Diverse Functions of Glycosaminoglycans in Infectious Diseases
Introduction
Infectious diseases are a major global health problem. They kill over 10 million people annually, accounting for approximately 25% of all deaths in the world. Microbial pathogens perform various functions to promote their survival in the host environment, which is generally hostile for the pathogens because the host mounts effective defense mechanisms to eradicate them. Infection occurs when the balance of host–pathogen interactions shifts to favor the pathogen. Hygienic, prophylactic, and therapeutic interventions are continuing to reduce the incidence and mortality of infectious diseases. However, infectious diseases continue to be a major public health threat in both developed and developing countries, and the emergence of new pathogens and drug-resistant strains, globalization of travel and trade, and bioterrorism are adding to this threat.
Microbial pathogens elaborate a multitude of virulence factors, which enable the pathogens to attach to and invade host cells, damage host tissues, disseminate and cause secondary infections, and evade host defense mechanisms, among other virulence activities. Virulence factors frequently subvert host components to promote pathogenesis. In essence, the outcome of an infection is largely governed by the ability of pathogens to exploit host components and their activities. For example, many pathogens express cell surface molecules called adhesins that specifically bind to host tissue components to facilitate their attachment. Pathogens also secrete enzymes that digest host components to generate nutrients and to inactivate host defense factors. Some pathogens synthesize toxins that not only kill host cells and cause tissue damage, but also modify the host cell's cytoskeleton to facilitate their internalization. Further, several pathogens express factors that inhibit specific arms of host defense (e.g., complement-mediated killing, phagocytosis) or dysregulate the host inflammatory response to their advantage. The genetic variability that microbial pathogens can generate allows variant pathogens to exploit host components for their growth, survival, and propagation.
Among the many host components subverted by microbial pathogens, glycosaminoglycans (GAGs) have been implicated in various steps during the course of infection. GAGs are expressed ubiquitously on the cell surface, in the ECM, and in intracellular compartments. Further, they play critical roles in various host defense mechanisms, allowing pathogens abundant opportunities to exploit them for infectious purposes. Consistent with this notion, studies during the last several decades have demonstrated that a wide variety of pathogens subvert GAGs for their attachment and invasion, cellular transmission, systemic dissemination, and evasion of host defense mechanisms.1, 2, 3, 4, 5 The list includes viruses, bacteria, parasites, and fungi, such as herpes simplex virus (HSV), dengue virus, Neisseria gonorrhoeae, Plasmodium falciparum, and Candida albicans, among many others.
GAGs are linear polysaccharides comprised of repeating disaccharide units of hexosamine and uronic acid or galactose with various substitutions. The list of GAGs includes heparan sulfate (HS)/heparin, chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS), and hyaluronan (HA) as described in other chapters of this book. Except for HA, all other GAGs are sulfated to various degrees and covalently complexed to proteoglycan core proteins. The biosynthesis of GAGs is a highly complex, template-free process catalyzed by specific enzymes. HS synthesis, for example, is initiated by the action of four glycosyltransferases assembling the initiation tetrasaccharide linkage sequence (-glucuronic acid-galactose-galactose-xylose) on certain serine residues of HS proteoglycan (HSPG) core proteins, such as syndecans and glypicans. The heparan (or heparosan) polysaccharide chain is elongated on the tetrasaccharide linkage region by adding alternate units of N-acetylglucosamine and glucuronic acid. The heparan precursor chain is then sequentially modified by N-deacetylase/N-sulfotransferases (NDSTs), C5 epimerase; and 2-O-sulfotransferase, 6-O-sulfotransferases, and 3-O sulfotransferases in the Golgi.6, 7 The mature HS chain can be further modified in the Golgi or extracellular compartments by the action of 6-O-sulfatases8 or heparanases.9 An important feature of HS biosynthesis is that the polymerization and modification reactions do not go to completion. Thus, the biosynthetic process generates an incredibly diverse array of HS structures. By one estimate, 1036 HS structures can potentially be synthesized.10 Perhaps this enormous structural variability explains, in part, why HS can interact with a diverse group of microbial pathogens.
GAG–pathogen interactions impinge on multiple steps of microbial pathogenesis. Many viral, bacterial, parasitic, and fungal pathogens use GAGs as low affinity, initial attachment sites to facilitate their interaction with respective secondary internalization receptors.2, 4, 11, 12 In some cases, pathogens bind to GAGs and use them as bridging molecules to bind to GAG-binding host components on the cell surface and in the ECM. Some pathogens also use GAGs as scaffolds that induce conformational changes in virulence factors.13, 14 To efficiently invade host cells, pathogens not only use GAGs as low affinity coreceptors or high affinity internalization receptors, but in some cases, also use certain GAGs to modulate endogenous processes, such as caveola-mediated endocytosis15 and filopodia formation and filopodia-mediated transport of viral particles to cell bodies.16 GAGs can also influence the cell–cell transmission of pathogens, such as in the transfer of viruses between host cells.17, 18, 19 In addition, recent studies suggest that certain pathogens subvert GAGs to inhibit host defense mechanisms to promote their pathogenesis.20, 21, 22, 23, 24 This chapter reviews these diverse functions of GAG–pathogen interactions in infectious diseases using select examples from recent studies.
