TY - JOUR T1 - Dual actions of group B <em>Streptococcus</em> capsular sialic acid provide resistance to platelet-mediated antimicrobial killing JF - Proceedings of the National Academy of Sciences JO - Proc Natl Acad Sci USA SP - 7465 LP - 7470 DO - 10.1073/pnas.1815572116 VL - 116 IS - 15 AU - Uchiyama, Satoshi AU - Sun, Josh AU - Fukahori, Kyoko AU - Ando, Nao AU - Wu, Mengyou AU - Schwarz, Flavio AU - Siddiqui, Shoib S. AU - Varki, Ajit AU - Marth, Jamey D. AU - Nizet, Victor Y1 - 2019/04/09 UR - //www.hmclip.net/content/116/15/7465.abstract N2 - Platelets have an important role in blood clotting, but also function in immune responses, including the release of antimicrobial peptides that eliminate pathogens such as Staphylococcus aureus. Here we observe that group B Streptococcus (GBS), a leading cause of sepsis and meningitis in human newborns, is not killed by platelets. The key to GBS platelet resistance is a polysaccharide capsule that coats the bacterial surface and contains sialic acid (Sia), a common sugar present on all human cells. GBS Sia blocks platelet-derived antimicrobial factors, and also engages an inhibitory receptor (Siglec-9) on the platelet surface to block platelet activation. Platelet resistance is a novel consequence of GBS 鈥渕olecular mimicry鈥?of its host and contributes to its propensity to produce bloodstream infection.Circulating platelets have important functions in thrombosis and in modulating immune and inflammatory responses. However, the role of platelets in innate immunity to bacterial infection is largely unexplored. While human platelets rapidly kill Staphylococcus aureus, we found the neonatal pathogen group B Streptococcus (GBS) to be remarkably resistant to platelet killing. GBS possesses a capsule polysaccharide (CPS) with terminal 伪2,3-linked sialic acid (Sia) residues that mimic a common epitope present on the human cell surface glycocalyx. A GBS mutant deficient in CPS Sia was more efficiently killed by human platelets, thrombin-activated platelet releasate, and synthetic platelet-associated antimicrobial peptides. GBS Sia is known to bind inhibitory Sia-recognizing Ig superfamily lectins (Siglecs) to block neutrophil and macrophage activation. We show that human platelets also express high levels of inhibitory Siglec-9 on their surface, and that GBS can engage this receptor in a Sia-dependent manner to suppress platelet activation. In a mouse i.v. infection model, antibody-mediated platelet depletion increased susceptibility to platelet-sensitive S. aureus but did not alter susceptibility to platelet-resistant GBS. Elimination of murine inhibitory Siglec-E partially reversed platelet suppression in response to GBS infection. We conclude that GBS Sia has dual roles in counteracting platelet antimicrobial immunity: conferring intrinsic resistance to platelet-derived antimicrobial components and inhibiting platelet activation through engagement of inhibitory Siglecs. We report a bacterial virulence factor for evasion of platelet-mediated innate immunity. ER -
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