Lectin site interaction with capsular polysaccharide mediates nonimmune phagocytosis of type III group B streptococci.

Group B Streptococcus (GBS) has been a leading cause of neonatal sepsis and meningitis since the 1970s. In the 1990s the incidence ranged from 0.5 to 3 cases per 1,000 live births (31). Despite advances in neonatal intensive care and antimicrobial therapy, case fatality ratios remain 4 to 6% for cases identified by population-based surveillance (30). A substantial burden of GBS-related illness occurs among nonpregnant adults, and the case fatality rate is 32% in this population (30). Those with immunocompromising conditions such as diabetes mellitus, renal failure, cirrhosis, and cancer are at particular risk for developing invasive infection. This ongoing disease burden highlights the importance of defining further the pathogenesis and immune response to GBS with the goal of formulating effective intervention strategies. The innate immune response is critical to host defense. This is particularly evident early in the host-pathogen encounter when specific immunity has not yet developed (10). Several pathogens express surface domains that are recognized by and activate host phagocytic cells in the absence of specific antibody (25). These interactions have been shown to have a role in the phagocytosis of Pseudomonas aeruginosa, Escherichia coli, Neisseria meningitidis, mycobacteria, and yeasts, among others (6, 9, 11, 17, 22). Complement receptor 3 (CR3, also known as CD11b/CD18, or Mac-1) is a β2 integrin expressed on the plasma membrane of mammalian polymorphonuclear neutrophils (PMN), most mononuclear phagocytes, and NK cells, and it has the ability to recognize multiple ligands. CR3 possesses an I-domain that binds inactivated C3b (iC3b), intracellular adhesion molecule 1 (ICAM-1), and numerous extracellular matrix proteins (5). It also possesses a lectin site with the capacity to bind certain saccharides, such as β-glucans and those containing N-acetyl d-glucosamine (NADG) (27, 32, 35, 44). Engagement of the CR3 lectin site results in priming of CR3-expressing PMN for cytotoxicity of iC3b-opsonized targets in the absence of specific antibody (36). Thus, the engagement of this site is required for the full activation of CR3. This occurs by a two-step process whereby iC3b-opsonized particles bind to CR3 via the I-domain and a polysaccharide, either exogenous or intrinsic to the opsonized particle, engages the lectin site. The capsular polysaccharide (CPS) of type III GBS consists of repeating units of glucose, galactose, NADG, and N-acetyl neuraminic acid. The molar ratios and tertiary configuration vary, but the CPSs of GBS serotypes Ia, Ib, II, III, and V all are comprised of a backbone and one or more side chains containing these four sugars (13, 15, 39, 40, 42). In the presence of complement, GBS III CPS-specific antibody optimizes opsonophagocytosis of type III GBS in vitro and protects against invasive infection in young infants (3, 7). Participation by PMN CR1 and CR3 as well as Fcγ receptor II (FcγRII) and FcγRIII mediates these phagocytic interactions. However, opsonophagocytosis of type III GBS can occur in the setting of a deficiency of CPS-specific immunoglobulin G (IgG) (7), and GBS can activate C3 and deposit iC3b in the absence of antibody (2). Furthermore, a majority of newborn infants exposed to a GBS-colonized mother at birth do not develop invasive disease in the face of low concentrations of CPS-specific antibody in serum. Based on the known saccharide-binding properties of the CR3 lectin site and the defined structure of the CPS of type III GBS, we hypothesized that in nonimmune sera engagement of the CR3 lectin site by GBS CPS would be an effective trigger to phagocytosis and killing of these organisms. We found that type III GBS triggers phagocytosis and killing by binding to the lectin site of CR3 and that type III GBS-specific CPS is a ligand for this interaction. In the presence of a sufficient concentration of type III GBS CPS-specific IgG, use of the lectin site is not required. There were differences among GBS serotypes in use of the lectin site that related to differences in the structures of these polysaccharides. Taken together, interactions of GBS CPS with the CR3 lectin site serves as an important arm of the innate immune response in the susceptible host. (This work was presented in abstract format at the 36th Annual Meeting of the Infectious Diseases Society of America, Denver, Colo., in November 1998 [abstr. #121].)