In a full and reciprocal collaboration with the laboratory of Ajit Varki, we have embarked on a series of interrelated projects that explore the role of the sugar sialic acid in microbial virulence and innate immunity. 

The single most extensively studied and widely appreciated virulence factor of GBS is its type-specific surface capsular polysaccharide (CPS). Human disease isolates are almost invariably encapsulated, and the CPS exerts important antiphagocytic properties through interference with normal host complement function.  The CPS is also the principal target of protective immunity against GBS.  A low level of maternal anticapsular IgG is a major risk factor for development of invasive GBS infection in the neonate.  The CPS structures of every identified GBS serotype (Ia, Ib, II – VIII) share in common a signature feature: a terminal a2Æ3-linked sialic acid [N-acetylneuraminic acid, Neu5Ac].  Sialic acids are a family of sugars present in abundance on the cell surface of all mammalian cells with important roles in biology, development, and evolution. It is the sialic acid moiety of the GBS that plays the key role in interfering with host complement activitation and opsonophagocytosis. We have recently discovered that many of the Neu5Ac residues of the native GBS capsule are O-acetylated, a major biochemical modification missed in previous studies. We have documented O-acetylation in the CPS of all GBS serotypes we have tested to date (Ia, Ib, II, III, V, and VI), and have used a molecular genetic approach to prove that O-acetylation occurs on free Neu5Ac during GBS CPS biosynthesis.


Interestingly, alpha2->3-linked, but non-O-acetylated, Neu5Ac residues are a common carbohydrate motif on the surface glycoproteins and glycolipids of all human cells. In immunologic terms, the presence of O-acetylation on the GBS capsule may represent a molecular feature allowing discrimination of pathogen from self.  Of equal importance, host sialic acids have been shown to play several key roles in cell-to-cell communication and of cellular function.  Mammalian leukocytes express on their surface sialic acid binding lectins that can mediate phagocytic uptake and modify patterns of inflammatory gene activation.  Sialic acid O-acetylation is known to have significant effects on the ability of the sugar to engage and activate these leukocyte receptors.  Given the multiple potential impacts of O-acetylation on host innate response, immunogenicity, and disease pathogenesis, we are currently reassessing several current concepts and approaches regarding GBS biology.

A key emerging concept in sialic acid biology is the function of Siglecs (Sialic acid-binding immunoglobulin superfamily lectins) – cell surface receptors mainly expressed by cells of the hematopoietic system.  Recognition of sialic acid by Siglecs is felt to play an important role in regulation of the innate immune system.  The CD-33 related Siglecs are notable for their terminal V-set domain that engages specific sialic acid epitopes, and its intracellular ITIM motif that represses gene expression of proinflammatory cytokines such as IL-8, IL-1alpha and TNFalpha .  In contrast, Siglec-1 (also known as sialoadhesin) is a unique receptor lacking the intracellular ITIM sequences and bearing a V-set domain that extends far from the host cell surface by virtue of 16 duplications of the C-2 set structural subunit.  We are using  a combined  bacterial and mammalian genetic approach to elucidate the roles of Siglecs in innate immune defense and the events that transpire when they encounter sialic acid-expressing bacteria such as GBS which may be using their sugar capsules as a form of molecular mimicry to avoid immune recognition.  Conversely, bacterial pathogens that elaborate sialidases (neuraminidases) could theoretically provoke unregulated immune activation as characteristic of septic shock.