Many parasitic protozoans and helminths synthesize unusual glycan structures and glycan-binding proteins (GBPs) that are often antigenic and involved in host invasion and parasitism. This chapter discusses these parasites and the roles of glycoconjugates in the disease process. Protozoan parasites have evolved unique lifestyles: They shuttle between insect vectors and vertebrate hosts, encountering extremely harsh environments specifically designed to keep microbial invaders at bay. Their survival strategies frequently involve the participation of glycoconjugates that form a protective barrier against hostile forces. The diversity of the glycoconjugate structures and the range of functions that have been ascribed to parasite glycoconjugates, from host-cell invasion to deception of the host’s immune system, are remarkable.
BACKGROUND ON PARASITIC INFECTIONS
Parasitism may be defined as a condition in which one organism (the parasite) either harms its host or in some way lives at the expense of the host. Parasites affect millions of people worldwide and cause tremendous suffering and death, especially in less-developed countries. Some sobering statistics are listed in Table 40.1. Worldwide, several million people die each year from parasitic diseases, with the bulk of those deaths coming from malaria and parasitic protozoans. Research into parasite glycobiology and biochemistry is important because of these worldwide human health problems. In addition, we may acquire important new insights into molecular pathology by studying such organisms, which have evolved to deceive and compromise the immune systems of infected animals with great success. However, parasite glycobiology can be frustrating because of the difficulty in obtaining sufficient amounts of material for study and the difficulty of doing in vitro experimentation. In addition, many parasites have specific primary and intermediate hosts, thus making it difficult to study all stages of the life cycle.
Some of the major parasitic diseases infecting humans and animals are listed here in two categories: those caused by protozoans (single-celled organisms) (Table 40.2) and those caused by helminths (worms/metazoans) (Table 40.3). The major protozoan parasites include Plasmodium species (causing malaria), Entamoeba histolytica (causing amebiasis), Leishmania species (causing leishmaniasis), and Trypanosoma species (causing sleeping sickness and Chagas’ disease). Parasitic worms (helminths) live within tissues outside of cells and have evolved a variety of infective and protective pathways involving complex glycoconjugates and their recognition. Some of the major parasitic helminths include nematodes, such as Ascaris lumbricoides, trematodes, such as Schistosoma mansoni (causing schistosomiasis), and cestodes or tapeworms, such as Taenia solium (causing taeniiasis).
It is often difficult to study parasites because, by definition, most of them require animal hosts to survive and parasites cannot be grown independently. However, exciting new results demonstrate that glycoconjugates are very important in the life cycles and pathology of most major parasites. Some of the parasitic protozoans and helminths rely on GBPs in the host to promote their parasitism, and they have elaborated intriguing strategies to defeat the antiglycan immunity of the host.
Malaria in humans is caused by Plasmodium species and several major species infect humans, with P. falciparum being the most virulent. These parasites lead a complicated life cycle, alternating between a sexual stage within the female Anopheles mosquito vector and an asexual stage within mammalian tissues (hepatocytes and erythrocytes) and the bloodstream (Figure 40.1). Cell–cell interactions between the parasite and host are critical for the successful completion of each stage.
Following inoculation into the bloodstream, the sporozoite’s major circumsporozoite protein interacts with the liver’s heparan sulfate (HS), thereby enabling invasion of hepatocytes, the initial site of replication in the mammalian host. HS from the liver possesses an unusually high degree of sulfation compared to similar glycosaminoglycans from other organs, suggesting the basis for the selective targeting of Plasmodium to hepatocytes.
Upon exit from the liver, merozoites can use multiple ligand–receptor interactions to invade host erythrocytes, which vary in their dependency on sialic acid residues on the surface. Multiple proteins on Plasmodium merozoites mediate invasion of erythrocytes (Table 40.4). These fall into two broad superfamilies, the erythrocyte-binding-like (EBL; or more appropriately, the Duffy-binding-like [DBL]) and the reticulocyte-binding-like (RBL) proteins. The merozoite protein EBA-175 (erythrocyte-binding antigen-175; a type of EBL) was originally identified based on its ability to bind erythrocytes, and it is now known that the P. falciparum genome contains six EBL paralogs. EBA-175 recognizes clusters of sialylated O-glycans attached to erythrocyte glycophorin A, particularly within a 30-amino-acid region that carries 11 O-glycans. Desialylation of erythrocytes precludes interactions of some strains of P. falciparum, and individuals lacking glycophorin A or glycophorin B are refractory to invasion. The glycophorins are the major sialic-acid-containing glycoproteins on erythrocytes. Although EBA-175 plays an important role in invasion, the roles of EBA-140/BAEBL and EBA-181/JSEBL are less clear. Some strains of P. falciparum can reversibly switch from sialic-acid-dependent to sialic-acid-independent invasion, which depends on parasite ligand use and involves the expression of a P. falciparum RBL-like homolog 4 (PfRh4). The ability to switch receptor usage for erythrocyte invasion from sialic-acid-dependent to sialic-acid–independent pathways has important implications for vaccine design against malaria parasites.
