Role of macrophage sialoadhesin in host defense against the sialylated pathogen group B Streptococcus

Abstract

Several bacterial pathogens decorate their surfaces with sialic acid (Sia) residues within cell wall components or capsular exopolysaccharides. Sialic acid expression can promote bacterial virulence by blocking complement activation or by engagement of inhibitory sialic acid-binding immunoglobulin-like lectins (Siglecs) on host leukocytes. Expressed at high levels on splenic and lymph node macrophages, sialoadhesin (Sn) is a unique Siglec with an elongated structure that lacks intracellular signaling motifs. Sialoadhesin allows macrophage to engage certain sialylated pathogens and stimulate inflammatory responses, but the in vivo significance of sialoadhesin in infection has not been shown. We demonstrate that macrophages phagocytose the sialylated pathogen group B Streptococcus (GBS) and increase bactericidal activity via sialoadhesin-sialic-acid-mediated recognition. Sialoadhesin expression on marginal zone metallophillic macrophages in the spleen trapped circulating GBS and restricted the spread of the GBS to distant organs, reducing mortality. Specific IgM antibody responses to GBS challenge were also impaired in sialoadhesin-deficient mice. Thus, sialoadhesin represents a key bridge to orchestrate innate and adaptive immune defenses against invasive sialylated bacterial pathogens.Key messageSialoadhesin is critical for macrophages to phagocytose and clear GBS.Increased GBS organ dissemination in the sialoadhesin-deficient mice.Reduced anti-GBS IgM production in the sialoadhesin-deficient mice.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-014-1157-y) contains supplementary material, which is available to authorized users.

Siglec-mediated regulation of immune cell function in disease

“…Sialoadhesin also lacks intrinsic signaling motifs and has the potential to contribute to host defense via scavenging functions. Direct support for this was provided in an infection model of GBS, where bacteria injected intravenously were taken up by marginal zone macrophages expressing the gene encoding sialoadhesin ( Siglec1 ) 34 (Fig. 2d).…”

“…2). In contrast, certain Siglecs such as sialoadhesin and the DAP-12-coupled Siglec-14 can interact with pathogen sialic acids and promote host defense functions 7, 34, 35 . Here we discuss recent progress in understanding how Siglecs modulate immune responses to infections and consider the pathways by which sialylated pathogens can both subvert and promote immune responses through Siglec-dependent interactions.…”

Siglecs at the Host–Pathogen Interface

“…This receptor, uniquely expressed in the marginal metallophilic and subcapsular sinus macrophages, recognizing the same key Sia epitope on the GBS surface, however lacks an intracellular ITM motif (Crocker and Gordon 1989;Crocker et al 1994). Siglec-1 binding to GBS CPS Sia promoted phagocytic and bactericidal activity of macrophages in vitro and restricts GBS dissemination in vivo (Chang et al 2014b). Loss of Siglec-1 expression not only affected the macrophage sampling and trapping capabilities but also the production of anti-GBS antibodies, suggesting a key role in optimization of antigen presentation and subsequent adaptive immune response against sialylated pathogens (Chang et al 2014b).…”

Glycans and glycan-binding proteins in immune regulation: A concise introduction to glycobiology for the allergist

“…In response to intravenous injection of GBS, wild type mice effectively cleared the pathogen into secondary lymphoid tissue macrophages, whereas mice lacking Siglec-1 suffered increased pathogen dissemination and decreased survival. 45 Likewise, injected C. jejuni were more effectively cleared into spleen macrophages in wild type compared to mice lacking functional Siglec-1, and capture was accompanied by a robust proinflammatory response. 46 …”