Group B Streptococcus Engages an Inhibitory Siglec through Sialic Acid Mimicry to Blunt Innate Immune and Inflammatory Responses In Vivo

Group B Streptococcus (GBS) is a common agent of bacterial sepsis and meningitis in newborns. The GBS surface capsule contains sialic acids (Sia) that engage Sia-binding immunoglobulin-like lectins (Siglecs) on leukocytes. Here we use mice lacking Siglec-E, an inhibitory Siglec of myelomonocytic cells, to study the significance of GBS Siglec engagement during in vivo infection. We found GBS bound to Siglec-E in a Sia-specific fashion to blunt NF-B and MAPK activation. As a consequence, Siglec-E-deficient macrophages had enhanced pro-inflammatory cytokine secretion, phagocytosis and bactericidal activity against the pathogen. Following pulmonary or low-dose intravenous GBS challenge, Siglec-E KO mice produced more pro-inflammatory cytokines and exhibited reduced GBS invasion of the central nervous system. In contrast, upon high dose lethal challenges, cytokine storm in Siglec-E KO mice was associated with accelerated mortality. We conclude that GBS Sia mimicry influences host innate immune and inflammatory responses in vivo through engagement of an inhibitory Siglec, with the ultimate outcome of the host response varying depending upon the site, stage and magnitude of infection. Author Summary The bacterium Group B Streptococcus (GBS) causes serious infections such as meningitis in human newborn babies. The surface of GBS is coated with a capsule made of sugar molecules. Prominent among these is sialic acid (Sia), a human-like sugar that interacts with protein receptors called Siglecs on the surface of our white blood cells. In a test tube, GBS Sia binding to human Siglecs can suppress white blood cell activation, reducing their bacterial killing abilities; however, the significance of this during actual infection was unknown. To answer this question, we studied mice for which a key white blood cell Siglec has been genetically deleted. When infected with GBS, white blood cells from the mutant mice are not shut off by the pathogen's Sia-containing sugar capsule. The white blood cells from the Siglec-deficient mice are better at killing GBS and are able to clear infection more quickly than a normal mouse. However, if the mice are given an overwhelming dose of GBS bacteria, exaggerated white blood activation can trigger shock and more rapid death. These studies show how molecular mimicry of sugar molecules in the host can influence a bacterial pathogen's interaction with the immune system and the outcome of infection.