Diverse Functions of Glycosaminoglycans in Infectious Diseases

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Abstract

Glycosaminoglycans (GAGs) are complex carbohydrates that are expressed ubiquitously and abundantly on the cell surface and in the extracellular matrix (ECM). The extraordinary structural diversity of GAGs enables them to interact with a wide variety of biological molecules. Through these interactions, GAGs modulate various biological processes, such as cell adhesion, proliferation and migration, ECM assembly, tissue repair, coagulation, and immune responses, among many others. Studies during the last several decades have indicated that GAGs also interact with microbial pathogens. GAG–pathogen interactions affect most, if not all, the key steps of microbial pathogenesis, including host cell attachment and invasion, cell–cell transmission, systemic dissemination and infection of secondary organs, and evasion of host defense mechanisms. These observations indicate that GAG–pathogen interactions serve diverse functions that affect the pathogenesis of 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)

  • J.G. Joyce et al.

    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

    (1999)
  • T.L. Cover et al.

    Helicobacter pylori in health and disease

    Gastroenterology

    (2009)
  • I.G. Sava et al.

    Novel interactions of glycosaminoglycans and bacterial glycolipids mediate binding of enterococci to human cells

    J Biol Chem

    (2009)
  • D. Rathore et al.

    Molecular mechanism of host specificity in Plasmodium falciparum infection: role of circumsporozoite protein

    J Biol Chem

    (2003)
  • A.P. Lima et al.

    Heparan sulfate modulates kinin release by Trypanosoma cruzi through the activity of cruzipain

    J Biol Chem

    (2002)
  • E. Feyzi et al.

    Structural requirement of heparan sulfate for interaction with herpes simplex virus type I virions and isolated glycoprotein C

    J Biol Chem

    (1997)
  • C.D. O'Donnell et al.

    A role for heparan sulfate 3-O-sulfotransferase isoform 2 in herpes simplex virus type 1 entry and spread

    Virology

    (2006)
  • D. Shukla et al.

    A novel role for 3-O-sulfated heparan sulfate in herpes simplex virus 1 entry

    Cell

    (1999)
  • V. Tiwari et al.

    A role for 3-O-sulfotransferase isoform-4 in assisting HSV-1 entry and spread

    Biochem Biophys Res Commun

    (2005)
  • B.W. Banfield et al.

    Evidence for an interaction of herpes simplex virus with chondroitin sulfate proteoglycans during infection

    Virology

    (1995)
  • K. Bergefall et al.

    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

    (2005)
  • T. Uyama et al.

    Chondroitin 4-O-sulfotransferase-1 regulates E disaccharide expression of chondroitin sulfate required for herpes simplex virus infectivity

    J Biol Chem

    (2006)
  • E.G. Argyris et al.

    The perlecan heparan sulfate proteoglycan mediates cellular uptake of HIV-1 Tat through a pathway responsible for biological activity

    Virology

    (2004)
  • M. Rusnati et al.

    Interaction of HIV-1 Tat protein with heparin. Role of the backbone structure, sulfation, and size

    J Biol Chem

    (1997)
  • M. Rusnati et al.

    Multiple interactions of HIV-1 Tat protein with size-defined heparin oligosaccharides

    J Biol Chem

    (1999)
  • M. Tyagi et al.

    Internalization of HIV-1 tat requires cell surface heparan sulfate proteoglycans

    J Biol Chem

    (2001)
  • M.J. Baron et al.

    Alpha C protein of group B Streptococcus binds host cell surface glycosaminoglycan and enters cells by an actin-dependent mechanism

    J Biol Chem

    (2004)
  • H. Grassmé et al.

    Acidic sphingomyelinase mediates entry of N. gonorrhoeae into nonphagocytic cells

    Cell

    (1997)
  • M.D. Bobardt et al.

    Syndecan captures, protects, and transmits HIV to T lymphocytes

    Immunity

    (2003)
  • F.D. Menozzi et al.

    Mycobacterium tuberculosis heparin-binding haemagglutinin adhesin (HBHA) triggers receptor-mediated transcytosis without altering the integrity of tight junctions

    Microbes Infect

    (2006)
  • A. Coppi et al.

    Heparan sulfate proteoglycans provide a signal to Plasmodium sporozoites to stop migrating and productively invade host cells

    Cell Host Microbe

    (2007)
  • Y. Lai et al.

    AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense

    Trends Immunol

    (2009)
  • Y. Chen et al.

    Streptococcus pneumoniae sheds syndecan-1 ectodomains via ZmpC, a metalloproteinase virulence factor

    J Biol Chem

    (2007)
  • P.W. Park et al.

    Activation of syndecan-1 ectodomain shedding by Staphylococcus aureus alpha-toxin and beta-toxin

    J Biol Chem

    (2004)
  • P.W. Park et al.

    Syndecan-1 shedding is enhanced by LasA, a secreted virulence factor of Pseudomonas aeruginosa

    J Biol Chem

    (2000)
  • M. Chmiela et al.

    Interaction of cells of Helicobacter pylori with human polymorphonuclear leucocytes: possible role of haemagglutinins

    FEMS Immunol Med Microbiol

    (1994)
  • J. Akhtar et al.

    Viral entry mechanisms: cellular and viral mediators of herpes simplex virus entry

    FEBS J

    (2009)
  • R.R. Vives et al.

    Heparan sulphate proteoglycans and viral vectors: ally or foe?

    Curr Gene Ther

    (2006)
  • J.D. Esko et al.

    Molecular diversity of heparan sulfate

    J Clin Invest

    (2001)
  • M. Bernfield et al.

    Functions of cell surface heparan sulfate proteoglycans

    Annu Rev Biochem

    (1999)
  • K.S. Rostand et al.

    Microbial adherence to and invasion through proteoglycans

    Infect Immun

    (1997)
  • R.C. Kines et al.

    The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding

    Proc Natl Acad Sci USA

    (2009)
  • V. O'Donnell et al.

    Heparan sulfate-binding foot-and-mouth disease virus enters cells via caveola-mediated endocytosis

    J Virol

    (2008)
  • M.J. Oh et al.

    A role for heparan sulfate in viral surfing

    Biochem Biophys Res Commun

    (2009)
  • A. Ceballos et al.

    Spermatozoa capture HIV-1 through heparan sulfate and efficiently transmit the virus to dendritic cells

    J Exp Med

    (2009)
  • W. Baranska-Rybak et al.

    Glycosaminoglycans inhibit the antibacterial activity of LL-37 in biological fluids

    J Antimicrob Chemother

    (2006)
  • G. Bergsson et al.

    LL-37 complexation with glycosaminoglycans in cystic fibrosis lungs inhibits antimicrobial activity, which can be restored by hypertonic saline

    J Immunol

    (2009)
  • J.D. Dubreuil et al.

    Effect of heparin binding on Helicobacter pylori resistance to serum

    J Med Microbiol

    (2004)
  • P.W. Park et al.

    Exploitation of syndecan-1 shedding by Pseudomonas aeruginosa enhances virulence

    Nature

    (2001)
  • A. Schmidtchen et al.

    Dermatan sulfate is released by proteinases of common pathogenic bacteria and inactivates antibacterial alpha-defensin

    Mol Microbiol

    (2001)
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