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Glycan arrays as tools for infectious disease research
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ScienceDirect Glycan arrays as tools for infectious disease research Andreas Geissner1,2, Chakkumkal Anish1 and Peter H Seeberger1,2 Infectious diseases cause millions of deaths worldwide each year and are a major burden for economies, especially in underdeveloped countries. Glycans and their interactions with other biomolecules are involved in all major steps of infection. Glycan arrays enable the rapid and sensitive detection of those interactions and are among the most powerful techniques to study the molecular biology of infectious diseases. This review will focus on recent developments and discuss the applications of glycan arrays to the elucidation of host–pathogen and pathogen–pathogen interactions, the development of tools for infection diagnosis and the use of glycan arrays in modern vaccine design. Addresses 1 Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mu¨hlenberg 1, 14424 Potsdam, Germany 2 Institute for Chemistry and Biochemistry, Freie Universita¨t Berlin, Arnimallee 22, 14195 Berlin, Germany Corresponding authors: Anish, Chakkumkal ([email protected]) and Seeberger, Peter H ([email protected])
Current Opinion in Chemical Biology 2014, 18:38–45 This review comes from a themed issue on Arrays Edited by Robert S Matson and David F Smith
1367-5931/$ – see front matter, # 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cbpa.2013.11.013
mediate attachment to host cells and subsequent invasion [4–7], while host GBPs promote pathogen recognition, immune activation and clearance. Some secreted bacterial proteins like toxins A and B from Clostridium difficile use cell surface glycans as receptors [8]. Plasmodium falciparum even secretes a glycosylphosphatidylinositol (GPI) glycan toxin [9,10]. Glycan arrays, also known as carbohydrate microarrays or glycochips, are powerful tools to study the role of carbohydrates and their interactions with GBPs during infection. The arrays are created by immobilizing carbohydrates that are either derived from natural sources or obtained by chemical synthesis on a surface. Today, modified glass slides are most commonly used for glycan presentation. Binding of molecules such as proteins or whole cells to immobilized glycans is then visualized by various detection methods (see Figure 1). Glycan arrays are ideal platforms requiring minimal amounts of glycans for interrogating a multitude of binding events. The most comprehensive glycan arrays carry several hundred structures, but in principle the platform can be expanded to many thousand glycans [11,12]. Tailored glycan microarrays carrying only few relevant structures in repetitive printing patterns allow for high-throughput analysis of multiple samples on the same slide. When multiple fluorescent probes are employed, different interaction partners such as antibody isotypes can be analyzed on the same array. Reviewed are applications of glycan arrays as they relate to different areas of ID research such as deciphering host–pathogen and pathogen–pathogen interactions, prevention of infection and development of diagnostic tools.
Investigation of host–pathogen interactions using glycan arrays Introduction Infectious diseases (IDs) are the major cause of death in many countries and prevention and successful treatment of IDs has been named a millennium goal of the United Nations [1]. A better understanding of the complex and interrelated factors that contribute to evolution and survival of infectious agents is required as a basis for true breakthroughs for vaccination and therapeutic approaches. Cell surface glycans and glycan binding proteins (GBPs) regulate many processes during disease manifestation and immune response. For example, bacterial capsular polysaccharide (CPS) is involved in the evasion of immune processes such as recognition, complement activation and opsonophagocytosis [2]. Being a surface-exposed antigen, CPS is the basis for highly successful vaccines against Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae that induce both direct and indirect protection through herd immunity and enjoy great economic success [3]. Pathogenic GBPs Current Opinion in Chemical Biology 2014, 18:38–45
Key events during onset and progression of infection and clearance of pathogens involve GBPs that recognize carbohydrates. These events include pathogen adhesion to host cells and subsequent invasion, cell binding and entry by toxins as well as immune recognition and evasion. A better understanding of these interactions by using glycan arrays may provide the basis for novel modes of therapy. All classes of pathogens rely on GBPs for cell adhesion (for recent reviews see [4–7]). Hemagglutinins (HAs) are surface proteins of influenza viruses that bind to sialic acid containing glycans on host cells to initiate the invasion process. The HAs determine the serotype of different strains. Carbohydrate binding preferences of recombinant HAs from different strains, including that responsible for the 1918 pandemic, were compared with the help of glycan arrays in a broad study as early as 2006 [13]. Many other studies have investigated influenza strains infecting www.sciencedirect.com
Glycan arrays as tools for infectious disease research Geissner, Anish and Seeberger 39
Figure 1
Quantification
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1,2 1,0 0,8 0,6 0,4 0,2 0,0
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0
20
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60 80 100 120 140 160 Glycan ID
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Schematic principle of glycan arrays. In the most common setup, carbohydrates dissolved in buffer are printed onto a chemically activated glass surface. Slides are subsequently incubated with a solution of the putative binding partner, starting from proteins (shown: hemagglutinin structure 2FK0 [13]) over viruses, bacteria, and engineered yeast cells [41] to whole mammalian cells [85]. Binding is detected either by using a directly fluorescently labeled construct as binding partner or by immunological means. For relative binding evaluation, the fluorescence intensities of the different spots are quantified.
