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.

Cysteine proteases of human hookwormNecator Americanus as virulencefactors and implications for drug design with anti-heparin and heparin analogs: A bioinformatics study

“…Such sites were searched to explore the possibility of (worm) heparin, with anticoagulation properties, being transported out to extracellular matrix while attached to the secretory NA CPs (if any), for impairing host coagulation system. Importantly, glycosaminoglycan molecules remain displayed on host proteoglycans [45] and are probably encountered for recognition by the worm ES products at the hostpathogen interface. The sequences were subjected to query by ProDom [46] , a protein domain family database derived from Uniprot knowledgebase, for finding any heparinbinding protein domains on the NA CPs; as such sites would be predisposed to noncovalently bind heparin that remain covalently attached to host proteins.…”

“…Heparin-like glycosaminoglycan present in animal plasma membrane and ECM, form components of the host-pathogen interface [45] . The GAGs serve as recognition factors for molecular interactions, controlling activities like cell adhesion and parasitic infection [41] [45] [62] .…”

“…The GAGs serve as recognition factors for molecular interactions, controlling activities like cell adhesion and parasitic infection [41] [45] [62] . These negatively charged molecules are covalently linked to syndecans and glypicans proteoglycans of host cells, and help to recognize and bind parasitic cysteine proteases [45] such as cruzain [41] [62] . The simultaneous binding of the proteases with their protein substrate and the latter's co-valently linked GAG results in the formation of ternary complexes [41] [62] , which facilitates the enzymatic action of the proteases.…”

“…NA-CPs' suggestive role in hemoglobin degradation and anticoagulation by HMWK-cleavage, assisted by covalently bound heparin on host proteins, underscores the importance of abolishing non-covalent GAG interaction with the NA-CPs, for controlling the proteases' pathogenic activities (Figure 4). Soluble heparin/heparin sulfate usage as competitive inhibitors have the chances of causing adverse physiological effects due to their anticoagulant/immunogenic properties [45] . However, synthetic GAG mimetics with limited biological activity (minimum active structure) or polysaccharides [67] [68] targeted at GAG binding site ( Table 2), could be used for inhibiting hookworm infection, in conjunction with active-site inhibitors.…”

2-O-Sulfated Domains in Syndecan-1 Heparan Sulfate Inhibit Neutrophil Cathelicidin and Promote Staphylococcus aureus Corneal Infection

“…Many microbial pathogens, including viruses, bacteria, and parasites, are thought to exploit the heparan sulfate (HS) 2 moiety of HS proteoglycans (HSPGs) to infect host cells and to evade immune mechanisms (8,9). HSPGs are expressed ubiquitously on the cell surface and in the extracellular matrix.…”