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Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology [Internet]. 4th edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2022. doi: 10.1101/glycobiology.4e.42
This chapter illustrates and discusses some key mechanisms by which glycans influence the pathogenesis and progression of bacterial and viral infections and describes examples of opportunities for therapeutic intervention.
Infectious diseases remain a major cause of death, disability, and social and economic disorder for millions of people throughout the world. Poverty, poor access to health care, human migration, emerging disease agents, and antibiotic resistance all contribute to the expanding impact of these illnesses. Prevention and treatment strategies for infectious diseases are derived from a thorough understanding of the complex interactions between specific viral or bacterial pathogens and the human (or animal) host.
Just as glycans are major components of the outermost surface of all animal and plant cells, so too are oligosaccharides and polysaccharides found on the surfaces of all bacteria and viruses of eukaryotes. Thus, most (if not all) interactions of microbial pathogens with their hosts are influenced to an important degree by the pattern of glycans and glycan-binding receptors that each expresses. This holds true at all stages of infection, from initial colonization of host cell surfaces, to tissue spread, to the induction of inflammation or host cell injury that results in clinical symptoms. The microbial molecules most responsible for disease manifestations are known as virulence factors.
A human in good health is colonized by as many as 1013 bacteria on the skin and mucosal surfaces, particularly in the gastrointestinal tract, a number that resembles the number of cells in our own body. Despite all these direct and continuous encounters, it is relatively rare that bacteria invade into the tissues to produce serious infections. Although not restricted to pathogenic species/strains, one feature shared by many of these disease-causing agents is the presence of diverse polysaccharide capsule structures, which encapsulate bacteria (Chapter 21). These structures can have many biological properties, both stimulating and thwarting immune detection in different settings. Capsules make key contributions to the virulence of multiple bacterial pathogens, reducing recognition by the innate and adaptive immune systems. However, capsular polysaccharides are also commonly the natural targets of the adaptive immune system. In fact, antibodies specific to different capsule structures often define the serology used to differentiate subtypes of particular bacterial species. Streptococcus pneumoniae (pneumococcus) encodes perhaps the most historically significant capsule in biology and medicine. Pioneering experiments by Frederick Griffith in 1928 showed the in vivo transfer of virulence from a dead encapsulated (smooth) disease-causing strain to an avirulent, nonencapsulated (rough) strain. Studies regarding immunogenicity of pneumococcal polysaccharides (Figure 42.1) provided the framework for the discoveries of Oswald Avery, Colin MacLeod, and Maclyn McCarty, which showed DNA to be the carrier of genetic information.
Classical experiments on the role of the pneumococcal polysaccharide capsule in virulence. Streptococcus pneumoniae (SPN) strains can be identified with either a “rough” (R) or a “smooth” (S) phenotype, the latter being (more...)
Killing of bacteria by phagocytes of the innate immune system, such as neutrophils or macrophages, is aided by opsonization, a process in which the bacterial surface is tagged with complement proteins or specific antibodies. Phagocytes express receptors for activated complement and antibody Fc domains, allowing them to bind, engulf, and kill bacteria. Together these processes are referred to as opsonophagocytosis. Genetic mutagenesis of capsule biosynthesis genes and infectious challenge in small animal models have illustrated the roles of bacterial capsules in resisting opsonophagocytosis. Compared with the wild-type parent bacterial strains, isogenic capsule-deficient mutants of group A Streptococcus (GAS), group B Streptococcus (GBS), pneumococcus, Haemophilus influenzae, Neisseria meningitidis (meningococcus), Salmonella serotype Typhi (typhoid fever), Bacillus anthracis (anthrax), and several other important human pathogens are rapidly cleared from the bloodstream by opsonophagocytosis and fail to establish systemic infection. Some bacteria mimic the anionic host molecule sialic acid in their capsules, including the neonatal pathogens GBS and Escherichia coli K1. These sialylated capsules bind the complement regulatory protein factor H and attenuate complement deposition. Independent of the complement system, GBS sialic acids also reduce neutrophil bactericidal activities by directly engaging the sialic acid–binding receptor Siglec-9.