humans, birds, swine and other animals using either purified protein or fluorescence labeled whole virus particles [14–25]. These experiments confirmed the decades-old [26] hypothesis that avian strains preferably bind to a2,3 linked and human strains to a2,6 linked sialic acids, including chemically modified ones [20]. However, significant binding to glycans containing sialic acids with the respective other linkage was also detected in many cases. Glycan arrays served as detection system for changes in binding behavior in a recent HA mutagenesis study determining the necessary HA amino acid changes for avian influenza strains to allow respiratory droplet transmission in humans leading to complete switching of hosts to humans [27]. Even the most elaborate glycan arrays used for influenza research still leave room for optimization as glycoproteomics studies demonstrated that even the array with the highest number of relevant structures available today — the mammalian array from the Consortium for Functional Glycomics (CFG) — only covers half of the sialic acid containing glycan structures that exist in the human respiratory tract [28]. For www.sciencedirect.com
example, structures containing extended N-acetyllactosamine repeats that are bound by HA are missing [29]. Glycan array analysis of parainfluenza virus [30,31] and Serotype 1 reovirus [32] also revealed binding to sialic acid terminated glycans. For serotype 1 reovirus, preferential binding to ganglioside GM2 was detected implicating participation of this glycan in the preferential infection of certain cell types, including cancer cells with aberrant glycosylation patterns. Overall, an analysis of all data of the CFG array using a motif-based algorithm revealed that viral lectins have the least diverse target structures [33]. Glycan array studies on non-viral lectins such as parasite micronemal protein MIC1 from Toxoplasma gondii [34] and the related MIC3 protein from the economically important avian parasite Eimeria tenella [35] also demonstrated binding to sialic acid terminated glycans. Both proteins play a crucial role in invasion and subsequent onset of intracellular infection. Sialic acid might also play Current Opinion in Chemical Biology 2014, 18:38–45
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a role in the initiation of placental malaria as implicated by preferential binding of whole Plasmodium falciparum infected red blood cells to Lewis-type glycans including sialyl LewisX on glycan array [36]. The glycotope in the Anopheles mosquito midgut that is recognized by a malarial transmission blocking monoclonal antibody (mAb) was mapped using glycan arrays suggesting the role of putative targets of malarial GBPs involved in homing to the midgut [37]. In the case of the opportunistic pathogen Campylobacter jejuni, binding of whole fluorescence labeled bacteria showed culture condition dependent binding not only to glycans with terminal sialic acids, but also mannoses, fucoses and galactoses [38,39]. Fucose was also identified as receptor for Burkholderia ambifaria BamBL [40] and galactose for the Candida glabrata EPA family [41,42] and Pseudomonas aeruginosa lectin PA-IL [43]. For PA-IL, quantitative evaluation of binding and inhibition on an array containing glycomimetic structures with terminal galactoses underlines the potential of glycan arrays in research for new anti-bacterial therapeutics [44]. In some cases, not only the pathogens themselves, but also secreted toxins bind to cell surface glycans in order to initiate cell entry. This mode of binding had been known for tetanus neurotoxin [45] and toxins from Clostridium [8] for some time. Recently, microarray analysis elucidated the heptasaccharide core of complex N-glycans as the glycan receptor of cytolysin from Vibrio cholerae [46] and was also used for elucidation of binding fine specificity of cholera toxin towards GM1 related glycans [47]. The examples above clearly demonstrate that the glycans on currently available microarrays are diverse enough to include the receptors — or at least similar glycans — of many important pathogens and their toxins. However, host–pathogen interactions also involve the recognition of bacterial glycan structures by host proteins. To study the GBPs involved here, binding events to bacterial glycans have to be measured. As the bacterial glycome is much more diverse than that of mammals [48], and the arrays designed for this purpose are not as advanced as those containing mammalian sugars [12], glycan array analysis in this field is still limited when compared to questions involving mammalian glycans. Generally, the mammalian innate immune system recognizes pathogens via pathogen associated molecular patterns (PAMPs) including carbohydrates. Those PAMPs are sensed by pattern recognition receptors such as Tolllike receptors (TLRs) and carbohydrate binding C-type lectin receptors (CLRs), prompting an inflammatory response [49,50]. For microarray analysis, the putative carbohydrate recognition domains of those transmembrane receptors have to be expressed in a soluble form, for example by fusing them to the heavy chain of immunoglobulin G, thereby also facilitating detection. These Current Opinion in Chemical Biology 2014, 18:38–45
Ig-fusion-proteins, like antibodies themselves, contain two binding sites. In a broad study on the CFG mammalian array, specific binding was observed for eight out of fourteen analyzed innate immune receptors allowing detailed conclusions regarding binding preferences [51]. No signals were seen for several CLRs and TLR2, possibly because the putative targets are pathogen-derived glycans and therefore not present on the CFG array. Failure to find binding partners may also be a result of dissociation of bound proteins during the washing steps. This was demonstrated recently for murine CLR SIGNR1 [52] when comparing its specificity to human DC-SIGN using a glycan array with evanescent field fluorescence detection [53]. With this technique that renders washing steps unnecessary, specific binding for SIGNR1 was seen in contrast to an earlier study on the CFG plate array [54]. Apart from the necessity and vigor of the washing procedures, numerous factors including differences in density and amount of arrayed glycans and the type of linker used for immobilization can also influence accurate detection of weak interactions on glycan arrays. The importance of the linker structure was recently demonstrated by Grant et al. [55] using molecular dynamics simulations of the various linkers employed by the CFG to study its effect on glycan presentation on array surfaces. In case of certain linkers, lower accessibility was observed [55]. Innate immune receptors that are not transmembrane proteins lend themselves very well to binding studies involving glycan arrays. The binding specificities of different galectins [53,56,57], ficolins [58,59], collectins such as surfactant protein D [60] and members of other families like ZG16p [61] have been elucidated using glycan arrays. Protein-carbohydrate interactions in immunity are not restricted to the innate immune system. Anti-glycan antibodies are also an important means of fighting infections. The possibility of studying these antibodies on glycan arrays will be discussed in the section on vaccines. Survival of pathogens in the host depends on their ability to evade the host’s immune system. Staphylococcus aureus has developed some very advanced mechanisms to achieve immune evasion (reviewed in [62]). Among those strategies are the superantigen-like proteins (SSLs) blocking specific immune mechanisms. Glycan arrays were employed to identify the sialic acid containing target glycans of SSL4, 5, and 11 and therefore helped to elucidate the mechanism of how these three proteins inhibit neutrophil recruitment and activation [63–65]. Another quite common evasion mechanism is formation of a polysaccharide capsule that inhibits complement deposition. GBPs are necessary to structure the capsule, as shown in the case of E. coli WZI, where glycan array analysis substantiated the hypothesis of glycan binding ability [66]. www.sciencedirect.com
Glycan arrays as tools for infectious disease research Geissner, Anish and Seeberger 41
Glycan arrays as tools to study pathogen– pathogen interactions Recognition of glycans by bacterial lectins is a major process in biofilm formation and cell-to-cell interactions. Numerous microbial lectins such as Pseudomonas aeruginosa lectin PA-IIL [67], PA-IL [43], Pseudomonas fluorescens Pf0-1 antiviral lectin [68], and Burkholderia cenocepacia lectin BC2L-C [69] have been analyzed for their binding specificities. Recently, synthetic fucosylated glycoclusters were evaluated on a glycan array for binding to PA-IIL, a lectin that regulates biofilm formation [66]. Burkholderia cenocepacia lectin A binding to lipopolysaccharides was mapped and saturation transfer difference NMR (STD NMR) was used to derive a structural explanation of the binding preference indicating the role this lectin plays in regulating bacteria to bacteria communication [70].
