Proteoglycans in host-pathogen interactions: molecular mechanisms and therapeutic implications

Abstract

Many microbial pathogens subvert proteoglycans for their adhesion to host tissues, invasion of host cells, infection of neighbouring cells, dissemination into the systemic circulation, and evasion of host defence mechanisms. Where studied, specific virulence factors mediate these proteoglycan-pathogen interactions, which are thus thought to affect the onset, progression and outcome of infection. Proteoglycans are composites of glycosaminoglycan (GAG) chains attached covalently to specific core proteins. Proteoglycans are expressed ubiquitously on the cell surface, in intracellular compartments, and in the extracellular matrix. GAGs mediate the majority of ligand-binding activities of proteoglycans, and many microbial pathogens elaborate cell-surface and secreted factors that interact with GAGs. Some pathogens also modulate the expression and function of proteoglycans through known virulence factors. Several GAG-binding pathogens can no longer attach to and invade host cells whose GAG expression has been reduced by mutagenesis or enzymatic treatment. Furthermore, GAG antagonists have been shown to inhibit microbial attachment and host cell entry in vitro and reduce virulence in vivo. Together, these observations underscore the biological significance of proteoglycan-pathogen interactions in infectious diseases.

Figure 1. Composition of heparan sulfate disaccharide units

Heparan sulfate is composed of repeating disaccharide units of hexuronic acid (either glucuronic or iduronic acid) alternating with an N-substituted (R′ = acetate or sulfate) or unsubstituted (R′ = H) glucosamine. Both N-acetylated and N-sulfated glucosamine are commonly found in mature HS chains, whereas N-unsubstituted glucosamine is not. Glucosamine can also be sulfated at the C-6 and C-3 position, although 3-O-sulfated glucosamine is rare in HS. The hexuronic acids can be sulfated at the C-2 position, and this is a common modification in iduronic acid (2-O-sulfated iduronic acid). In general, the unique sulfation pattern dictates the ligand-binding specificity of HS.

Figure 2. Structures of representative proteoglycans

The structures of several cell-surface (syndecans, glypicans, CD44), intracellular (serglycin), and matrix (bamacan, perlecan, agrin, fibromodulin, lumican) proteoglycans are shown. Serglycin is decorated with highly sulfated HS (i.e. heparin) and CS chains, whereas syndecans and CD44 harbour HS and CS chains. Glypicans, perlecan and agrin contain HS chains, and bamacan contains CS chains. The small leucine-rich proteoglycans fibromodulin and lumican are decorated with KS chains. These proteoglycans interact with various ligands through their glycosaminoglycan chains. Abbreviations: CD, cluster of differentiation; CS, chondroitin sulfate; HS, heparan sulfate; KS, keratan sulfate.

Figure 3. Mechanisms of proteoglycans in microbial attachment, entry and dissemination

(a) Enhanced microbial attachment and internalisation. Pathogens use proteoglycans as coreceptors to increase pathogen concentration on the cell surface, facilitating binding to specific secondary receptors. This binding often results in internalisation of the pathogen. (b) Enhanced virulence factor function. Vaccinia virus produces the virulence factor N1L after internalisation. N1L binds to the CSPG bamacan, resulting in improved viral growth in vitro and neurovirulence in vivo. (c) Sequestration of parasite-infected cells. Placental tissue expresses a CS-A (purple), which binds Plasmodium falciparum-infected red blood cells, leading to their sequestration and clinical manifestations including anaemia. (d) Enhanced virulence factor internalisation. HIV Tat binds to cell-surface HSPGs and is then internalised where it can activate transcription. Abbreviations: CS-A, chondroitin sulfate A; CSPG, chondroitin sulfate proteoglycan; HIV, human immunodeficiency virus; HSPG, heparan sulfate proteoglycan; RBC, red blood cell; Tat, transactivator of transcription.

Figure 4. Mechanisms of proteoglycans in pathogen evasion of host defence

(a) Pathogens including Pseudomonas aeruginosa secrete proteases that cleave decorin, releasing dermatan sulfate. Dermatan sulfate binds to and neutralises cationic antimicrobial peptides such as α-defensin. (b) P. aeruginosa virulence factor LasA usurps the host cell machinery to enhance syndecan-1 shedding into the airspace. Shed syndecan-1 can bind and neutralise antimicrobial peptides such as cathelicidins. (c) Helicobacter pylori binds heparin, enhancing its ability to resist complement-mediated killing by preventing assembly of the membrane attack complex.