37 microbial lectins: hemagglutinins, adhesins, and...

37 Microbial Lectins: Hemagglutinins,Adhesins, and ToxinsVictor Nizet, Ajit Varki, and Markus Aebi

BACKGROUND, 1

VIRAL GLYCAN-BINDING PROTEINS, 2

BACTERIAL ADHESION TO GLYCANS, 5

TOXINS THAT BIND GLYCANS, 7

PARASITE LECTINS, 9

THERAPEUTIC IMPLICATIONS, 10

ACKNOWLEDGMENTS, 10

FURTHER READING, 10

Many microorganisms exploit cell-surface glycans as targets for the interaction with othercells. Proteins at the surface of microorganisms (adhesins or agglutinins) mediate the bind-

ing to such glycan “receptors,” and a large number of pathogenic species depend on these inter-actions for infection. In addition, antagonistic interactions are mediated by secreted toxins thatuse surface glycan targets for internalization by various mechanisms. This chapter highlightsexamples of such microbial lectins and their roles in pathogenicity. In addition, the mode ofaction of glycan-dependent toxins is discussed.

BACKGROUND

Viruses, bacteria, fungi, and protozoa express an enormous array of glycan-binding proteins,also called lectins. Many of these microbial lectins were originally detected based on their abilityto aggregate or induce the hemagglutination of red blood cells (erythrocytes). The first micro-bial hemagglutinin identified was isolated from the influenza virus, and it was shown by AlfredGottschalk in the early 1950s to bind erythrocytes and other cells via the sialic acid componentof host cell-surface glycoconjugates. Don Wiley and associates crystallized the influenza hemag-glutinin and determined its structure in 1981. Later they solved the structure of hemagglutinincocrystals bound to sialyllactose, providing molecular insight into the affinity and specificity ofthe receptor-ligand binding sites. Since then, a number of viral hemagglutinins have been iden-tified and structurally elucidated.

Nathan Sharon and colleagues first described bacterial surface lectins in the 1970s. Their pri-mary function is to facilitate the attachment or adherence of bacteria to host cells, a prerequisitefor bacterial colonization and infection (Chapter 42). Thus, bacterial lectins are often called adhe-sins, and these bind corresponding glycan receptors on the surface of the host cells via

Copyright # 2017 The Consortium of Glycobiology Editors, La Jolla, California;published by Cold Spring Harbor Laboratory Press; doi: 10.1101/glycobiology.3e.037 1

carbohydrate-recognition domains (CRDs) (“receptor” in this case is equivalent to “ligand”for animal cell lectins). Like animal lectins, some microbial adhesins bind to terminal sugarresidues via the CRD, whereas others bind to internal sequences found in linear or branchedoligosaccharide chains. The interaction of adhesins with host glycans is an important determi-nant of the tropism of the corresponding pathogen or symbiont. Detailed studies of the specificityof such microbial lectins have led to the identification and synthesis of powerful inhibitors ofadhesion that may form the basis for novel therapeutic agents to combat infectious disease(Chapter 42).

Bacteria also produce soluble toxins, whose actions often depend on glycan-binding subunitsthat allow the toxin to combine with membrane glycoconjugates to deliver the functionallyactive toxic subunit across the membrane. During the last 30 years, many microbial agglutinins,adhesins and toxins have been described, cloned, and characterized.

Colonization of tissues by microorganisms is usually nonpathogenic. For example, the nor-mal flora of the lower gastrointestinal tract is determined by appropriate and desirable coloni-zation by beneficial bacteria. Likewise, the initial formation of nitrogen-fixing nodules inleguminous root tips by species of Rhizobium involves lectins on the root tip binding to gly-can-containing Nod factors generated by the bacterium (Chapter 24).