Bacteria also use molecular mimicry to evade antibody generation by the adaptive immune system. Generally, humans can generate effective antibodies against bacterial polysaccharide capsules, but this ability is diminished early and late in life. Infants and the elderly are particularly prone to invasive infections with encapsulated pathogens. Molecular mimicry of common host glycan structures allows bacteria to masquerade as “self” to avoid being recognized by the adaptive immune system. For example, the GAS pathogen expresses a nonimmunogenic capsule of hyaluronan, identical to the nonsulfated glycosaminoglycan that is highly abundant in host skin and cartilage (Chapter 16). The contribution of capsule-based host mimicry to bacterial immune evasion is also illustrated by the homopolymeric sialic acid capsules of E. coli and meningococcus, an important cause of sepsis and meningitis. Whereas the group C meningococcal capsule is composed of an α2-9-linked sialic acid polymer that is a unique bacterial structure, the group B meningococcal capsule is composed of an α2-8-linked sialic acid polymer that is identical to a motif present on neural cell adhesion molecules (NCAMs) found in human neural tissues (Chapter 15). The group C capsule has proven to be a successful vaccine antigen in human populations, whereas the group B capsule is essentially nonimmunogenic. Bacterial polysaccharide capsules can also cloak immunogenic surface proteins to which antibodies might be directed.
One of the challenges posed to the host is that different strains of the same bacterial species can display diverse compositions and linkages of repeating sugar units in their capsule structures. Often, these structures are immunologically distinct, allowing classification of different capsule “serotype” strains. For example, there are five major capsule serotypes of meningococcus (A, B, C, Y, and W-135), six different capsule serotypes of the respiratory pathogen H. influenzae (a–f), nine capsule serotypes of GBS (Ia, Ib, and II–VIII), and more than 90 different serotypes of pneumococcus, which is a leading cause of bacterial pneumonia, sepsis, and meningitis. Antibodies generated by the host against the capsule of one serotype strain typically do not provide cross-protective immunity. Thus, individuals can be repeatedly infected over their lifetime by different serotypes of the same bacterial pathogen. Figuratively, although the strategy of capsular molecular mimicry used for example by GAS renders the pathogen invisible to immune surveillance, the strategy of antigenic diversity of capsule types presents a moving target to the immune system. Genetic exchange of capsule biosynthetic genes among serotype strains of an individual species (e.g., the polysialyltransferase gene of meningococcus) can lead to capsule switching in vivo, which provides another means of pathogen escape from protective immunity.
In addition to a polysaccharide capsule, Gram-negative bacteria have an outer membrane that is rich in lipopolysaccharide (LPS; Chapter 21), also known as endotoxin. As its name suggests, LPS consists of two parts, a lipid A moiety and glycan components. Lipid A is comprised of two glucosamines, acyl chains and phosphates, which are embedded in the outer membrane. The glycan components extend outward into the bacterial niche. A core oligosaccharide contains some sugars not found in vertebrates (such as ketodeoxyoctulonate [Kdo] and heptose) and a repeating polysaccharide known as the O-antigen that can vary widely among strains within an individual species. Many mucosal pathogens such as H. influenzae, Campylobacter jejuni, and Neisseria gonorrhoeae lack O-antigens; instead, they produce lipooligosaccharides (LOSs) that contain only lipid A and an extended core structure.
LPS is a pathogen-associated molecular pattern (PAMP) that is recognized by the innate immune system and stimulates inflammatory processes, including the classic fever response. Bacteria that have breached the barrier defenses of the skin or mucosa release soluble LPS, which is recognized by membrane receptors CD14 and Toll-like receptor 4 (TLR4), initiating downstream immune signaling processes (Figure 42.2). TLR4 belongs to an evolutionarily conserved family of receptors (TLRs) that can detect a wide array of microbe-derived ligands. For example, the TLR2 receptor can recognize peptidoglycan or lipoteichoic acid derived from the cell walls of Gram-positive bacteria that generally lack LPS. A signaling cascade ultimately leads to the activation of the transcription factor nuclear factor-κB (NF-κB). Translocation of NF-κB into the nucleus leads to the regulation of cellular processes ranging from immune cell differentiation, activation of the inflammasome, and up-regulation of proinflammatory chemokines and cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1).
