Heparan Sulfate Proteoglycans in Infection

To cause infections, microbial pathogens elaborate a multitude of factors that interact with host components. Using these host–pathogen interactions to their advantage, pathogens attach, invade, disseminate, and evade host defense mechanisms to promote their survival in the hostile host environment. Many viruses, bacteria, and parasites express adhesins that bind to cell surface heparan sulfate proteoglycans (HSPGs) to facilitate their initial attachment and subsequent cellular entry. Some pathogens also secrete virulence factors that modify HSPG expression. HSPGs are ubiquitously expressed on the cell surface of adherent cells and in the extracellular matrix. HSPGs are composed of one or several heparan sulfate (HS) glycosaminoglycan chains attached covalently to specific core proteins. For most intracellular pathogens, cell surface HSPGs serve as a scaffold that facilitates the interaction of microbes with secondary receptors that mediate host cell entry. Consistent with this mechanism, addition of HS or its pharmaceutical functional mimic, heparin, inhibits microbial attachment and entry into cultured host cells, and HS-binding pathogens can no longer attach or enter cultured host cells whose HS expression has been reduced by enzymatic treatment or chemical mutagenesis. In pathogens where the specific HS adhesin has been identified, mutant strains lacking HS adhesins are viable and show normal growth rates, suggesting that the capacity to interact with HSPGs is strictly a virulence activity. The goal of this chapter is to provide a mechanistic overview of our current understanding of how certain microbial pathogens subvert HSPGs to promote their infection, using specific HSPG– pathogen interactions as representative examples. A.H. Bartlett Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA P.W. Park (*) Division of Respiratory Diseases, Children’s Hospital, Harvard Medical School, 320 Longwood Avenue, Enders-461, Boston, MA 02115, USA e-mail: [email protected] M.S.G. Pavão (ed.), Glycans in Diseases and Therapeutics, Biology of Extracellular Matrix, DOI 10.1007/978-3-642-16833-8_2, # Springer-Verlag Berlin Heidelberg 2011 31 2.1 Primer on HSPG Biology The complex interplay between hosts and pathogens has many common themes. One of the first steps in infection is attachment to host tissues. The expression pattern of host cell surface proteins that serve as receptors for pathogen attachment has a significant role in determining the initiation, progression, outcome, and tissue tropism of infections. Among these, HSPGs are expressed ubiquitously on the surface of adherent cells and in the extracellular matrix (ECM), and many viral, bacterial, and parasitic pathogens have been described to interact with HSPGs (Rostand and Esko 1997; Bernfield et al. 1999; Spillmann 2001; Chen et al. 2008). HSPGs bind to and regulate growth factors, cytokines, and chemokines, and ECM components (Bernfield et al. 1999; Park et al. 2000; Bartlett et al. 2008) and are known to be involved in processes as diverse as wound healing (Fears and Woods 2006; Alexopoulou et al. 2007), angiogenesis (Stringer 2006), and neuronal development (Reizes et al. 2008). HSPGs are composed of a protein core to which one or more heparan sulfate (HS) glycosaminoglycan (GAG) chains are covalently attached. HS chains can be both Nand O-sulfated, and it is with these chains that most pathogens interact. The highly complex mechanisms of HSPG biosynthesis have been partially defined and are discussed in detail in other chapters of this book. The major ECM HSPGs, perlecan and agrin, help to form the structure of the basement membrane (BM) and modulate growth factors to affect cell survival, motility, and tissue morphogenesis (Iozzo 2005). The major cell surface HSPGs are syndecans and glypicans (Bernfield et al. 1999). There are four syndecans in mammals (syndecan-1 through -4) with distinct extracellular domains to which HS chains are attached distally to the plasma membrane, and highly conserved transmembrane and cytoplasmic domains. Syndecan cytoplasmic domains contain one invariant serine and three invariant tyrosine residues as well as a C-terminal Glu–Phe–Tyr–Ala PDZ binding domain. Syndecan cytoplasmic domains can regulate interactions with host proteins such as c-Src (Kinnunen et al. 1998), cortactin (Kinnunen et al. 1998), syntenin (Grootjans et al. 1997), protein kinase A (Hayashida et al. 2006), CASK/LIN2A (Cohen et al. 1998; Hsueh et al. 1998), and protein kinase Ca (Kessler et al. 1997), among other signaling and scaffolding proteins. There are six glypicans in mammals that differ from syndecans in several ways. Syndecan core proteins are type 1 transmembrane proteins, whereas glypicans are covalently linked to the cell surface by glycosylphosphatidylinositol (GPI) anchors (David et al. 1990). The extracellular core proteins of syndecans are rich in secondary structure-breaking proline residues and considered linear, whereas glypicans are thought to have a compact globular structure held in place by multiple disulfide bonds formed between several conserved cysteine residues (Chen and Lander 2001). Further, HS attachment sites in syndecans are distal to the plasma membrane, whereas those of glypicans are proximal (Chen and Lander 2001). In addition, syndecans and glypicans show distinct temporal and spatial expression patterns, which in part explain how these HSPGs may function specifically in vivo. 32 A.H. Bartlett and P.W. Park