VIRAL GLYCAN-BINDING PROTEINS

By far, the most well-studied example of a viral glycan-binding protein is the influenza virushemagglutinin, which binds to sialic acid–containing glycans on the host cell surface. Althoughthe affinity of this interaction is low, like that of other lectins with their glycan ligands, the avid-ity is increased by hemagglutinin trimerization and a high density of glycan receptors present onthe host cell. This binding event is required for internalization of the virus by endocytosis andsubsequently the pH-dependent fusion of the viral envelope with the endosomal membrane,ultimately triggering release of the viral RNA into the cytosol. The specificity of the hostglycan-hemagglutinin interaction varies considerably for different subtypes of influenza.For example, human strains of influenza-A and -B viruses bind primarily to cells containingN-acetylneuraminic acid (Neu5Aca)2–6Gal-containing receptors. However, avian influenzaviruses bind to receptors expressing Neu5Aca2–3Gal-, and porcine strains bind to bothNeu5Aca2–6Gal- and -3Gal-containing receptors (Table 37.1). This linkage preference is aresult of structural differences of the hemagglutinin (Figure 37.1). Viral adherence also dependson receptor abundance, such that tracheal epithelial cells in humans express glycans with a pre-ponderance of Neu5Aca2–6Gal linkages, whereas other deeper airway surfaces contain manymore Neu5Aca2–3Gal-terminated glycans. Thus, the specificity of the hemagglutinin deter-mines the tropism of the virus with respect to species and target cells. The hemagglutinin isalso the major antigen against which neutralizing antibodies are produced, and antigenicchanges in this protein are in part responsible for new viral outbreaks and considered in formu-lation of the annual influenza vaccine.

In addition to the hemagglutinin “H,” influenza-A and -B virions express a sialidase (tradi-tionally and incorrectly called neuraminidase “N”) that cleaves sialic acids from glycoconjugates.Its functions may include (1) prevention of viral aggregation by removal of sialic acid residuesfrom virion envelope glycoproteins, (2) dissociation of newly synthesized virions inside the cellor as they bud from the cell surface, and (3) desialylation of soluble mucins at sites of infectionto improve access to membrane-bound sialic acids. Inhibitors have been designed based on thecrystal structure of the sialidase from influenza-A virus. Some of these (e.g., oseltamivir) inhibitthe enzyme activity at nanomolar concentrations and are used clinically as antiviral agents(Chapter 57). Influenza-C virions (and some coronaviruses) contain a single glycoprotein

2 | CHAPTER 37

that possesses both hemagglutinin and receptor-destroying activities, which in this case is anesterase that cleaves the 9-O-acetyl group from the target O-acetylated sialic acid receptors (Fig-ure 37.1). Some coronaviruses have evolved further, adapting the spike “S” proteins targetO-acetylated sialic acid receptors.

Rotaviruses, the major killer of children worldwide, can also bind to sialic acid residues.These viruses only bind to the intestinal epithelium of newborn infants during a period thatappears to correlate with the expression of specific types and arrangements of sialic acids onglycoproteins. Claims regarding “sialic acid–independent” rotaviruses may be explained byinternal sialic acids resistant to bacterial sialidases. Many other viruses (e.g., adenovirus, reovi-rus, Sendai virus, and polyomavirus) also use sialic acids for infection, and crystal structures arenow available for several of their sialic acid–binding domains.

A number of viruses, including herpes simplex virus [HSV], foot-and-mouth disease virus,human immunodeficiency virus (HIV), and dengue flavivirus, use heparan sulfate proteogly-cans as adhesion receptors (Table 37.1). In many cases, the proteoglycans may be part of aco-receptor system in which viruses make initial contact with a cell-surface proteoglycan andlater with another receptor. For example, HSV infection is thought to initially involve the

TABLE 37.1. Examples of viral lectins and hemagglutinins

Virus Lectin Glycan-receptor specificity Site of infection

MyxovirusesInfluenza A and B

(human, ferret, andporcine)

hemagglutinin Neu5Aca2-6Gal- upper respiratory tractmucosa (trachealepithelial cells)

Influenza A and B(avian and porcine)

hemagglutinin Neu5Aca2-3Gal- intestinal mucosa

Influenza C hemagglutinin-esterase

9-O-acetyl-Siaa- unknown

Newcastle disease hemagglutinin-neuraminidase

Neu5Aca2-3Gal- unknown

Sendai hemagglutinin-neuraminidase

Neu5Aca2-8Neu5Ac- upper respiratory tractmucosa

PolyomavirusesPolyoma capsid protein

VP1Neu5Aca2-3Gal-,

Neu5Aca2- 3Galb1-3(Neu5Aca2-6)GalNAc- ongangliosides such as GM1and GT1b/GD1a

Kidney and brain glialcells

HerpesvirusesHerpes simplex glycoproteins gB,

gC, and gD3-O-sulfated heparan sulfate mucosal surfaces of the

mouth, eyes, genital,and respiratory tracts

PicornavirusesFoot-and-mouth

disease (enterovirus)caspid proteins heparan sulfate gastrointestinal and

upper respiratorytracts

RetrovirusesHIV gp120 V3 loop heparan sulfate CD4 lymphocytesFlavivirusesDengue envelope protein heparan sulfate macrophages?CalcivirusesNorovirus capsid proteins Fucose, GalNAc, or Gal on A