Glycan arrays in infectious disease prevention Vaccination is the most effective way to prevent infectious diseases. This section will discuss the application of glycan arrays in developing better carbohydrate vaccines. The first major task in the development of glycan-based vaccines is the assignment of candidate structures. Detailed analysis of antibodies elicited during infection can be performed quickly for many potential structures on glycan array to yield information on glycotopes that are recognized by the immune system of patients
(see Figure 2). This antibody analysis is usually performed on large sets of sera, but in case of human immunodeficiency virus (HIV), patient-derived broadly neutralizing monoclonal antibodies (bnmAbs) are routinely investigated. A large number of HIV bnmAbs has been studied on glycan arrays, beginning with 2G12 a decade ago [14,71,72], and recently completely new, even more potent sets of antibodies that were obtained through innovative cloning methods [73]. Most of those antibodies were shown to bind to high mannose Nglycans, albeit with fine specificities that differ from each other and from 2G12 as shown by an analysis of the deletion sequences that contain only parts of the putative target [74,75]. In contrast, bnmAb PGT121 was recently shown to bind complex-type N-glycans, but other characterization data suggested that the actual epitope involves high mannose glycans with an interaction too weak to be picked up by glycan arrays or that is dependent on interactions with non-glycan parts of the epitope [76,77]. As already stated, similar glycan array analyses, including binding to deletion sequences, have been performed for other pathogens using large numbers of serum samples. In addition to the GPIs from Plasmodium falciparum [78], isolated glycans from Schistosoma mansoni [79] and very recently synthetic structures based on PS-I surface glycan and lipoteichoic acid of Clostridium difficile [80,81] have
Figure 2
Specificity evaluation
Synthesis
Candidate structures
monoclonal antibody
or
sera from patients
Neoglycoconjugates
Immunological evaluation
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Sample workflow for glycan array assisted analysis of antibodies in vaccine design. Specificities of either existing, highly potent monoclonal antibodies or of antibodies in a large number of sera from patients are evaluated on glycan array. Glycans that are picked up in those screens are subsequently conjugated to carrier proteins for evaluation of immunogenicity. www.sciencedirect.com
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been investigated to define promising glycotopes for potential vaccines. Once candidate structures for vaccines have been defined, their suitability is tested in immunization experiments. Again, glycan arrays can help to determine the success of immunizations in terms of antibody titers, specificity analysis, isotype switching and subtyping of immunoglobulins [81,82]. Apart from vaccination, shielding potential hosts from contact with the causative agent may also confer protection. In an elegant study, Yu et al. [83] isolated, separated and printed glycans from human milk and showed that some viruses, including the influenza virus, were able to bind to the printed glycans. This binding proves that human milk contains soluble receptors for those viruses which probably inhibit binding to the host cells. Shielding hosts is also performed by isolating patients of highly contagious diseases to prevent epidemics. For that, a quick and reliable detection of certain pathogens is necessary. Development of tools for this task can be assisted by glycan arrays, as seen recently for monoclonal antibodies with the ability to specifically detect the causative agent of plague, Yersinia pestis [82].
Glycan array assisted development of diagnostic tools Glycan specific antibodies are regarded as biomarkers to detect and diagnose numerous infections. Glycan arrays offer a versatile platform to analyze clinical specimens to screen for anti-glycan antibodies for serodiagnosis of infectious agents. Glycan arrays of synthetic Plasmodium falciparum GPI glycans were used to compare anti-GPI IgG levels in individuals from malaria-endemic areas with non-exposed individuals and to determine the effect of exposure to the malaria parasite in previously nonexposed individuals [78]. Results revealed distinct differences in GPI antigens recognized as a result of malaria exposure. Recently, we showed that antibodies to Clostridium difficile surface glycans correlate with decreased disease severity, indicating the vaccine potential of those glycans [81]. Other examples to illustrate the approach include profiling of mellidosis patients and animals vaccinated or infected with anthrax or tularemia-causing bacteria, salmonellosis patients, Clostridium difficile patients, and Schistosoma mansoni infected individuals [84].
Conclusions Glycan arrays have become versatile tools to address various aspects of ID research. Arrays containing diverse mammalian glycans have been used to study mammalian pathogen receptors and yielded impressive results even though the most elaborate and diverse arrays still leave room for improvement. Glycan arrays that cover a broad spectrum of chemically defined glycans from important Current Opinion in Chemical Biology 2014, 18:38–45
pathogens are still missing. Given the immense diversity of the bacterial glycome, creating such arrays is going to be a huge undertaking. However, arrays of pathogen related glycans are an important step towards a better understanding of glycan involvement in infectious diseases.
Acknowledgements The authors gratefully acknowledge generous financial support by the Max Planck Society, the German Federal Ministry of Education and Research and the Ko¨rber Foundation. Felix Broecker and Benjamin Schumann are acknowledged for critically reviewing the article.
