a population at high risk of gonorrhea
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