Sialic acids from the Group B Streptococcus (GBS) capsule dampen mast cell activation through Siglec-9

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Abstract GBS is a leading cause of bacterial infection in newborns, adult diabetics, pregnant women, and the elderly. A key virulence factor of GBS is its surface capsular polysaccharide, which displays terminal sialic acids that suppress host innate immune responses by engaging host inhibitory receptors like Sialic acid-binding immunoglobin-like lectin- 9 (Siglec-9). We reported that human mast cells (MC) express Siglec-9 and that engaging it with native ligands or antibodies results in reduced mast cell activation in vitro. We hypothesized that capsular sialic acids engage Siglec-9 to impair MC ability to initiate the host response. Mice expressing human Siglec -7 and -9 were infected with WT GBS or a sialic acid deficient strain, ΔcpsK, and the ΔcpsK infected mice showed reduced bacterial burden and less dissemination. Using bone marrow-cultured MC from a transgenic mouse expressing Siglec-9, we confirmed that GBS interacts with MC Siglec-9, which inhibited the release of the pro-inflammatory cytokine IL-6. Challenge of primary human MC with WT, ΔcpsK, or ΔneuA, another sialic acid deficient GBS strain, showed that MC interact more with ΔcpsK and ΔneuA GBS, and that MC kill sialic acid deficient GBS. MC challenged with ΔcpsK or ΔneuA GBS also produce more IL-8 and undergo cell death more than WT infected MC. Together, this data shows that sialylated GBS capsule engages MC Siglec-9 to dampen activation, which reduces the immune response and benefits the pathogen.

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