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45. Chen C, Fu Z, Kim JP, Barbieri JT, Baldwin MR: Gangliosides as high affinity receptors for tetanus neurotoxin. J Biol Chem 2009, 284:26569-26577. 46. Levan S, De S, Olson R: Vibrio cholerae cytolysin recognizes the heptasaccharide core of complex N-glycans with nanomolar affinity. J Mol Biol 2013, 425:944-957. 47. Kim CS, Seo JH, Cha HJ: Functional interaction analysis of GM1-related carbohydrates and Vibrio cholerae toxins using carbohydrate microarray. Anal Chem 2012, 84:6884-6890. 48. Adibekian A, Stallforth P, Hecht M, Werz DB, Gagneux P, Seeberger PH: Comparative bioinformatics analysis of the mammalian and bacterial glycomes. Chem Sci 2011, 2:337. A bioinformatic comparison of mammalian and bacterial glycomes outlining similarities and differences that influence design of vaccines and diagnostic tools. 49. Takeuchi O, Akira S: Pattern recognition receptors and inflammation. Cell 2010, 140:805-820. 50. Geijtenbeek TBH, Gringhuis SI: Signalling through C-type lectin receptors: shaping immune responses. Nat Rev Immunol 2009, 9:465-479. 51. Hsu T, Cheng S, Yang W, Chin S, Chen B, Huang M, Hsieh S, Wong C: Profiling carbohydrate–receptor interaction with recombinant innate immunity receptor-Fc fusion proteins. J Biol Chem 2009, 284:34479-34489. 52. Takahara K, Arita T, Tokieda S, Shibata N, Okawa Y, Tateno H, Hirabayashi J, Inaba K: Difference in fine specificity to polysaccharides of Candida albicans mannoprotein between mouse SIGNR1 and human DC-SIGN. Infect Immun 2012, 80:1699-1706. A comparative study of similar immune receptors between humans and mice showing the potential of glycan arrays to elucidate differences in receptor fine specificity. Also underlines the potential of evanescent-field fluorescence detection. 53. Tateno H, Mori A, Uchiyama N, Yabe R, Iwaki J, Shikanai T, Angata T, Narimatsu H, Hirabayashi J: Glycoconjugate microarray based on an evanescent-field fluorescenceassisted detection principle for investigation of glycanbinding proteins. Glycobiology 2008, 18:789-798. 54. Powlesland AS, Ward EM, Sadhu SK, Guo Y, Taylor ME, Drickamer K: Widely divergent biochemical properties of the complete set of mouse DC-SIGN-related proteins. J Biol Chem 2006, 281:20440-20449. 55. Grant OC, Smith HMK, Firsova D, Fadda E, Woods RJ: Presentation, presentation, presentation! Molecular level insight into linker effects on glycan array screening data. Glycobiology 2014, 24:17-25. 56. Horlacher T, Oberli MA, Werz DB, Kro¨ck L, Bufali S, Mishra R, Sobek J, Simons K, Hirashima M, Niki T et al.: Determination of carbohydrate-binding preferences of human galectins with carbohydrate microarrays. ChemBioChem 2010, 11: 1563-1573. 57. Stowell SR, Arthur CM, Dias-Baruffi M, Rodrigues LC, Gourdine J, Heimburg-Molinaro J, Ju T, Molinaro RJ, Rivera-Marrero C, Xia B et al.: Innate immune lectins kill bacteria expressing blood group antigen. Nat Med 2010, 16:295-301. 58. Krarup A, Mitchell DA, Sim RB: Recognition of acetylated oligosaccharides by human L-ficolin. Immunol Lett 2008, 118:152-156. 59. Gout E, Garlatti V, Smith DF, Lacroix M, Dumestre-Perard C, Lunardi T, Martin L, Cesbron J, Arlaud GJ, Gaboriaud C et al.: Carbohydrate recognition properties of human ficolins: glycan array screening reveals the sialic acid binding specificity of Mficolin. J Biol Chem 2010, 285:6612-6622. 60. Crouch E, Hartshorn K, Horlacher T, McDonald B, Smith K, Cafarella T, Seaton B, Seeberger PH, Head J: Recognition of mannosylated ligands and influenza A virus by human surfactant protein D: contributions of an extended site and residue 343. Biochemistry 2009, 48:3335-3345. 61. Tateno H, Yabe R, Sato T, Shibazaki A, Shikanai T, Gonoi T, Narimatsu H, Hirabayashi J: Human ZG16p recognizes Current Opinion in Chemical Biology 2014, 18:38–45
pathogenic fungi through non-self polyvalent mannose in the digestive system. Glycobiology 2012, 22:210-220. 62. Zecconi A, Scali F: Staphylococcus aureus virulence factors in evasion from innate immune defenses in human and animal diseases. Immunol Lett 2013, 150:12-22. 63. Chung MC, Wines BD, Baker H, Langley RJ, Baker EN, Fraser JD: The crystal structure of staphylococcal superantigen-like protein 11 in complex with sialyl Lewis X reveals the mechanism for cell binding and immune inhibition. Mol Microbiol 2007, 66:1342-1355. 64. Hu H, Armstrong PCJ, Khalil E, Chen Y, Straub A, Li M, Soosairajah J, Hagemeyer CE, Bassler N, Huang D et al.: GPVI and GPIba mediate staphylococcal superantigen-like protein 5 (SSL5) induced platelet activation and direct toward glycans as potential inhibitors. PLOS ONE 2011, 6:e19190. 65. Hermans SJ, Baker HM, Sequeira RP, Langley RJ, Baker EN, Fraser JD: Structural and functional properties of staphylococcal superantigen-like protein 4. Infect Immun 2012, 80:4004-4013. 66. Bushell SR, Mainprize IL, Wear MA, Lou H, Whitfield C, Naismith JH: Wzi is an outer membrane lectin that underpins group 1 capsule assembly in Escherichia coli. Structure 2013, 21:844-853. 67. Gerland B, Goudot A, Pourceau G, Meyer A, Dugas V, Cecioni S, Vidal S, Souteyrand E, Vasseur J, Chevolot Y et al.: Synthesis of a library of fucosylated glycoclusters and determination of their binding toward Pseudomonas aeruginosa lectin B (PA-IIL) using a DNA-based carbohydrate microarray. Bioconjug Chem 2012, 23:1534-1547. 