Activation of immune signaling by bacterial lipopolysaccharide (LPS). LPS from the cell wall of Gram-negative bacteria is bound by the pattern-recognition molecule Toll-like receptor 4 (TLR4) in conjunction with the cell-surface receptor CD14. The binding (more...)
Although TLR-mediated detection of LPS and other microbial molecules is critical for triggering host innate immunity, a dangerous condition known as sepsis can develop in the setting of overwhelming bacterial infections that lead to dysregulated systemic immune responses. Symptoms include fever, low blood pressure, rapid heart rate, abnormal white blood cell counts, and dysfunction of multiple organ systems that may lead to lung or kidney failure and death.
Processes of selection have led to many examples of Gram-negative bacteria that vary or modify the structure of LPS to interfere with antibiotic action and host defenses. For example, some LPS modifications reduce the overall negative charge of LPS (e.g., as phosphoethanolamine or 4-amino-4-deoxy-L-arabinose [L-Ara4N]) and in doing so can repel cationic antimicrobial peptides of host and microbial origin, such as host defensins or bacterial polymyxins. The plague bacillus Yersinia pestis changes the number and type of acyl groups on the lipid A of its LPS in response to temperature changes. At environmental temperatures (∼21°C), Y. pestis, which lacks O-antigens, predominantly expresses a more immunostimulatory hexa-acylated lipid A, whereas at mammalian body temperature (37°C), the pathogen expresses a less immunostimulatory tetra-acylated lipid A. These data suggest that the production of a less immunostimulatory form of LPS on entry into a mammalian host might confer avoidance to immune detection.
Sialic acids and related nonulosonic acids are also synthesized de novo or scavenged from the host for incorporation into the LOS of several Gram-negative pathogens, including pathogenic members of the genera Haemophilus, Neisseria, Campylobacter, and Vibrio. This can be accomplished by several distinct mechanisms and often confers properties of immune evasive and enhanced virulence. For example, the human-specific pathogen N. gonorrhoeae uses a surface sialyltransferase and scavenges the activated form of sialic acid (CMP-Neu5Ac) from the host. Such incorporation thwarts multiple arms of the host complement system and confers resistance to the cationic antimicrobial peptides (CAMPS). An Achilles’ heel of this increasingly drug-resistant pathogen may be the promiscuity of its sialyltransferase toward related nonulosonic acids. Unnatural incorporation of legionaminic acid (CMP-Leg5,7Ac2) in N. gonorrhoeae prevents the immune evasion benefits typically afforded by Neu5Ac; moreover, vaginal administration of CMP-Leg5,7Ac2 leads to more rapid bacterial clearance of genital infections in mice.
Studies of another Gram-negative bacterium, Vibrio vulnificus, underscore that the presence of legionaminic acid in LOS may not always be a deterrence to virulence. V. vulnificus is normally present in environmental (aquatic) ecosystems and is pathogenic in humans only during accidental contact with susceptible individuals, often following consumption of raw or undercooked seafood. Although it is a rare human pathogen, the bacterium can cause bloodstream and disseminated infections that are commonly fatal when they strike. Legionaminic acid contributes to the ability of V. vulnificus to survive in bloodstream and cause disseminated infection following intravenous administration.
Occasionally, the host mounts an (auto)immune response to “self” antigens, including sialylated LOS. For example, the foodborne pathogen, C. jejuni, is capable of expressing a variety of sialylated LOS structures that mimic human gangliosides (Chapters 11 and 46). Sialylation of C. jejuni LOS results in CD14-dependent amplification of mucosal dendritic cell (DC) responses, which promote B-cell proliferation in a T-cell-independent manner. These events may help explain why in a small subset of infections, self-reacting (autoimmune) antibodies are inappropriately produced by B cells, leading to the attack of nerve fibers expressing the relevant gangliosides. These events can result in a life-threatening paralytic disorder known as Guillain–Barré syndrome (GBS). For most patients, GBS symptoms have to be managed by removing cross-reactive antibodies (plasmapheresis) or immunomodulatory therapies such as intravenous immunoglobulin (IVIg).