and B blood group antigenssecretory cells of the

intestinal epithelium

MICROBIAL LECTINS: HEMAGGLUTININS, ADHESINS, AND TOXINS | 3

binding of viral glycoproteins gB and/or gC to cell-surface heparan sulfate proteoglycans. Gly-coprotein gB promotes virus-cell fusion, syncytium formation (cell–cell fusion), and adherence,whereas gC binds to the C3b component of the complement receptor and blocks complement-mediated inhibition of the virus. These events are followed by HSV glycoprotein gD binding toone of several cell-surface receptors, including protein receptors and heparan sulfate, ultimatelyleading to fusion of the viral envelope with the host-cell plasma membrane. Interestingly, theinteraction of gD with heparan sulfate shows specificity for a particular substructure in heparansulfate containing a 3-O-sulfated glucosamine residue, the formation of which is catalyzed byspecific isozymes of the glucosaminyl 3-O-sulfotransferase gene family. Thus, the heparan-sul-fate-binding adhesins appear to pick out specific carbohydrate units within the polysaccharidechains as opposed to binding terminal sugars.

Dengue flavivirus, the causative agent of dengue hemorrhagic fever, also binds to heparansulfate. Computational modeling to compare the primary dengue viral envelope proteinsequence with the crystal structure of a related virion envelope protein suggests that the hep-aran sulfate–binding site may lie along a positively charged amino acid groove (Figure 37.2).The recently emerging Zika virus belongs to the same family. Furthermore, HIV can bindheparan sulfate and other sulfated polysaccharides by way of the V3 loop of its gp120glycoprotein.

Receptorbindingsite

Asn-193

190-Helix

Glu-190

GlcNAc-3

Sialic acid

130-Loop

Gal-2

Gln-226

Thr-136

4

23

137

135

227

Lys-222

Asp-225

220-Loop

A B

FIGURE 37.1. Structure of the influenza virus hemagglutinin (HA) ectodomain. (A) A schematic diagram of thetrimeric ectodomain of the H3 avian HA from A/duck/Ukr/63 showing residues HA1 9 – 326 and HA2 1 – 172.Modeled carbohydrate side chains (gray, red, blue); disulfide bonds (black, green). The six polypeptide chains areshown in light blue (HA1), magenta (HA2), dark blue (HA10), light red (HA20), green (HA100), and yellow (HA200).(Redrawn, with permission of Elsevier, from Ha Y, et al. 2003. Virology 309: 209 – 218.) (B) Combining site of humaninfluenza virus HA in complex with the human trisaccharide receptor NeuAca2-6Galb1-4GlcNAc. Hydrogenbonds (dashed lines); residues making interactions via main-chain carbonyl groups (red spheres) or nitrogens(blue spheres); trisaccharide carbon ( yellow), nitrogen (blue), and oxygen (red) atoms; water molecules (greenspheres). (Redrawn, with permission of AAAS, from Gamblin SJ, et al. 2004. Science 303: 1838 – 1842.)

4 | CHAPTER 37

BACTERIAL ADHESION TO GLYCANS

Bacterial lectins occur commonly in the form of elongated, submicroscopic, multisubunit pro-tein appendages, known as fimbriae (hairs) or pili (threads), which interact with glycoproteinand glycolipid receptors on host cells. Similar to viral glycan-binding proteins, adhesin-receptorbinding is generally of low affinity. Because the adhesins and the receptors often cluster in theplane of the membrane, the resulting combinatorial avidity can be great. Perhaps an appropriateanalogy for adhesin-receptor binding is the interaction of the two faces of Velcro strips. Themost well-characterized bacterial lectins include the mannose-specific type-1 fimbriae, the gal-abiose-specific P fimbriae, and the N-acetylglucosamine-binding F-17 fimbriae, which are pro-duced by different strains of Escherichia coli (E. coli). Fimbriated bacteria express 100 to 400 ofthese appendages, which typically have a diameter of 5–7 nm and can extend hundreds ofnanometers in length (Figure 37.3) Thus, pili extend well beyond the bacterial glycocalyx com-prised of lipopolysaccharide and capsular polysaccharides (see Chapter 21).