Eruption of the merozoites from infected erythrocytes results in the release of glycosylphosphatidylinositols (GPIs), which are believed to be prominent virulence factors that contribute to malaria pathogenesis (see Chapter 11). These P. falciparum GPIs, which are free or arise by proteolytic processing of GPI-anchored proteins, may mimic host-cell GPIs and activate GPI-associated signaling pathways, such as Src-related protein tyrosine kinases. The GPIs can activate the host’s macrophages, leading to the production of inflammatory cytokines as well as cell-adhesion molecules, such as intracellular adhesion molecule-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1), and E-selectin in endothelial cells. Antibodies to these GPIs can neutralize their effects and mitigate the pathology of the disease independently of infection.
The presence of N- and O-linked glycans in Plasmodia has been controversial. Several Plasmodium proteins (MSP-1, MSP-2, and EBA-175) are believed to be nonglycosylated in vivo, even though potential N-glycosylation sites are present in the primary amino acid sequences. Recent studies show that Plasmodium and Giardia can synthesize dolichol-P-P-GlcNAc2, which is a normal intermediate in the synthesis of the longer types of dolichol-P-P-oligosaccharides commonly found in vertebrates and that are precursors for N-glycosylation in glycoproteins. Thus, Plasmodium and Giardia may contain N-glycans with only the disaccharide motif GlcNAcβ1-4GlcNAcβ-Asn. Little is known about O-glycosylation in Plasmodium, if it occurs at all. Thus, GPI anchor synthesis emerges as the major form of protein glycosylation, a situation unique in eukaryotic cells.
African trypanosomes of the species brucei are the etiologic agents of nagana disease in cattle and sleeping sickness in humans. After transmission by blood-sucking tsetse flies, a remarkable feature of these organisms is their ability to survive extracellularly in the bloodstream of the host where they are constantly exposed to the host immune system. Evasion of the host immune response depends on “antigenic variation,” a highly evolved strategy of survival that relies heavily on structural variance of the surface GPI-anchored glycoproteins (VSGs) (Figure 40.2). As the main component of the dense glycocalyx, the VSGs are dimeric proteins, consisting of two 55-kD monomers, each of which carries N-linked oligomannose-type oligosaccharides. As parasites multiply in the host bloodstream, the host immune system mounts an immune response that is effective against only a certain population of trypanosomes, those expressing the antigenic VSG. Those that have switched to an alternative VSG coat (encoded among 1000 distinct VSG genes) escape immunological destruction.
Within the gut of the tsetse fly vector, the trypanosome replaces the entire VSG coat with acidic glycoproteins called procyclins (Figure 40.2). These GPI-anchored proteins form a dense glycocalyx and are composed of polyanionic polypeptide repeat domains projecting from the membrane. Unusual features are the presence of a single type of N-glycan (Man5GlcNAc2) and GPI anchors that are modified with branched poly-N-acetyllactosamine [Galβ1-4GlcNAc]n glycans. The terminating galactose residue can be substituted with sialic acids by the action of a trans-sialidase. The surface sialic acids appear to protect the parasite from the digestive and trypanocidal environments in the midgut of the tsetse fly.
Trypanosoma cruzi is the etiologic agent of Chagas’ disease or South American trypanosomiasis and it is transmitted by reduviid bugs. T. cruzi has a dense coat composed of a layer of glycosylinositolphospholipids (GIPLs) and mucins that project above the GIPL layer (Figure 40.3). The GIPLs contain the same basic structure as other GPI anchors, except that they are heavily substituted with galactose, N-acetylglucosamine, and sialic acid. The mucins contain large amounts of O-linked glycans composed of serine- or threonine-linked N-acetylglucosamine with one to five additional galactose residues. The terminal β-galactose can be further substituted by α2-3-linked sialic acid, which arises from a parasitic trans-sialidase that transfers sialic acid from host glycoconjugates. The surface coat has a protective function, providing the parasite with the ability to survive in hydrolytic environments and promoting adherence to macrophages for invasion. Sialylation is also believed to reduce the susceptibility of the parasite to anti-α-Gal antibodies that are normally present in the mammalian bloodstream. These parasites also express a surface heparin-binding protein (~60 kD) called penetrin that interacts with HS of host cells.