Adherence to skin or mucosal surfaces is a fundamental characteristic of the normal human microbiome and also an essential first step in the pathogenesis of many important infectious diseases (Chapter 34). Most microorganisms express more than one type of adherence factor or “adhesin” (Chapter 37). A large fraction of microbial adhesins are lectins that bind directly to cell-surface glycoproteins, glycosphingolipids, or glycosaminoglycans. Adhesion may be mediated through terminal sugars or internal carbohydrate motifs. In other cases, the bacteria express adhesins that bind matrix glycoproteins (e.g., fibronectin, collagen, or laminin) or mucin, mediating attachment to the mucosal surface. The specific carbohydrate ligands for bacterial attachment on the animal cell are often referred to as adhesin receptors, and they are quite diverse in nature. The tropism of individual bacteria for particular host tissues (e.g., skin vs. respiratory tract vs. gastrointestinal tract) is determined by specific combinations of adhesin–receptor pairs.
Pili or fimbriae are assemblies of protein subunits that project from the bacterial surface in hair-like threads whose tips often adhere to host glycans (Figure 42.3A). Such pili are usually composed of a repeating structural subunit providing extension and a different “tip adhesin” responsible for binding. The structural proteins for pilus assembly are often encoded in a bacterial operon. Lateral mobility of pili structures in the bacterial membrane provides a Velcro-like binding effect to epithelial surfaces. Certain strains of E. coli express pili that bind avidly to P-blood group–related glycosphingolipids in the bladder epithelium, leading to urinary tract infection. Pathogenic strains of Salmonella produce pili that facilitate adherence to human intestinal cell mucosa, thereby causing food poisoning and infectious diarrhea. In other cases, a surface-anchored protein (afimbrial adhesin) expressed by the bacteria represents a critical colonization factor (Figure 42.3B). For example, the filamentous hemagglutinin (FHA) of Bordetella pertussis promotes strong attachment of the bacteria to the ciliated epithelial cells of the bronchi and trachea, triggering local inflammation and tissue injury that results in the “whooping cough” disease. FHA is a component of modern pertussis vaccines given in infancy and early childhood to block infection.
Examples of mechanisms of bacterial adherence to host cell surfaces. (A) Pili or fimbriae are organelles that project from the cell surface. They are made up of a repeating structural subunit and a protein at their tip that mediates recognition of a specific (more...)
Adhesins can be glycoproteins as well. In Pasteurellaceae and some H. influenzae strains adhesins are N-glucosylated by a cytoplasmic N-glucosylation system that is homologous to the cytoplasmic O-GlcNAc transferase of eukaryotes. Similarly, transfer of heptose residues by the dodecameric bacterial autotransporter heptosyltransferase (BAHT) family of enzymes to autotransporter adhesins in several different Gram-negative pathogens is essential for the adhesion process.
Glycan–lectin interactions play pivotal roles in enabling certain pathogens to penetrate or invade through epithelial barriers, whereupon they may disseminate into and through the bloodstream to produce deep-seated infections. Samonella Typhi causes typhoid fever in humans, a process that begins with intracellular invasion of intestinal epithelial cells. The outer core oligosaccharide structure of the LPS is required for internalization into epithelial cells. Removal of a key terminal sugar residue on the outer core markedly reduces the efficiency of bacterial uptake. Once invasion has occurred, the secreted A2B5 typhoid toxin mediates illness by first binding preferentially to the sialic acid Neu5Ac, which is enriched in humans. Streptococcus pyogenes (GAS), the cause of strep throat, as well as serious invasive infections, attaches to human pharyngeal and skin epithelial cells via interaction of its hyaluronan capsular polysaccharide with the host hyaluronan-binding protein CD44 (Chapter 16). This binding induces marked cytoskeletal rearrangements manifested by membrane ruffling and opening of intercellular junctions that allow tissue penetration by GAS through a paracellular route.
Bacterial glycosyltransferases are also involved in the intracellular manipulation of host responses. For example, injection of the NleB glycosyltransferase into host cells by enteropathogenic E. coli (EPEC) results in the N-GlcNAc modification of arginine residues of host proteins, leading to the suppression of NF-κB-driven responses. Another bacterial glycosyltransferase with an intracellular target is the GlcNAc transferase toxin of Photorhabdus asymbiotica PaTox. PaTox modifies the host Rho GTPase at tyrosine residues, resulting in reduced phagocytosis and disassembly of the actin cytoskeleton in insect and mammalian cells.