Section snippets
GAGs in Pathogen Attachment
The initial attachment of pathogens to host tissues is a critical step in the pathogenesis of most infectious diseases. Pathogens that lack the capacity to rapidly and firmly attach to host tissues are effectively removed by nonspecific mechanical defenses, such as ciliary motion, intestinal peristalsis, and lung reflexes (coughing and sneezing). Many pathogens express GAG-binding adhesins that mediate their attachment to host tissues.1, 4, 5 In most cases, GAGs serve as coreceptors that allow
GAGs in Evasion of Host Defense
The host environment is generally hostile for pathogens because it contains various physical barriers, creates inhabitable conditions (e.g., low pH in stomach, limited access to essential nutrients like iron), constantly operates several nonspecific mechanical systems that remove pathogens (e.g., coughing, sneezing, ciliary motion), and also because the host can mount effective innate and adaptive defense mechanisms to eradicate pathogens. Interestingly, several studies suggest that certain
Concluding Remarks
The diverse functions of GAGs in the pathogenesis of infectious diseases reflect the multitude of virulence mechanisms elaborated by microbial pathogens. As discussed, GAGs impinge on key steps of pathogenesis, such as adhesion and invasion of host cells, cell–cell transmission, dissemination into the systemic circulation and secondary infection of distant organs, and evasion of host defense mechanisms. Given the ubiquitous nature and versatile capacity of GAGs to modulate many molecular and
References (114)
- et al.
Microbial subversion of heparan sulfate proteoglycans
Mol Cells
(2008) - et al.
The role of syndecans in disease and wound healing
Matrix Biol
(2006) Heparan sulfate: anchor for viral intruders?
Biochimie
(2001)- et al.
Biosynthesis of heparin and heparan sulfate
- et al.
Heparin/heparan sulfate N-sulfamidase from Flavobacterium heparinum: structural and biochemical investigation of catalytic nitrogen-sulfur bond cleavage
J Biol Chem
(2009) - et al.
Heparanase: busy at the cell surface
Trends Biochem Sci
(2009) - et al.
Structural differences of heparan sulfates according to the tissue and species of origin
Biochem Biophys Res Commun
(1983) - et al.
Surface-exposed amino acid residues of HPV16 L1 protein mediating interaction with cell surface heparan sulfate
J Biol Chem
(2007) - et al.
HTLV-1 uses HSPG and neuropilin-1 for entry by molecular mimicry of VEGF165
Blood
(2009) - et al.
HIV-1 Tat and heparan sulfate proteoglycan interaction: a novel mechanism of lymphocyte adhesion and migration across the endothelium
Blood
(2009)
The L1 major capsid protein of human papillomavirus type 11 recombinant virus-like particles interacts with heparin and cell-surface glycosaminoglycans on human keratinocytes
J Biol Chem
Helicobacter pylori in health and disease
Gastroenterology
Novel interactions of glycosaminoglycans and bacterial glycolipids mediate binding of enterococci to human cells
J Biol Chem
Molecular mechanism of host specificity in Plasmodium falciparum infection: role of circumsporozoite protein
J Biol Chem
Heparan sulfate modulates kinin release by Trypanosoma cruzi through the activity of cruzipain
J Biol Chem
Structural requirement of heparan sulfate for interaction with herpes simplex virus type I virions and isolated glycoprotein C
J Biol Chem
A role for heparan sulfate 3-O-sulfotransferase isoform 2 in herpes simplex virus type 1 entry and spread
Virology
A novel role for 3-O-sulfated heparan sulfate in herpes simplex virus 1 entry
Cell
A role for 3-O-sulfotransferase isoform-4 in assisting HSV-1 entry and spread
Biochem Biophys Res Commun
Evidence for an interaction of herpes simplex virus with chondroitin sulfate proteoglycans during infection
Virology
Chondroitin sulfate characterized by the E-disaccharide unit is a potent inhibitor of herpes simplex virus infectivity and provides the virus binding sites on gro2C cells
J Biol Chem
Chondroitin 4-O-sulfotransferase-1 regulates E disaccharide expression of chondroitin sulfate required for herpes simplex virus infectivity
J Biol Chem
The perlecan heparan sulfate proteoglycan mediates cellular uptake of HIV-1 Tat through a pathway responsible for biological activity
Virology
Interaction of HIV-1 Tat protein with heparin. Role of the backbone structure, sulfation, and size
J Biol Chem
Multiple interactions of HIV-1 Tat protein with size-defined heparin oligosaccharides
J Biol Chem
Internalization of HIV-1 tat requires cell surface heparan sulfate proteoglycans
J Biol Chem
Alpha C protein of group B Streptococcus binds host cell surface glycosaminoglycan and enters cells by an actin-dependent mechanism
J Biol Chem
Acidic sphingomyelinase mediates entry of N. gonorrhoeae into nonphagocytic cells
Cell
Syndecan captures, protects, and transmits HIV to T lymphocytes
Immunity
Mycobacterium tuberculosis heparin-binding haemagglutinin adhesin (HBHA) triggers receptor-mediated transcytosis without altering the integrity of tight junctions
Microbes Infect
Heparan sulfate proteoglycans provide a signal to Plasmodium sporozoites to stop migrating and productively invade host cells
Cell Host Microbe
AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense
Trends Immunol
Streptococcus pneumoniae sheds syndecan-1 ectodomains via ZmpC, a metalloproteinase virulence factor
J Biol Chem
Activation of syndecan-1 ectodomain shedding by Staphylococcus aureus alpha-toxin and beta-toxin
J Biol Chem
Syndecan-1 shedding is enhanced by LasA, a secreted virulence factor of Pseudomonas aeruginosa
J Biol Chem
Interaction of cells of Helicobacter pylori with human polymorphonuclear leucocytes: possible role of haemagglutinins
FEMS Immunol Med Microbiol
Viral entry mechanisms: cellular and viral mediators of herpes simplex virus entry
FEBS J
Heparan sulphate proteoglycans and viral vectors: ally or foe?