Another important glycoconjugate of T. cruzi is lipopeptidophosphoglycan (LPPG), which is the major surface glycan of the insect stage of the parasite (Figure 40.3). Depending on the life-cycle stage, LPPG is composed of an inositolphosphoceramide-anchored glycan or an alkylacylphosphatidylinositol-anchored glycan that includes nonacetylated glucosamine, mannose, galactofuranose, and 2-aminoethylphosphonate. The lack of ceramide anchors and galactofuranose in mammalian cells suggests potential targets for the development of chemotherapeutic agents.
Leishmania are responsible for a spectrum of human diseases, termed leishmaniasis. Species-specific leishmaniasis manifests clinically in three forms: cutaneous, mucocutaneous, and visceral, the last being fatal if untreated. These parasites have a remarkable capacity to avoid destruction in the hostile environments they encounter during their life cycle, alternating between intracellular macrophage parasitism and extracellular life in the gut of their sandfly vector (Figure 40.4).
Stage-specific adhesion is mediated by structural variation involving the abundant cell-surface glycoconjugate lipophosphoglycan (LPG), which contributes to parasite survival in the hydrolytic midgut environment (Figure 40.5). The basic LPG structure in all Leishmania species consists of a 1-O-alkyl-2-lyso-phosphatidyl(myo)inositol lipid anchor, a heptasaccharide glycan core, a long phosphoglycan (PG) polymer composed of (-6Galβ1-4Manα 1-PO4-) repeat units (n ~10–40), and a small oligosaccharide cap. In many species, the PG repeats contain additional substitutions that mediate key roles in stage-specific adhesion. For example, in L. major, the LPG phosphoglycan [Gal-Man-P]n back-bone repeat units bear β1-3-galactosyl side-chain modifications, which form the attachment ligand for the sandfly galectin, PpGalec. As parasites differentiate, the LPG is replaced with a structurally modified LPG where α1-2 arabinosyl residues cap the β1-3 Gal-modified LPG phosphoglycans, giving rise to a structure that does not bind to the midgut galectin receptor, thereby facilitating detachment of the parasite from the sandfly midgut. The abundance of LPG on the parasite surface, which is the site of the primary interface with the host, suggests a central role for the glycoconjugate in the parasite’s infectious cycle. Besides a role in binding and detachment of the parasite in the midgut of the sandfly, LPG has also been implicated in resistance to complement-mediated lysis upon inoculation into the mammalian host, binding and uptake by macrophages, modulating macrophage signal transduction, resistance to oxidative attack, and, ultimately, allowing the parasite to establish successful infections.
In addition to LPG, Leishmania express an abundance of other important glycoconjugates, such as GIPLs, GPI-anchored proteins, and secreted proteophosphoglycans (PPG) (Figure 40.5) (also see Chapter 11). In PPG molecules, most of the serine residues are phosphoglyco-sylated with Gal-Man-P repeat units via unique phosphodiester linkages. In L. mexicana, these highly anionic substances form a gel-like matrix composed of interlocking filaments that enhance parasite development in the sandfly and contribute to the formation of a parasitophorous vacuole in macrophages of the mammalian host, where the parasite replicates.
The early steps in LPG and GPI biosynthesis (up to Man-Man-GlcN-PI) occur in the endoplasmic reticulum (see Chapter 11). The distal mannose of all GPI anchors and some GIPLs is α1-6-linked, whereas it is α1-3-linked to the inner mannose in LPG, and some GIPLs contain the α1-3 mannose. Galactosylation of the LPG glycan core and assembly of the PG repeat unit occur in the Golgi apparatus. Virtually every known glycoconjugate of Leishmania shows some intersection with the LPG biosynthetic pathway, especially in the synthesis of the repeat units and GPI anchors. The presence of molecules bearing similar modifications raises the possibility that they share biosynthetic steps. The phosphoglycan portions of LPG and PPG are assembled by the sequential and alternating transfer of mannose-P and galactose from their respective nucleotide-sugar donors, forming the characteristic -Galβ1-4Manα1-P repeat units. Depending on the species of Leishmania, additional branching sugars can then be added, creating a remarkable array of side chains that drive Leishmania–sandfly vectorial competence.