Biofilms are assemblies of bacteria affixed to environmental or host surfaces. Within the body, biofilms form on catheters, implanted devices, and other medical products in which their metabolic dormancy together with other physical, biochemical, and biological properties help resist the action of host defenses and antimicrobials. Layers of biofilm are often joined together by extracellular polysaccharides (EPS) that contribute architectural, adhesive, and protective functions. The EPS synthesized by bacteria in biofilms varies greatly in composition and in chemical and physical properties. Likewise, EPSs can have wide-ranging functions within biofilms, which depend on their exact compositions and the many facets of the niches in which they reside. Polysaccharides can also contribute to biofilm persistence by scavenging reactive oxygen species, trapping cationic antimicrobial peptides and antibiotics, and protecting against desiccation.
In the human mouth, polymicrobial biofilms contribute to dental plaque, caries, and periodontal (gum) disease. Dental plaque is a polymicrobial biofilm comprised of hundreds of species in which dense, mushroom-like clumps of bacteria pop up from the surface of the tooth enamel. Biofilm bacteria are interspersed with bacteria-free diffusion channels filled with nucleic acids, proteins, lipids, and EPS (Figure 42.4). Streptococcus species are often the initial colonizers of the tooth enamel and comprise 60%–90% of dental plaque. In periodontal (gum) disease, “early-” and “late-colonizers” of the biofilm are bridged by an impressive variety of lectin-glycan interactions involving the “middle colonizer” Fusobacterium nucleatum. This bacterium is found ubiquitously in the human mouth, but overgrows in the setting of periodontitis, binding to members of the outermost layers of the mature biofilm.
Structure of a polymicrobial biofilm. Dental plaque is an example of a polymicrobial biofilm in which Streptococcus species and other bacteria secrete a thick exopolysaccharide matrix and exist within this matrix in a dormant or sessile state of low metabolic (more...)
Many EPS types are polyanionic because of the presence of either uronic acids (D-glucuronic, D-galacturonic, or D-mannuronic acids) or ketal-linked pyruvate. Inorganic residues, such as phosphate or sulfate, also contribute to the negative charge and modifications such as O-acetylation or sugar epimerization further contribute to EPS complexity.
In several cases, EPS is a homoglycan composed of β-1,6-linked N-acetylglucosamine residues known as poly-N-acetylglucosamine (or PNAG), as exemplified by the adhesive polymer obtained from Staphylococcus epidermidis strains that produce biofilms on catheters. PNAG is common among many oral pathogens and multidrug-resistant bacteria resulting in concerted efforts to target this polymer, especially because antibodies raised against the deacetylated form of PNAG mediate opsonic killing. Interestingly, the periodontal pathogen Aggregatibacter actinomycetemcomitans secretes a PNAG hydrolase known as dispersin B (DspB) that has been shown to effectively disperse biofilms formed by PNAG-producing bacteria and is therefore also being developed as an adjuvant to antibiotic therapy.
Viruses bind to host cells as a prerequisite for entry and intracellular replication. The enrichment of glycans on cell surfaces make them an attractive target for viral attachment and entry. Virus–glycan interactions are often responsible for species and tissue tropism (Table 37.1), as illustrated here with examples of three human pathogens: influenza virus, herpes simplex virus 1 (HSV-1), and human immunodeficiency virus (HIV), showing different modes of glycan-mediated viral interactions (Figure 42.5). Influenza viruses use a sialic acid–recognizing protein (hemagglutinin) for binding and entry (Figure 42.5A). HSV-1 has multiple envelope proteins that bind to heparan sulfate (HS) as the first step in recruitment of a multiprotein virus entry complex (Figure 42.5B). HIV expresses surface glycans that co-opt host lectins to enhance cell dissemination, but has also evolved to use specific protein receptors (Figure 42.5C). In contrast to these three examples, coronaviruses seem to be undergoing more rapid evolution, with regard to preferred ligands. Many of these viruses have a hemagglutinin-esterase (HE) that binds to specific O-acetylated sialic acids and they possess an esterase that cleaves the O-acetyl group. Some coronaviruses have eliminated the HE protein entirely and switched to sialic acid-binding via a spike protein. A few appear to have evolved further to preferentially bind to very specific host glycoproteins such as the angiotensin-converting enzyme 2 (ACE2, for the SARS viruses). SARS-CoV-2 (the cause of the COVID-19 pandemic) has also been shown to bind HS, an interaction that appears necessary for infecting ACE2-positive cells through stabilizing the up conformation of the spike receptor binding domain. Numerous reviews have been pulished on the glycosylation of SARS-CoV-2 proteins (including the spike glycoprotein shown on the cover image), the host glycoproteins involved in viral interaction, and the relevance of glycosylation in SARS-CoV-2 infectivity and immune avoidance, numerous reviews have been published.