68. Sato Y, Morimoto K, Kubo T, Yanagihara K, Seyama T, Chammas R: High mannose-binding antiviral lectin PFL from Pseudomonas fluorescens Pf0-1 promotes cell death of gastric cancer cell MKN28 via interaction with a2-integrin. PLOS ONE 2012, 7:e45922. 69. Sˇula´k O, Cioci G, Lameigne`re E, Balloy V, Round A, Gutsche I, Malinovska´ L, Chignard M, Kosma P, Aubert DF et al.: Burkholderia cenocepacia BC2L-C is a super lectin with dual specificity and proinflammatory activity. PLoS Pathog 2011, 7:e1002238. 70. Marchetti R, Malinovska L, Lameigne`re E, Adamova L, Castro C, de Cioci G, Stanetty C, Kosma P, Molinaro A, Wimmerova M et al.: Burkholderia cenocepacia lectin A binding to heptoses from the bacterial lipopolysaccharide. Glycobiology 2012, 22:13871398. 71. Adams EW, Ratner DM, Bokesch HR, McMahon JB, O’Keefe BR, Seeberger PH: Oligosaccharide and glycoprotein microarrays as tools in HIV glycobiology: glycan-dependent gp120/protein interactions. Chem Biol 2004, 11:875-881. 72. Bryan MC, Fazio F, Lee H, Huang C, Chang A, Best MD, Calarese DA, Blixt O, Paulson JC, Burton D et al.: Covalent display of oligosaccharide arrays in microtiter plates. J Am Chem Soc 2004, 126:8640-8641. 73. Klein F, Gaebler C, Mouquet H, Sather DN, Lehmann C, Scheid JF, Kraft Z, Liu Y, Pietzsch J, Hurley A et al.: Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein. J Exp Med 2012, 209:1469-1479. 74. Walker LM, Huber M, Doores KJ, Falkowska E, Pejchal R, Julien J, Wang S, Ramos A, Chan-Hui P, Moyle M et al.: Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 2011, 477:466-470. A study examining fine specificity of 23 broadly neutralizing monoclonal HIV antibodies, clearly shows how glycan array deletion sequence analysis can help to define possible target structures for carbohydrate vaccines. 75. Pejchal R, Doores KJ, Walker LM, Khayat R, Huang P, Wang S, Stanfield RL, Julien J, Ramos A, Crispin M et al.: A potent and broad neutralizing antibody recognizes and penetrates the HIV glycan shield. Science 2011, 334:1097-1103. 76. Mouquet H, Scharf L, Euler Z, Liu Y, Eden C, Scheid JF, HalperStromberg A, Gnanapragasam PNP, Spencer DIR, Seaman MS www.sciencedirect.com
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et al.: Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies. Proc Natl Acad Sci USA 2012, 109:E3268. 77. Julien J, Sok D, Khayat R, Lee JH, Doores KJ, Walker LM, Ramos A, Diwanji DC, Pejchal R, Cupo A et al.: Broadly neutralizing antibody PGT121 allosterically modulates CD4 binding via recognition of the HIV-1 gp120 V3 base and multiple surrounding glycans. PLoS Pathog 2013, 9:e1003342.
81. Martin CE, Broecker F, Oberli MA, Komor J, Mattner J, Anish C, Seeberger PH: Immunological evaluation of a synthetic Clostridium difficile oligosaccharide conjugate vaccine candidate and identification of a minimal epitope. J Am Chem Soc 2013, 135:9713-9722. Study on Clostridium difficile PS-I surface glycan showing the power of glycan arrays in pre-clinical evaluation of synthetic glycans as vaccine candidates, including serum antibody screening and immunogenicity evaluation in the mouse model.
78. Kamena F, Tamborrini M, Liu X, Kwon Y, Thompson F, Pluschke G, Seeberger PH: Synthetic GPI array to study antitoxic malaria response. Nat Chem Biol 2008, 4:238-240.
82. Anish C, Guo X, Wahlbrink A, Seeberger PH: Plague detection by anti-carbohydrate antibodies. Angew Chem Int Ed Engl 2013, 52:9524-9528.
79. van Diepen A, Smit CH, van Egmond L, Kabatereine NB, Pinot de Moira A, Dunne DW, Hokke CH, Oliveira SC: Differential antiglycan antibody responses in Schistosoma mansoni-infected children and adults studied by shotgun glycan microarray. PLoS Negl Trop Dis 2012, 6:e1922. Study underlining the potential of glycan arrays to characterize antiglycan immune response. Glycans isolated from different life stages of the parasite Schistosoma mansoni were printed onto a shotgun glycan array. This approach allows immune profiling without previous knowledge of the glycotopes.
83. Yu Y, Mishra S, Song X, Lasanajak Y, Bradley KC, Tappert MM, Air GM, Steinhauer DA, Halder S, Cotmore S et al.: Functional glycomic analysis of human milk glycans reveals the presence of virus receptors and embryonic stem cell biomarkers. J Biol Chem 2012, 287:44784-44799. A conclusive study correlating glycomics data obtained by different approaches, including binding on shotgun glycan array, to assign structure and function of free human milk glycans.
80. Martin CE, Broecker F, Eller S, Oberli MA, Anish C, Pereira CL, Seeberger PH: Glycan arrays containing synthetic Clostridium difficile lipoteichoic acid oligomers as tools toward a carbohydrate vaccine. Chem Commun 2013, 49:7159.
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84. Oyelaran O, Gildersleeve JC: Glycan arrays: recent advances and future challenges. Curr Opin Chem Biol 2009, 13:406-413. 85. Nimrichter L, Gargir A, Gortler M, Altstock RT, Shtevi A, Weisshaus O, Fire E, Dotan N, Schnaar RL: Intact cell adhesion to glycan microarrays. Glycobiology 2004, 14:197-203.