Entamoeba histolytica, the etiologic agent of amebic dysentery and hepatic abscesses, has a life cycle that includes two stages, the disease-inducing amebic or trophozoite stage and the infectious cyst stage. Binding to the colonic mucins is mediated by a galactose/N-acetyl-galactosamine lectin, a GPI-anchored protein with a critical role in parasite viability. This lectin is a 260-kD heterodimeric glycoprotein consisting of heavy subunit (170 kD) and light subunit (either 35 or 31 kD) disulfide bonded together.
Entamoeba trophozoites synthesize a cell-surface lipoglycoconjugate (LPG) and a lipopeptidophosphoglycan (LPPG) (Figure 40.6). The LPG consists of a lipid anchor and a phosphoglycan component that resembles the phosphoglycans of Leishmania LPG. These molecules are important as virulence factors because antibodies raised against them inhibit the ability of the parasites to kill target cells, and vaccination retards the development of liver abscess in animal models. The serine residues of LPPG are extensively modified with chains of 2–23 α1-6-linked glucose residues that are presumably attached to the peptide backbone via a Gal-1-P-serine linkage. The LPPG GPI anchors are unique in that they have a novel glycan backbone that contains the sequence Gal1Man2GlcN-(myo)inositol, the terminal α1-2 mannose residues of other protein anchors being replaced by the α-Gal residue. The anchor is also modified with 1–20 α-Gal residues.
The Entamoeba cyst wall is mostly composed of chitin, and there is evidence that the encystation process is accompanied by the appearance of sialylated glycoconjugates on the surface. It has been hypothesized that the negative charge on the cyst surface afforded by the sialylated glycoconjugates may repel the cyst from the intestinal mucosa and thus promote expulsion from the host’s intestine.
Schistosomiasis is caused by a parasitic trematode, and three major species infect humans worldwide: Schistosoma japonicum, S. mansoni, and S. haematobium (Figure 40.7). This parasite is unique among helminths in that the male/female pair live together in the blood vessels of the human host. It lays eggs that adhere to the endothelium and migrate through vessels into tissues. The eggs may become lodged in the host tissues, where they induce granulomatous inflammatory responses and egg sequestration, and such entrapped eggs in the peripheral circulation can lead to portal hypertension and fibrosis, which are characteristic of chronic schistosomiasis and lead to the associated morbidity and mortality. However, many eggs eventually pass into the stool and continue the cycle through intermediate snail hosts, which are unique for each Schistosoma species. Thus, the real geographical limitation to the spread of the disease is the range of the intermediate host snails.
Schistosomes, and especially their eggs (which are laid about 4–6 weeks after infection when sexual maturity is attained), generate huge quantities of membrane-bound and circulating glycoproteins containing fucosylated antigens. Some of the notable antigenic glycan structures found in schistosome glycans include Lewisx (Lex) antigen, LacdiNAc (LDN), fucosylated LacdiNAc (LDNF), and polyfucose branches (Figure 40.8). Overall, fucosylation is a common theme for most schistosome glycoconjugates. Interestingly, other helminths (such as Echinococcus granulosus, Dirofilaria immitis, and Haemonchus contortus) also synthesize glycoproteins containing LDN and LDNF, in addition to other fucosylated and xylosylated glycans (Figure 40.8). In general, schistosomes are especially rich in complex glycan structures and contain an impressive array of glycosphingolipids and O- and N-linked glycans on a multitude of glycoproteins. It is interesting that a few helminths, including schistosomes and Dictyocaulus viviparus, a parasitic nematode in cattle, appear to synthesize the Lex antigen. Another theme in glycoconjugates derived from schistosomes and other helminths studied so far is the absence of sialic acid and sialyltransferase activities.
Schistosomes also synthesize many other interesting glycoconjugates in their so-called cercarial glycocalyx and in their eggs. Glycoproteins derived from the tegument, gut, and eggs of the parasite are highly antigenic and occur in the circulation of the infected animal. The expression of many of these glycan structures is developmentally regulated and stage specific, but their fundamental roles in parasite development and host pathogenesis are not clear. It is also likely that the different schistosome species differ in several ways in terms of their glycoconjugate structures. For example, the S. mansoni glycosphingolipids have extended difucosylated oligosaccharides, but the terminal difucosylated N-acetylgalatcosamine is absent from glycosphingolipids of S. japonicum.