Mechanisms of viral entry into host cells. (A) Influenza virus initiates host cell contact and entry by binding to cell-surface sialic acid receptors through its surface glycoprotein hemagglutinin. After intracellular replication, a cell-surface neuraminidase (more...)
Influenza viruses are common human pathogens of the upper respiratory tract. Seasonal epidemics result in hundreds of thousands of deaths annually, with occasional, much more deadly pandemics. Influenza gains entry into cells of the human upper airway by binding to glycans terminated with α2-6-linked sialic acid (preferentially the human enriched one, N-acetylneuraminic acid or Neu5Ac) (Chapter 15). The entry process is mediated by influenza hemagglutinin, named for the method of its discovery. When first isolated in the 1930s, influenza was found to cause clumping (agglutination) of human red blood cells in vitro. Upon continued incubation, the red cells disaggregated and were not reagglutinated by fresh virus. It was hypothesized that a “receptor-destroying enzyme” was responsible. Isolation of the virus-released receptor revealed sialic acid that had been released by a sialidase, a term that is synonymous with neuraminidase. The familiar numbering system H1N1 represents hemagglutinin (H) and neuraminidase (N).
The life cycle of influenza starts with binding of the viral hemagglutinin to cell-surface sialic acids followed by hemagglutinin-mediated fusion with the host cell membrane, release of the virions intracellularly, replication, and then budding of newly assembled virions from the host cell surface. The hemagglutinin directs species and tissue tropism, whereas the neuraminidase is essential for propagation of the infection to neighboring cells. On completing its cellular replication cycle, the release of influenza viruses from infected cell surfaces relies on viral neuraminidase, which removes sialic acid from the surface of the host cells and the virion envelope. Without neuraminidase, newly formed virions stick together, form large rafts, and do not spread to other cells. Two rationally designed influenza virus neuraminidase inhibitor-based anti-influenza drugs, Relenza and Tamiflu, operate on this basis (Chapters 55 and 57).
Emergence of new human influenza strains occurs via transmission from other animal species, especially poultry. Sialic acid linkages in these different systems is key to understanding species tropism. Glycan array screening revealed that avian influenza binds to glycans terminated with α2-3 linked Neu5Ac, whereas human isolates bind to glycans terminated with α2-6 Neu5Ac. Neu5Ac in the α2-3 linkage is common in the intestinal tracts of birds but not found at substantial levels in the human upper airway. In contrast, α2-6-linked Neu5Ac predominates in the human upper airway. The switch from α2-3 to α2-6 binding is thought to underlie the emergence of new human influenza strains. This switch can occur by mutation of one or two amino acids in the hemagglutinin sialic acid–binding pocket. The emergence of animal influenza strains that bind α2-6 sialic acids is now monitored to detect potential new human influenza pathogens. Pigs are susceptible to both α2-3 (avian) and α2-6 (human) viruses, and can act as a “mixing vessel” to produce recombinant viruses capable of transmission from birds to humans. Direct avian–human transmission is often associated with enhanced morbidity, but human-to-human spread of avian influenza is uncommon. Notably, ferrets are the most effective animal model for human influenza studies as they have similar upper airway glycans terminated with α2-6 Neu5Ac.
Several nonenveloped viruses also have sialic acid–binding proteins on their icosahedral capsids including reovirus, adenovirus, parvovirus, and rotavirus, each of which binds to different sets of sialoglycans.