Current Opinion in Chemical Biology 2014, 18:38–45
ScienceDirect Glycan arrays as tools for infectious disease research Andreas Geissner1,2, Chakkumkal Anish1 and Peter H Seeberger1,2 Infectious diseases cause millions of deaths worldwide each year and are a major burden for economies, especially in underdeveloped countries. Glycans and their interactions with other biomolecules are involved in all major steps of infection. Glycan arrays enable the rapid and sensitive detection of those interactions and are among the most powerful techniques to study the molecular biology of infectious diseases. This review will focus on recent developments and discuss the applications of glycan arrays to the elucidation of host–pathogen and pathogen–pathogen interactions, the development of tools for infection diagnosis and the use of glycan arrays in modern vaccine design. Addresses 1 Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mu¨hlenberg 1, 14424 Potsdam, Germany 2 Institute for Chemistry and Biochemistry, Freie Universita¨t Berlin, Arnimallee 22, 14195 Berlin, Germany Corresponding authors: Anish, Chakkumkal ([email protected]) and Seeberger, Peter H ([email protected])
Current Opinion in Chemical Biology 2014, 18:38–45 This review comes from a themed issue on Arrays Edited by Robert S Matson and David F Smith
1367-5931/$ – see front matter, # 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cbpa.2013.11.013
mediate attachment to host cells and subsequent invasion [4–7], while host GBPs promote pathogen recognition, immune activation and clearance. Some secreted bacterial proteins like toxins A and B from Clostridium difficile use cell surface glycans as receptors [8]. Plasmodium falciparum even secretes a glycosylphosphatidylinositol (GPI) glycan toxin [9,10]. Glycan arrays, also known as carbohydrate microarrays or glycochips, are powerful tools to study the role of carbohydrates and their interactions with GBPs during infection. The arrays are created by immobilizing carbohydrates that are either derived from natural sources or obtained by chemical synthesis on a surface. Today, modified glass slides are most commonly used for glycan presentation. Binding of molecules such as proteins or whole cells to immobilized glycans is then visualized by various detection methods (see Figure 1). Glycan arrays are ideal platforms requiring minimal amounts of glycans for interrogating a multitude of binding events. The most comprehensive glycan arrays carry several hundred structures, but in principle the platform can be expanded to many thousand glycans [11,12]. Tailored glycan microarrays carrying only few relevant structures in repetitive printing patterns allow for high-throughput analysis of multiple samples on the same slide. When multiple fluorescent probes are employed, different interaction partners such as antibody isotypes can be analyzed on the same array. Reviewed are applications of glycan arrays as they relate to different areas of ID research such as deciphering host–pathogen and pathogen–pathogen interactions, prevention of infection and development of diagnostic tools.
Investigation of host–pathogen interactions using glycan arrays Introduction Infectious diseases (IDs) are the major cause of death in many countries and prevention and successful treatment of IDs has been named a millennium goal of the United Nations [1]. A better understanding of the complex and interrelated factors that contribute to evolution and survival of infectious agents is required as a basis for true breakthroughs for vaccination and therapeutic approaches. Cell surface glycans and glycan binding proteins (GBPs) regulate many processes during disease manifestation and immune response. For example, bacterial capsular polysaccharide (CPS) is involved in the evasion of immune processes such as recognition, complement activation and opsonophagocytosis [2]. Being a surface-exposed antigen, CPS is the basis for highly successful vaccines against Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae that induce both direct and indirect protection through herd immunity and enjoy great economic success [3]. Pathogenic GBPs Current Opinion in Chemical Biology 2014, 18:38–45
Key events during onset and progression of infection and clearance of pathogens involve GBPs that recognize carbohydrates. These events include pathogen adhesion to host cells and subsequent invasion, cell binding and entry by toxins as well as immune recognition and evasion. A better understanding of these interactions by using glycan arrays may provide the basis for novel modes of therapy. All classes of pathogens rely on GBPs for cell adhesion (for recent reviews see [4–7]). Hemagglutinins (HAs) are surface proteins of influenza viruses that bind to sialic acid containing glycans on host cells to initiate the invasion process. The HAs determine the serotype of different strains. Carbohydrate binding preferences of recombinant HAs from different strains, including that responsible for the 1918 pandemic, were compared with the help of glycan arrays in a broad study as early as 2006 [13]. Many other studies have investigated influenza strains infecting www.sciencedirect.com
Glycan arrays as tools for infectious disease research Geissner, Anish and Seeberger 39
Figure 1
Quantification
Detection
Relative fluorescence
1,2 1,0 0,8 0,6 0,4 0,2 0,0
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0
20
40
60 80 100 120 140 160 Glycan ID
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Schematic principle of glycan arrays. In the most common setup, carbohydrates dissolved in buffer are printed onto a chemically activated glass surface. Slides are subsequently incubated with a solution of the putative binding partner, starting from proteins (shown: hemagglutinin structure 2FK0 [13]) over viruses, bacteria, and engineered yeast cells [41] to whole mammalian cells [85]. Binding is detected either by using a directly fluorescently labeled construct as binding partner or by immunological means. For relative binding evaluation, the fluorescence intensities of the different spots are quantified.