Examination of a high-resolution, three-dimensional structure of FimH bound to mannoserevealed that, although mannose exists as a mixture of a and b anomers in solution, only theformer was found in the complex. Mannose binds FimH at a deep and negatively charged site of

FIGURE 37.3. Escherichia coli express hundreds of pili, asindicated by the fine filaments extending from the bacte-rium. (Reprinted, with permission of Elsevier, from SharonN. 2006. Biochim Biophys Acta 1760: 527 – 537; courtesy ofDavid L. Hasty, University of Tennessee, Memphis, TN.)

FIGURE 37.2. Two views of a putative heparin sulfate – binding site on the dengue virus envelope protein. Theenvelope protein monomer is shown in ribbon form, displayed along its longitudinal axis and as an external sideview. Note the alignment of positively charged amino acids along an open face of the protein (top). (Redrawn, withpermission, from Chen YP, et al. 1997. Nat Med 3: 866 – 871, # Macmillan Publishers Ltd.)


FimH (Figure 37.4). FimH has “catch-bond” properties, such that the binding strength of indi-vidual FimH adhesins is augmented by increasing the shear forces on surface-bound E. coli cells.This is relevant for urinary tract infections, in which type-1 fimbriae mediate binding of thebacteria to the glycoprotein uroplakin Ia on the surface of bladder epithelial cells. UroplakinIa presents high levels of terminally exposed mannose residues that are capable of specificallyinteracting with FimH. Alternatively, type-1 fimbriae can bind to the soluble urinaryTamm–Horsfall glycoprotein, which inhibits bacterial adhesion. Indeed, mice lacking theTamm–Horsfall gene are considerably more susceptible to bladder colonization by type-1-fim-briated E. coli than normal mice, whereas they are equally susceptible to P-fimbriated E. coli thatbind a different glycoprotein receptor.

Most bacteria (and possibly other microorganisms) have multiple adhesins with diverse carbo-hydrate specificities. Many of these have been described (examples in Table 37.2), wherein the spe-cificity of lectin binding can help define the range of susceptible tissues in the host (i.e., themicrobe’s ecological niche). The columnar epithelium that lines the large intestine expresses recep-tors with Gala1–4Gal-Cer residues, whereas cells lining the small intestine do not. Thus, Bacter-ioides, Clostridium, E. coli, and Lactobacillus only colonize the large intestine under normalconditions. P-fimbriated E. coli and some toxins bind specifically to galabiose (Gala1–4Gal)and galabiose-containing oligosaccharides, most commonly as constituents of glycolipids. Bindingcan occur to either internal (i.e., when the disaccharide is capped by other sugars) or terminal non-reducing galabiose units. P-fimbriated E. coli adhere mainly to the upper part of the kidney, wheregalabiose is abundant. The fine specificity of bacterial surface lectins and their relationship to theanimal tropism of the bacteria can be further illustrated by E. coli K99. This organism binds to gly-colipids that contain N-glycolylneuraminic acid (Neu5Gc), in the form of Neu5Gca2–3Galb1–4Glc, but not to those that contain N-acetylneuraminic acid (Neu5Ac). These two sugars differ by asingle hydroxyl group that is present only on Neu5Gc. Interestingly, Neu5Gc-containing receptorsare expressed on the intestinal cells of newborn piglets, but disappear as the animals grow anddevelop. As Neu5Gc is not normally biosynthesized by humans, this may explain why E. coliK99 can cause often lethal diarrhea in piglets but not in adult pigs or humans.

FIGURE 37.4. The a anomer of mannose in the combining site of FimH. The mannose residue is buried in aunique site at the tip of the carbohydrate-recognition domain (left) in a deep and negatively charged pocket(right). FimH prefers to bind D-mannose in the a-anomeric configuration. The hydroxyl groups of D-mannoseinteract with residues Phe1, Asn46, Asp47, Asp54, Gln133, Asn135, Asp140, and Phe142 by hydrogen-bondingand hydrophobic interactions. Residues in direct contact are shown as a ball-and-stick model. W1, water.(Redrawn, with permission, from Hung CS, et al. 2002. Mol Microbiol 44: 903 – 915, # Blackwell Publishing Ltd.)