Heparan sulfate (HS) proteoglycans, which are widely distributed on vertebrate cells (Chapter 17), are implicated in the infective process of many pathogenic viruses including adeno-associated viruses, dengue viruses, hepatitis C virus, vaccinia virus, HIV, papillomavirus, and virtually all herpesviruses. In many cases, HS is a coreceptor, initiating attachment before recruitment of other host receptor proteins that support viral entry. A prominent example is HSV-1, also known as human herpesvirus 1 (HHV-1), one of the eight currently known human herpesviruses that cause widespread disease.
HSV-1 establishes latent, recurrent infections of mucous membranes, particularly lesions of the mouth and lips (cold sores, fever blisters) but also of genital tract and cornea, the latter of which may cause blindness. Unlike most other viruses, in which host cell binding and entry are mediated by one or two viral proteins, herpesvirus entry requires several viral entry glycoproteins, some of which are shared among all herpesvirus family members. One shared viral glycoprotein, gB, initiates virus attachment by binding to cell-surface HS, as does gC in HSV-1. Once bound, the virus “surfs” the cell surface until it encounters other receptors, including a specific HS structure, 3-O-sulfation on GlcNAc. This relatively rare HS modification induces binding of gD, another glycoprotein shared in the herpesvirus family. Once gD binds, it recruits additional proteins required for fusion and host cell entry.
Removal of HS from cell surfaces enzymatically or by selection of mutant cells defective in HS expression renders the cells resistant to HSV-1 infection by reducing virus attachment. Soluble heparin and HS mimetics inhibit viral infection by masking the HS-binding domain on the virus envelope. Immobilized HS columns bind to the HSV-1 viral entry proteins gB and gC, and HSV-1 deletion mutants lacking gB and gC exhibit impaired virus binding. Genetic evidence of a role of 3-O-sulfation of HS GlcNAc in HSV-1 infection was obtained by altering the expression of 3-O-sulfotransferase genes in cells and living organisms. Recent evidence suggests that up-regulation of the host's own heparanase helps newly budded HSV-1 to disseminate to neighboring cells, analogous to the role of influenza neuraminidase. Although the herpesviruses have evolved much more complex systems for host cell binding and entry, some of which remain to be established, it is clear that HS plays important roles in viral pathogenesis.
HIV is a retrovirus and the etiologic agent of the acquired immunodeficiency syndrome (AIDS), a pandemic disease affecting tens of millions of people worldwide. HIV is an enveloped virus with a surface dominated by spikes made of two proteins, gp120 and gp41, of which gp120 mediates viral attachment to host cells, primarily CD4+ T cells, by binding to the host cell-surface receptor CD4 and a chemokine receptor coreceptor such as CCR5 or CXCR4. HIV gp120 is heavily glycosylated, with N-linked glycans comprising half of the spike mass and densely covering much of the spike surface. Dense glycosylation is thought to aid in immune evasion by masking the underlying polypeptide. However, gp120 glycans also actively support infection by co-opting host lectins, including C-type lectins on DCs (Chapter 34).
DCs are innate immune cells that capture and present antigens to T cells to initiate adaptive immunity. DCs capture antigens, in part, using C-type lectins that bind to glycan determinants common to pathogens but uncommon on host cells. Although DCs are not numerous, they are important in recognizing and presenting pathogen antigens to the adaptive immune system. DCs that reside in submucosal tissues of the vagina and rectum are early targets for HIV. Even with low levels of viral exposure, C-type lectins on DCs trap and concentrate HIV for subsequent presentation to T cells, the main site of HIV replication. DC-SIGN (dendritic cell–specific intercellular adhesion molecule-3-grabbing nonintegrin), mannose receptor, and Langerin are some of the C-type lectins that are important for this process. These lectins recognize dense arrays of mannose on pathogens including certain viruses (HIV, CMV [cytomegalovirus], hepatitis C virus, dengue virus), bacteria (Helicobacter, Klebsiella, Mycobacteria), fungi (Candida), and parasites (Leishmania, Schistosoma). Although T cells normally function to destroy pathogens and process their antigens for presentation, lectin-bound HIV evades destruction for extended periods. The natural role of DCs in presentation to T cells makes them ideal conduits for transmission of HIV to CD4+ T cells, in which CD4 and cytokine receptors support binding, fusion, and viral replication. This process is termed trans-infection and facilitates early establishment of the HIV infection. DCs are not the only cells co-opted by HIV; macrophages express the same lectins and may also facilitate trans-infection. Other host lectins on DCs and macrophages, such as Siglec-1 (Chapter 35) play a similar role in facilitating uptake of viruses with heavily sialylated envelopes.