humans, birds, swine and other animals using either purified protein or fluorescence labeled whole virus particles [14–25]. These experiments confirmed the decades-old [26] hypothesis that avian strains preferably bind to a2,3 linked and human strains to a2,6 linked sialic acids, including chemically modified ones [20]. However, significant binding to glycans containing sialic acids with the respective other linkage was also detected in many cases. Glycan arrays served as detection system for changes in binding behavior in a recent HA mutagenesis study determining the necessary HA amino acid changes for avian influenza strains to allow respiratory droplet transmission in humans leading to complete switching of hosts to humans [27]. Even the most elaborate glycan arrays used for influenza research still leave room for optimization as glycoproteomics studies demonstrated that even the array with the highest number of relevant structures available today — the mammalian array from the Consortium for Functional Glycomics (CFG) — only covers half of the sialic acid containing glycan structures that exist in the human respiratory tract [28]. For www.sciencedirect.com
example, structures containing extended N-acetyllactosamine repeats that are bound by HA are missing [29]. Glycan array analysis of parainfluenza virus [30,31] and Serotype 1 reovirus [32] also revealed binding to sialic acid terminated glycans. For serotype 1 reovirus, preferential binding to ganglioside GM2 was detected implicating participation of this glycan in the preferential infection of certain cell types, including cancer cells with aberrant glycosylation patterns. Overall, an analysis of all data of the CFG array using a motif-based algorithm revealed that viral lectins have the least diverse target structures [33]. Glycan array studies on non-viral lectins such as parasite micronemal protein MIC1 from Toxoplasma gondii [34] and the related MIC3 protein from the economically important avian parasite Eimeria tenella [35] also demonstrated binding to sialic acid terminated glycans. Both proteins play a crucial role in invasion and subsequent onset of intracellular infection. Sialic acid might also play Current Opinion in Chemical Biology 2014, 18:38–45
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a role in the initiation of placental malaria as implicated by preferential binding of whole Plasmodium falciparum infected red blood cells to Lewis-type glycans including sialyl LewisX on glycan array [36]. The glycotope in the Anopheles mosquito midgut that is recognized by a malarial transmission blocking monoclonal antibody (mAb) was mapped using glycan arrays suggesting the role of putative targets of malarial GBPs involved in homing to the midgut [37]. In the case of the opportunistic pathogen Campylobacter jejuni, binding of whole fluorescence labeled bacteria showed culture condition dependent binding not only to glycans with terminal sialic acids, but also mannoses, fucoses and galactoses [38,39]. Fucose was also identified as receptor for Burkholderia ambifaria BamBL [40] and galactose for the Candida glabrata EPA family [41,42] and Pseudomonas aeruginosa lectin PA-IL [43]. For PA-IL, quantitative evaluation of binding and inhibition on an array containing glycomimetic structures with terminal galactoses underlines the potential of glycan arrays in research for new anti-bacterial therapeutics [44]. In some cases, not only the pathogens themselves, but also secreted toxins bind to cell surface glycans in order to initiate cell entry. This mode of binding had been known for tetanus neurotoxin [45] and toxins from Clostridium [8] for some time. Recently, microarray analysis elucidated the heptasaccharide core of complex N-glycans as the glycan receptor of cytolysin from Vibrio cholerae [46] and was also used for elucidation of binding fine specificity of cholera toxin towards GM1 related glycans [47]. The examples above clearly demonstrate that the glycans on currently available microarrays are diverse enough to include the receptors — or at least similar glycans — of many important pathogens and their toxins. However, host–pathogen interactions also involve the recognition of bacterial glycan structures by host proteins. To study the GBPs involved here, binding events to bacterial glycans have to be measured. As the bacterial glycome is much more diverse than that of mammals [48], and the arrays designed for this purpose are not as advanced as those containing mammalian sugars [12], glycan array analysis in this field is still limited when compared to questions involving mammalian glycans. Generally, the mammalian innate immune system recognizes pathogens via pathogen associated molecular patterns (PAMPs) including carbohydrates. Those PAMPs are sensed by pattern recognition receptors such as Tolllike receptors (TLRs) and carbohydrate binding C-type lectin receptors (CLRs), prompting an inflammatory response [49,50]. For microarray analysis, the putative carbohydrate recognition domains of those transmembrane receptors have to be expressed in a soluble form, for example by fusing them to the heavy chain of immunoglobulin G, thereby also facilitating detection. These Current Opinion in Chemical Biology 2014, 18:38–45
Ig-fusion-proteins, like antibodies themselves, contain two binding sites. In a broad study on the CFG mammalian array, specific binding was observed for eight out of fourteen analyzed innate immune receptors allowing detailed conclusions regarding binding preferences [51]. No signals were seen for several CLRs and TLR2, possibly because the putative targets are pathogen-derived glycans and therefore not present on the CFG array. Failure to find binding partners may also be a result of dissociation of bound proteins during the washing steps. This was demonstrated recently for murine CLR SIGNR1 [52] when comparing its specificity to human DC-SIGN using a glycan array with evanescent field fluorescence detection [53]. With this technique that renders washing steps unnecessary, specific binding for SIGNR1 was seen in contrast to an earlier study on the CFG plate array [54]. Apart from the necessity and vigor of the washing procedures, numerous factors including differences in density and amount of arrayed glycans and the type of linker used for immobilization can also influence accurate detection of weak interactions on glycan arrays. The importance of the linker structure was recently demonstrated by Grant et al. [55] using molecular dynamics simulations of the various linkers employed by the CFG to study its effect on glycan presentation on array surfaces. In case of certain linkers, lower accessibility was observed [55]. Innate immune receptors that are not transmembrane proteins lend themselves very well to binding studies involving glycan arrays. The binding specificities of different galectins [53,56,57], ficolins [58,59], collectins such as surfactant protein D [60] and members of other families like ZG16p [61] have been elucidated using glycan arrays. Protein-carbohydrate interactions in immunity are not restricted to the innate immune system. Anti-glycan antibodies are also an important means of fighting infections. The possibility of studying these antibodies on glycan arrays will be discussed in the section on vaccines. Survival of pathogens in the host depends on their ability to evade the host’s immune system. Staphylococcus aureus has developed some very advanced mechanisms to achieve immune evasion (reviewed in [62]). Among those strategies are the superantigen-like proteins (SSLs) blocking specific immune mechanisms. Glycan arrays were employed to identify the sialic acid containing target glycans of SSL4, 5, and 11 and therefore helped to elucidate the mechanism of how these three proteins inhibit neutrophil recruitment and activation [63–65]. Another quite common evasion mechanism is formation of a polysaccharide capsule that inhibits complement deposition. GBPs are necessary to structure the capsule, as shown in the case of E. coli WZI, where glycan array analysis substantiated the hypothesis of glycan binding ability [66]. www.sciencedirect.com
Glycan arrays as tools for infectious disease research Geissner, Anish and Seeberger 41
Glycan arrays as tools to study pathogen– pathogen interactions Recognition of glycans by bacterial lectins is a major process in biofilm formation and cell-to-cell interactions. Numerous microbial lectins such as Pseudomonas aeruginosa lectin PA-IIL [67], PA-IL [43], Pseudomonas fluorescens Pf0-1 antiviral lectin [68], and Burkholderia cenocepacia lectin BC2L-C [69] have been analyzed for their binding specificities. Recently, synthetic fucosylated glycoclusters were evaluated on a glycan array for binding to PA-IIL, a lectin that regulates biofilm formation [66]. Burkholderia cenocepacia lectin A binding to lipopolysaccharides was mapped and saturation transfer difference NMR (STD NMR) was used to derive a structural explanation of the binding preference indicating the role this lectin plays in regulating bacteria to bacteria communication [70].