6 | CHAPTER 37

TOXINS THAT BIND GLYCANS

A number of secreted bacterial toxins also bind glycans (Table 37.3). The toxin from Vibriocholera (cholera toxin), which consists of A and B subunits in the ratio AB5, has been extensivelystudied. The crystal structure of cholera toxin shows that the carbohydrate-recognition domainsare located at the base of the B subunits, which bind to the Galb1–3GalNAc moiety of GM1ganglioside (Chapter 11) receptors (Figure 37.5). Upon binding of the B subunits to membraneglycolipids, the AB5 complex is endocytosed to the Golgi apparatus and then undergoes retro-grade transport to the endoplasmic reticulum (ER). The A1 and A2 chains are proteolyticallycleaved on toxin secretion, but remain stably associated until arrival in the ER. There, the enzy-matic A1 chain unfolds, dissociates from the A2-B5 complex, and retrotranslocates to the cytosolwhere it rapidly refolds, thereby avoiding degradation by the proteasome. Catalytically active A1then ADP-ribosylates a regulatory homotrimeric G-protein to activate adenylyl cyclase, severlyaltering ion homeostasis of the infected cell.

TABLE 37.2. Examples of interactions of bacterial adhesins with glycans

Microorganism Adhesin Glycan-receptor specificity Site of infection

Actinomycesnaeslundii

fimbriae Galb1 – 3GalNAcb- oral

Bordetella pertussis filamentoushemagglutinin (FHA)

sulfated glycolipids, heparin ciliated epithelium inrespiratory tract

Borreliaburgdorferi

ErpG protein heparan sulfate endothelium,epithelium, andextracellular matrix

Campylobacterjejuni

flagella, LPS Fuca1-2Galb1-4GlcNAcb-(H-antigen)

intestinal cells

Escherichia coli P fimbriae Gala1-4Galb- urinary tractS fimbriae gangliosides GM3, GM2 neuraltype-1 fimbriae Mana1-3(Mana6Mana1-6)

Manurinary tract

K99 fimbriae gangliosides GM3,Neu5Gca2-3Galb1-4Glc

intestinal cells

Haemophilusinfluenzae

HMW1 adhesin Neu5Aca2-3Galb1-4GlcNAcb-, heparan sulfate

respiratory epithelium

Helicobacter pylori BabA sialyl Lewis x stomachHelicobacter pylori SabA lewis b stomach and stomach

duodenumMycobacterium

tuberculosisheparin-binding

hemagglutininadhesin (HBHA)

heparan sulfate respiratory epithelium

Neisseriagonorrhoeae

Opa proteins protein LacCer; Neu5Aca2-3Galb1-4GlcNAcb-, syndecans,heparan sulfate

genital tract

Pseudomonasaeruginosa

type IV pili asialo GM1 and GM2 respiratory tract

Staphylococcusaureus

signal peptide of pantonvalentine leukocidin

heparan sulfate connective tissuesand endothelial cells

Streptococcusagalactiae

aC protein heparan sulfate brain endothelial cells

Streptococcuspneumoniae

carbohydrate-bindingmodules of b-galactosidase, BgaA

lactose or N-acetyl-lactosamine

respiratory tract


Shiga toxin, produced by Shigella dysenteria, will bind to Gala1-4Gal determinants onboth glycolipids and glycoproteins. However, only binding to the glycosphingolipid receptorGb3 results in cell death. Similar to cholera toxin, the AB5 complex is endocytosed andtransported to the ER of the target cells, and then the A1 subunit is retrotranslocated tothe cytosol. There, the catalytic A1 chain of shiga toxin inactivates ribosomes, and thus

TABLE 37.3. Examples of glycan receptors for bacterial toxins

Microorganism Toxin Glycan-receptor specificity Site of infection

Bacillusthuringiensis

crystal toxins Galb1-3/6Gala/b1-3(+Glcb1-6)GalNAcb GlcNAcb1-3Manb1-4GlcbCer

intestinal epithelium ofinsects/nematodes

Clostridiumbotulinum

botulinumtoxins (A – E)

gangliosides GT1b and GQ1b nerve membrane

Clostridiumdifficile

toxin A GalNAcb1-3Galb1-4GlcNAcb1-3Galb1-4GlcbCer

large intestine

Clostridium tetani tetanus toxin ganglioside GT1b nerve membraneEscherichia coli heat-labile toxin GM1 intestineShigella

dysenteriaeShiga toxin Gala1-4GalbCer, ;Gala1-4Galb1-4

GlcbCerlarge intestine

Vibrio cholerae cholera toxin GM1 small intestine

Gangliosides are defined using the Svennerholm nomenclature (see Chapter 11).Cer, ceramide.