The nature of the relationship between microbes and the human host spans the spectrum from mutually beneficial (symbiotic), to benefiting the microbe without harming the host (commensal), to benefiting the microbe at the expense of the host (pathogenic). Glycans are key factors in the microbe–host interactions that occur along this continuum.
Bacteroides thetaiotaomicron is an anaerobic bacterium that is a common member of the normal colonic microbiota in mice and humans. This microbe has evolved mechanisms to maintain a mutually beneficial relationship with its mammalian host. A clue to this symbiosis came from examination of the gut epithelium of mice that are raised under germ-free conditions. Without bacterial exposure, the intestinal epithelium lacks expression of fucosylated glycoconjugates; when normal colonic bacteria are present, Fucα1-2Gal glycan expression is abundant on the surface of these host cells. B. thetaiotaomicron preferentially uses fucose both as an energy source and for incorporation into its own surface capsule and glycoproteins, phenotypes that are required for successful colonization and for proper immune development of the host. When dietary fucose is low, the bacterium induces the expression of host α1-2 fucosyltransferase, resulting in the expression of fucosylated (Fucα1-2Gal) glycoconjugates on the epithelium. B. thetaiotaomicron also expresses multiple fucosidases to cleave these terminal fucose residues and a fucose permease for uptake of the released sugar. Thus, the gut commensal has evolved a system for engineering the production of its own nutrient source from its host. This system is regulated for use only in times of need (during host fasting). B. thetaiotaomicron has evolved elaborate systems for regulating the expression of polysaccharide-binding proteins and glycosidases to forage and consume sugars from the host's diet or to switch over to glycans in the host mucus lining when sufficient polysaccharides are missing from the diet.
Helicobacter pylori colonizes nearly half the world's population, but it triggers chronic gastritis and stomach ulcers (conditions that are known to increase the risk of stomach cancer) in a subset of these individuals. Glycans of both the host and microbe contribute to whether H. pylori persists as a benign commensal or triggers disease pathology. H. pylori expresses an adhesin (BabA) that can interact with terminal Lewis b blood group antigen-containing glycans of the gastric epithelium. Lewis b expression in human intestines is limited to mucus-producing pit cells in the gastric epithelium. Transgenic mice engineered to express Lewis b show enhanced binding of H. pylori to their gastric epithelium, which triggers an enhanced cellular immune response and more severe gastritis. This microenvironment of immune activation appears to set the stage for a glycan-based process of molecular mimicry that can promote further host cell damage. H. pylori also expresses Lewis x–containing structures in the O-antigen of its LPS, which resemble Lewis x–modified glycans on the surface of parietal cells in the gastric lining. This Lewis antigen mimicry can be varied through the expression of two variable α1,3 fucosyltransferases, FutA and FutB. Similar to B. thetaiotaomicron, H. pylori has also developed mechanisms to obtain fucose from its host. The presence of H. pylori stimulates the host to secrete α-L-fucosidase 2 (FUCA2). This, in turn, increases the expression of the Lewis x–containing LPS O-antigen in H. pylori. Variation in both organism and host in the expression of Lewis x glycan structures and/or the adhesins may help explain the wide range of potential clinical outcomes following colonization by H. pylori.
This chapter provides only a glimpse of the diverse roles glycans play in the interactions between individual viruses and bacteria with their hosts. As scientists explore varying environments and their associated microbial communities (which also include parasites, fungi, and bacteriophages), it is becoming increasingly apparent that glycans influence every aspect of these interactions and there remains so much more to discover.
The authors acknowledge contributions to the previous version of this chapter from Victor Nizet and Jeffrey D. Esko and helpful comments and suggestions from Frederique Lisacek.
The content of this book is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 Unported license. To view the terms and conditions of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/
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