Glycan arrays in infectious disease prevention Vaccination is the most effective way to prevent infectious diseases. This section will discuss the application of glycan arrays in developing better carbohydrate vaccines. The first major task in the development of glycan-based vaccines is the assignment of candidate structures. Detailed analysis of antibodies elicited during infection can be performed quickly for many potential structures on glycan array to yield information on glycotopes that are recognized by the immune system of patients
(see Figure 2). This antibody analysis is usually performed on large sets of sera, but in case of human immunodeficiency virus (HIV), patient-derived broadly neutralizing monoclonal antibodies (bnmAbs) are routinely investigated. A large number of HIV bnmAbs has been studied on glycan arrays, beginning with 2G12 a decade ago [14,71,72], and recently completely new, even more potent sets of antibodies that were obtained through innovative cloning methods [73]. Most of those antibodies were shown to bind to high mannose Nglycans, albeit with fine specificities that differ from each other and from 2G12 as shown by an analysis of the deletion sequences that contain only parts of the putative target [74,75]. In contrast, bnmAb PGT121 was recently shown to bind complex-type N-glycans, but other characterization data suggested that the actual epitope involves high mannose glycans with an interaction too weak to be picked up by glycan arrays or that is dependent on interactions with non-glycan parts of the epitope [76,77]. As already stated, similar glycan array analyses, including binding to deletion sequences, have been performed for other pathogens using large numbers of serum samples. In addition to the GPIs from Plasmodium falciparum [78], isolated glycans from Schistosoma mansoni [79] and very recently synthetic structures based on PS-I surface glycan and lipoteichoic acid of Clostridium difficile [80,81] have
Figure 2
Specificity evaluation
Synthesis
Candidate structures
monoclonal antibody
or
sera from patients
Neoglycoconjugates
Immunological evaluation
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Sample workflow for glycan array assisted analysis of antibodies in vaccine design. Specificities of either existing, highly potent monoclonal antibodies or of antibodies in a large number of sera from patients are evaluated on glycan array. Glycans that are picked up in those screens are subsequently conjugated to carrier proteins for evaluation of immunogenicity. www.sciencedirect.com
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been investigated to define promising glycotopes for potential vaccines. Once candidate structures for vaccines have been defined, their suitability is tested in immunization experiments. Again, glycan arrays can help to determine the success of immunizations in terms of antibody titers, specificity analysis, isotype switching and subtyping of immunoglobulins [81,82]. Apart from vaccination, shielding potential hosts from contact with the causative agent may also confer protection. In an elegant study, Yu et al. [83] isolated, separated and printed glycans from human milk and showed that some viruses, including the influenza virus, were able to bind to the printed glycans. This binding proves that human milk contains soluble receptors for those viruses which probably inhibit binding to the host cells. Shielding hosts is also performed by isolating patients of highly contagious diseases to prevent epidemics. For that, a quick and reliable detection of certain pathogens is necessary. Development of tools for this task can be assisted by glycan arrays, as seen recently for monoclonal antibodies with the ability to specifically detect the causative agent of plague, Yersinia pestis [82].
Glycan array assisted development of diagnostic tools Glycan specific antibodies are regarded as biomarkers to detect and diagnose numerous infections. Glycan arrays offer a versatile platform to analyze clinical specimens to screen for anti-glycan antibodies for serodiagnosis of infectious agents. Glycan arrays of synthetic Plasmodium falciparum GPI glycans were used to compare anti-GPI IgG levels in individuals from malaria-endemic areas with non-exposed individuals and to determine the effect of exposure to the malaria parasite in previously nonexposed individuals [78]. Results revealed distinct differences in GPI antigens recognized as a result of malaria exposure. Recently, we showed that antibodies to Clostridium difficile surface glycans correlate with decreased disease severity, indicating the vaccine potential of those glycans [81]. Other examples to illustrate the approach include profiling of mellidosis patients and animals vaccinated or infected with anthrax or tularemia-causing bacteria, salmonellosis patients, Clostridium difficile patients, and Schistosoma mansoni infected individuals [84].
Conclusions Glycan arrays have become versatile tools to address various aspects of ID research. Arrays containing diverse mammalian glycans have been used to study mammalian pathogen receptors and yielded impressive results even though the most elaborate and diverse arrays still leave room for improvement. Glycan arrays that cover a broad spectrum of chemically defined glycans from important Current Opinion in Chemical Biology 2014, 18:38–45
pathogens are still missing. Given the immense diversity of the bacterial glycome, creating such arrays is going to be a huge undertaking. However, arrays of pathogen related glycans are an important step towards a better understanding of glycan involvement in infectious diseases.
Acknowledgements The authors gratefully acknowledge generous financial support by the Max Planck Society, the German Federal Ministry of Education and Research and the Ko¨rber Foundation. Felix Broecker and Benjamin Schumann are acknowledged for critically reviewing the article.
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