FIGURE 37.5. Crystal structure of the cholera toxin B-subunit pentamer bound to GM1 pentasaccharide, shownfrom the bottom (A) and the side (B). (Redrawn, with permission, from Merritt EA, et al. 1994. Protein Sci 3: 166 –175.) (C ) Crystal structure of the Shiga toxin pentamer bound to an artificial pentavalent ligand, a powerful inhibi-tor of the toxin. The carbohydrate ligands are shown in a ball-and-stick representation. Possible conformation ofthe linker is indicated by the dashed magenta lines. (Redrawn, with permission of Macmillan Publisher Ltd., fromKitov PI, et al. 2000. Nature 403: 669 – 672.)

8 | CHAPTER 37

the essential process of cytoplasmic protein synthesis, by an N-glycosidic cleavage event thatdepurinates 28S rRNA.

Crystal toxins (Bt toxins) are produced by the soil-dwelling bacterium Bacillus thuringiensis(Bt). Bt toxins are used for crop protection by spraying plants or by genetically engineeringcrops to express the toxins. Bt belongs to the most common class of bacterial toxins that arecharacterized by their pore-forming capability. As such, these toxins function by binding glyco-lipids that line the gut and generating pores in the membrane. More specifically, the Bt toxinglycolipid receptors include in their structure the characteristic ceramide-linked, mannose-con-taining core tetrasaccharide GalNAcb1-4GlcNAcb1-3Manb1-4GlcbCer. This structure is con-served between nematodes and insects (see Chapter 25), but is absent in vertebratesincluding. This explains why Bt can kill larval stages of insects but is harmless to humans.

PARASITE LECTINS

In addition to viruses and bacteria, a number of parasites use glycans as receptors for adhesion(Table 37.4). Entamoeba histolytica (E. histolytica) expresses a 260 kDa heterodimeric lectin thatbinds to terminal Gal/GalNAc residues on glycoproteins and glycolipids via a cysteine-rich gly-can-binding domain. T his adhesin is essential for virulence, such that adhesin-glycan binding isrequired for parasitic attachment, invasion, and cytolysis of the intestinal epithelium. Further-more, it may function in binding E. histolytica to bacteria as a food source. The adhesin elicitsprotective immunity, and is a potential target to manage E. histolytica infection (43).

The initial interaction of Plasmodium falciparum (malaria) merozoites with red blood cells(erythrocytes) depends on sialic acid residues present on the host cell, in particular on the majorerythrocyte membrane protein glycophorin. Parasite-host attachment is mediated by a family ofsialic acid-binding adhesins on merozoites, the most prominent of which is called erythro-cyte-binding antigen-175 (EBA-175). This adhesin preferentially binds Neu5Ac sialic acids,rather than 9-O-acetyl-Neu5Ac or Neu5Gc, and is sensitive to the linkage of the sialic acidto the underlying galactose. This is highlighted by the fact that Neu5Aca2–3Gal-containing

TABLE 37.4. Examples of glycan receptors for parasites

Parasite Adhesin Glycan-receptor specificity Site of infection

Entamoebahistolytica

260-kDa surface-anchored lectin ontrophozoites

terminal Gal/GalNAc residues mucosa of humancolon

Plasmodiumfalciparum

EBA-175;circumsporozoite(CS) protein

sialic acid – containing glycans(Neu5Aca2-3Galb-) onglycophorins; heparansulfate proteoglycans

erythrocytes (infectedcells bind to placentalvasculature) andhepatocytes

Trypanosomacruzi

surface “mucins” sialic acid – containing glycansand heparan sulfate

multiple cell types

Leishmaniaamazonensis

unknown heparan sulfate macrophages,fibroblasts, andepithelium

Cryptosporidiumparum

lectin p30 terminal Gal-GalNAc intestinal epithelium

Giardia lamblia unknown mannose-terminatedoligosaccharides

duodenum and smallintestine

Toxoplasmagondii

microneme protein 1(TgMIC1)

a2-3-linked sialyl-N-acetyllactosaminesequences

intestinal epithelium


oligosaccharides effectively inhibit the binding of EBA-175 to erythrocytes, whereas solubleNeu5Ac and Neu5Aca2–6Gal-containing oligosaccharides do not. Adhesin-glycan bindingtriggers invasion of the merozoites into red blood cells, where they develop into mature schiz-onts that rupture and release newly formed merozoites into the bloodstream. Many commonlyused clinical anti-malarial medications, such as chloroquine, target the parasite during thiserythrocytic asexual reproduction stage.