Curr Gene Ther
Molecular diversity of heparan sulfate
J Clin Invest
Functions of cell surface heparan sulfate proteoglycans
Annu Rev Biochem
Microbial adherence to and invasion through proteoglycans
Infect Immun
The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding
Proc Natl Acad Sci USA
Heparan sulfate-binding foot-and-mouth disease virus enters cells via caveola-mediated endocytosis
J Virol
A role for heparan sulfate in viral surfing
Biochem Biophys Res Commun
Spermatozoa capture HIV-1 through heparan sulfate and efficiently transmit the virus to dendritic cells
J Exp Med
Glycosaminoglycans inhibit the antibacterial activity of LL-37 in biological fluids
J Antimicrob Chemother
LL-37 complexation with glycosaminoglycans in cystic fibrosis lungs inhibits antimicrobial activity, which can be restored by hypertonic saline
J Immunol
Effect of heparin binding on Helicobacter pylori resistance to serum
J Med Microbiol
Exploitation of syndecan-1 shedding by Pseudomonas aeruginosa enhances virulence
Nature
Dermatan sulfate is released by proteinases of common pathogenic bacteria and inactivates antibacterial alpha-defensin
Mol Microbiol
Cited by (36)
The influenza-injured lung microenvironment promotes MRSA virulence, contributing to severe secondary bacterial pneumonia
2022, Cell ReportsCitation Excerpt :Most notably, HS interacts with the coronavirus Spike protein and the ACE2 receptor.67,68,69,70 Broadly, GAGs have been primarily investigated regarding their impact on pathogens’ ability or inability adhere to cell surfaces, a necessary step in the establishment of infection.37,71 HS-protein interactions commonly occur at spatial clusters of one to three basic amino acids spaced with one to two nonbasic residues.72
Dissociation of DNA damage sensing by endoglycosidase HPSE
2021, iScienceCitation Excerpt :Although discovered decades ago as a key extracellular component serving as an attachment point for numerous growth factors, cellular signals, and microbes, the glycosaminoglycan heparan sulfate (HS) continues to be assigned new functions in the maintenance of cellular homeostasis and regulation of disease (Aquino et al., 2010; Xu and Esko, 2014; Zhang et al., 2014).
Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1
2017, Cell ReportsCitation Excerpt :HPSE catalyzes cleavage of the β-(1,4)-glycosidic bond between glucuronic acid and glucosamine residues of HS; thus, through ECM remodeling, it is involved in several important biological functions (Vlodavsky and Friedmann, 2001; Goldberg et al., 2013; Xu and Esko, 2014). While HS is known to be an important attachment receptor for a wide variety of human pathogens (Aquino et al., 2010; Tiwari et al., 2012; Park and Shukla, 2013), very little understanding exists on the significance of host-encoded HPSE in infection. We recently reported that host-encoded HPSE is upregulated upon infection by multiple herpesviruses and facilitates the release of viral progeny from parent cells after herpes simplex virus (HSV) infection (Hadigal et al., 2015).
Drugs affecting glycosaminoglycan metabolism
2016, Drug Discovery TodayCitation Excerpt :With the exception of HA, GAGs are made in the Golgi and attached as single or multiple chains to proteins by a xylose-O-serine (or threonine) link, thus forming proteoglycans (PG) [1–3]. GAGs bind and coordinate the activity of proteins involved in cell attachment, migration and differentiation; inflammation; neuronal plasticity; blood coagulation; lipid metabolism; and pathogen infectivity [4–7]. The chemical complexity of sulfated GAGs arises from the extensive modification of the precursor polymer through epimerization of uronic acids and/or sulfation at various positions along the chain.
Proteoglycans
2016, Encyclopedia of Cell Biology