Individuals infected with Schistosoma species develop a wide variety of antibodies to glycan antigens, and these may be partly protective against further infections, because the adult and mature worms are refractory to immune killing. The adult worms have a rough tegument composed of a syncytial membrane that is highly regenerative, even in response to complement attack. There is mounting evidence that the glycan antigens expressed by schistosomes can influence the immune system and are bioactive in compromising host cellular immunity. During chronic schistosome infection, T-helper 2 (Th2) immune responses (promoting humoral immunity) predominate over Th1 responses (promoting cellular immunity). In response to glycans containing the Lex antigen, murine B-1 cells secrete large amounts of interleukin-10 (IL-10) in vitro. Because IL-10 can depress Th1 responses in animals, this may partly contribute to Th2 dominance in early stages of schistosomiasis. In addition, schistosome glycans are recognized by C-type lectins, such as DC-SIGN, and other types of GBPs in antigen-presenting cells such as dendritic cells and macrophages. Internalization and processing of parasite glycans by these cells can lead to altered dendritic cell maturation (see Chapter 31).
The identification of many different antigenic glycoconjugates from schistosomes is helping in the design of new diagnostic procedures for schistosomiasis. In addition, the characterization of glycosyltransferases from schistosomes and the enzymes responsible for antigenic glycan biosynthesis, together with enzymes from the intermediate snail hosts, may help in the identification of new drug targets and the development of glycan-based vaccines.
GLYCOBIOLOGY OF OTHER PARASITES
Glycoconjugates and GBPs, as discussed above, play an impressive role in host infection by many different parasites. Several additional examples are shown in Table 40.4. Many protozoan parasites appear to use GBPs as a major mechanism for host-cell attachment and invasion (see Chapter 34). As mentioned earlier, one of the major glycoproteins expressed by E. histolytica, a major cause of amebic dysentery, is a lectin that recognizes galactose/N-acetylgalatcosamine residues, resulting in adherence of trophozoites to host cells. Adhesion is followed by contact-dependent cytolysis of host cells. Acanthamoeba keratitis, which causes severe eye infections involving the corneal epithelium, also adheres via a lectin interaction. This lectin-mediated adhesion of A. keratitis to host cells is a prerequisite for ameba-induced cytolysis of target cells. The adhesion occurs via a mannose-binding protein that is highly inhibited by Manα1-3Man disaccharides. Interestingly, mannose and mannose-6-phosphate can inhibit adhesion of Giardia lamblia trophozoites. One of the proteins from the parasite that may bind mannose and mannose-6-phosphate is termed taglin. The cDNAs of several galectin family members, identified initially as antigenic proteins, have been cloned from parasitic nematodes, such as Teladorsagia circumcincta. Sporozoites from Cryptosporidium parvum, an opportunistic protozoan that infects individuals with compromised immunity, have hemagglutinating activity, and a lectin on the parasite surface may play a crucial role in host-cell attachment.
In addition to these ongoing studies on GBPs in parasites, the glycan antigens of many parasites are being characterized in the hope that the information may lead to development of vaccines and new diagnostics for these diseases. For example, the major antigenic glycoconjugates synthesized by larvae of the parasitic nematodes Toxocara canis and T. cati are O-methylated trisaccharides that contain 2-O-methyl fucosyl and galactosyl residues (see Chapter 23). The intestinal nematode Trichinella spiralis synthesizes several highly immunogenic glycoproteins that contain the unusual sugar tyvelose (3,6-dideoxy-D-arabino-hexose). Tyvelose is found in complex N-glycans of larvae from T. spiralis and is a critical antigenic determinant recognized by antibodies in infected animals. Strong immunity to these glycans provides protective immunity, which causes expulsion of the invading larvae from the intestine. Protective immunity is also provided by antibodies to uncharacterized glycan antigens from Haemonchus contortus, an intestinal parasitic nematode of ruminants.
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Richard Cummings and Salvatore Turco.
Cold Spring Harbor Laboratory Press, Cold Spring Harbor (NY)
Cummings R, Turco S. Parasitic Infections. In: Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology. 2nd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009. Chapter 40.