THERAPEUTIC IMPLICATIONS

Lectins mediate adhesion of microorganisms to host cells or tissues, which is a prerequisite forinfection and/or symbiosis to occur. Consequently, lectin-deficient microbial mutants are oftenunable to initiate infection. Interestingly, glycans recognized by microbial surface lectins havebeen shown to block the adhesion of bacteria to animal cells in vitro and in vivo, and thusmay protect animals against infection by such microorganisms. For example, coadministrationof methyl a-mannoside with type-1-fimbriated E. coli into the bladder of mice significantlyreduces the rate of urinary tract infection, whereas methyl a-glucoside, which does not bindto FimH, has no effect. Furthermore, Lacto-N-neotetraose (LNnT) and its a2-3- and a2-6-sia-lylated derivatives block the adherence of Streptococcus pneumoniae to respiratory epithelial cellsin vitro. In addition, these glycans prevent colonization of the nasopharynx and attenuate thecourse of pneumonia in rodent models of pneumococcal infection.

Exogenous heparin and structurally related polysaccharides are known to inhibit viral repli-cation, suggesting a potential approach for the development of polysaccharide-based antiviralpharmaceutical agents. For example, heparin octasaccharide decoy liposomes were recentlyshown to inhibit the replication of numerous viruses including HSV and respiratory syncytialvirus. As more crystal structures are elucidated, the ability to design small-molecule inhibitorsthat fit into the carbohydrate-recognition domains of adhesins should improve. Already, thestructures of influenza hemagglutinin and sialidase have suggested numerous ways to modifysialic acid to fit better into the active sites. Some of these compounds are presently in clinicaluse to limit the spread of influenza.

ACKNOWLEDGMENTS

The authors acknowledge contributions to the previous version of this chapter from JeffreyD. Esko and the late Nathan Sharon and helpful comments and suggestions from Taroh Kinosh-ita, Andreas Geissner, Jen Groves, Robyn Peterson, and Paeton L.A. Wantuch.

FURTHER READING

Rostand KS, Esko JD. 1997. Microbial adherence to and invasion through proteoglycans. Infect Immun 65:1–8.

Kitov PI, Sadowska JM, Mulvey G, Armstrong GD, Ling H, Pannu NS, Read RJ, Bundle DR. 2000. Shiga-like toxins are neutralized by tailored multivalent carbohydrate ligands. Nature 403: 669–672.

Griffitts JS, Aroian RV. 2005. Many roads to resistance: How invertebrates adapt to Bt toxins. BioEssays 27:614–624.

Olofsson S, Bergstrom T. 2005. Glycoconjugate glycans as viral receptors. Ann Med 37: 154–172.Mazmanian SK, Kasper DL. 2006. The love–hate relationship between bacterial polysaccharides and the

host immune system. Nat Rev Immunol 6: 849–858.

10 | CHAPTER 37

Sinnis P, Coppi A. 2007. A long and winding road: The Plasmodium sporozoite’s journey in the mamma-lian host. Parasitol Int 56: 171–178.

Patsos G, Corfield A. 2009. Management of the human mucosal defensive barrier: Evidence for glycanlegislation. Biol Chem 390: 581–590.

Krachler AM, Orth K. 2013. Targeting the bacteria–host interface: Strategies in anti-adhesion therapy.Virulence 4: 284–294.

Edinger TO, Pohl MO, Stertz S. 2014. Entry of influenza A virus: Host factors and antiviral targets. J GenVirol 95: 263–277.

Stencel-Baerenwald JE, Reiss K, Reiter DM, Stehle T, Dermody TS. 2014. The sweet spot: Defining virus–sialic acid interactions. Nat Rev Microbiol 12: 739–749.


37 microbial lectins: hemagglutinins, adhesins, and...

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