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Murugesan, Gavuthami, Viviana G. Correia, Angelina S. Palma, Wengang Chai, Chunxia Li, Ten Feizi, Eva Martin, Brigitte Laux, Alexandra Franz, Klaus Fuchs, Bernd Weigle, and Paul R. Crocker. "Siglec-15 recognition of sialoglycans on tumor cell lines can occur independently of sialyl Tn antigen expression." Glycobiology (2020). Abstract

Siglec-15 is a conserved sialic acid-binding Ig-like lectin expressed on osteoclast progenitors that plays an important role in osteoclast development and function. It is also expressed by tumor-associated macrophages and by some tumors, where it is thought to contribute to the immunosuppressive microenvironment. It was shown previously that engagement of macrophage-expressed Siglec-15 with tumor cells expressing its ligand, sialyl Tn (sTn), triggered production of TGF-$\beta$. In the present study, we have further investigated the interaction between Siglec-15 and sTn on tumor cells and its functional consequences. Based on binding assays with lung and breast cancer cell lines and glycan-modified cells, we failed to see evidence for recognition of sTn by Siglec-15. However, using a microarray of diverse, structurally-defined glycans, we show that Siglec-15 binds with higher avidity to sialylated glycans other than sTn or related antigen sequences. In addition, we were unable to demonstrate enhanced TGF-$\beta$ secretion following co-culture of Siglec-15-expressing monocytic cells lines with tumor cells expressing sTn, or following Siglec-15 cross-linking with monoclonal antibodies. However, we did observe activation of the SYK/MAPK signaling pathway following antibody cross-linking of Siglec-15 that may modulate the functional activity of macrophages.

Ribeiro, Diana O., Aldino Viegas, Virgínia M. R. Pires, João Medeiros-Silva, Pedro Bule, Wengang Chai, Filipa Marcelo, Carlos M. G. A. Fontes, Eurico J. Cabrita, Angelina S. Palma, and Ana Luísa Carvalho. "Molecular basis for the preferential recognition of beta 1,3-1,4-glucans by the family 11 carbohydrate-binding module from Clostridium thermocellum." The FEBS journal. 287 (2020): 2723-2743. Abstract

Understanding the specific molecular interactions between proteins and $\beta$1,3-1,4-mixed-linked d-glucans is fundamental to harvest the full biological and biotechnological potential of these carbohydrates and of proteins that specifically recognize them. The family 11 carbohydrate-binding module from Clostridium thermocellum (CtCBM11) is known for its binding preference for $\beta$1,3-1,4-mixed-linked over $\beta$1,4-linked glucans. Despite the growing industrial interest of this protein for the biotransformation of lignocellulosic biomass, the molecular determinants of its ligand specificity are not well defined. In this report, a combined approach of methodologies was used to unravel, at a molecular level, the ligand recognition of CtCBM11. The analysis of the interaction by carbohydrate microarrays and NMR and the crystal structures of CtCBM11 bound to $\beta$1,3-1,4-linked glucose oligosaccharides showed that both the chain length and the position of the $\beta$1,3-linkage are important for recognition, and identified the tetrasaccharide Glc$\beta$1,4Glc$\beta$1,4Glc$\beta$1,3Glc sequence as a minimum epitope required for binding. The structural data, along with site-directed mutagenesis and ITC studies, demonstrated the specificity of CtCBM11 for the twisted conformation of $\beta$1,3-1,4-mixed-linked glucans. This is mediated by a conformation-selection mechanism of the ligand in the binding cleft through CH-$π$ stacking and a hydrogen bonding network, which is dependent not only on ligand chain length, but also on the presence of a $\beta$1,3-linkage at the reducing end and at specific positions along the $\beta$1,4-linked glucan chain. The understanding of the detailed mechanism by which CtCBM11 can distinguish between linear and mixed-linked $\beta$-glucans strengthens its exploitation for the design of new biomolecules with improved capabilities and applications in health and agriculture. DATABASE: Structural data are available in the Protein Data Bank under the accession codes 6R3M and 6R31.

Vendele, Ingrida, Janet A. Willment, Lisete M. Silva, Angelina S. Palma, Wengang Chai, Yan Liu, Ten Feizi, Maria Spyrou, Mark H. T. Stappers, Gordon D. Brown, and Neil A. R. Gow. "{Mannan detecting C-type lectin receptor probes recognise immune epitopes with diverse chemical, spatial and phylogenetic heterogeneity in fungal cell walls.}." PLoS pathogens. 16 (2020): e1007927. Abstract

During the course of fungal infection, pathogen recognition by the innate immune system is critical to initiate efficient protective immune responses. The primary event that triggers immune responses is the binding of Pattern Recognition Receptors (PRRs), which are expressed at the surface of host immune cells, to Pathogen-Associated Molecular Patterns (PAMPs) located predominantly in the fungal cell wall. Most fungi have mannosylated PAMPs in their cell walls and these are recognized by a range of C-type lectin receptors (CTLs). However, the precise spatial distribution of the ligands that induce immune responses within the cell walls of fungi are not well defined. We used recombinant IgG Fc-CTLs fusions of three murine mannan detecting CTLs, including dectin-2, the mannose receptor (MR) carbohydrate recognition domains (CRDs) 4-7 (CRD4-7), and human DC-SIGN (hDC-SIGN) and of the $\beta$-1,3 glucan-binding lectin dectin-1 to map PRR ligands in the fungal cell wall of fungi grown in vitro in rich and minimal media. We show that epitopes of mannan-specific CTL receptors can be clustered or diffuse, superficial or buried in the inner cell wall. We demonstrate that PRR ligands do not correlate well with phylogenetic relationships between fungi, and that Fc-lectin binding discriminated between mannosides expressed on different cell morphologies of the same fungus. We also demonstrate CTL epitope differentiation during different phases of the growth cycle of Candida albicans and that MR and DC-SIGN labelled outer chain N-mannans whilst dectin-2 labelled core N-mannans displayed deeper in the cell wall. These immune receptor maps of fungal walls of in vitro grown cells therefore reveal remarkable spatial, temporal and chemical diversity, indicating that the triggering of immune recognition events originates from multiple physical origins at the fungal cell surface.

Pandeirada, Carolina O., Élia Maricato, Sónia S. Ferreira, Viviana G. Correia, Benedita A. Pinheiro, Dmitry V. Evtuguin, Angelina S. Palma, Alexandra Correia, Manuel Vilanova, Manuel A. Coimbra, and Cláudia Nunes. "{Structural analysis and potential immunostimulatory activity of Nannochloropsis oculata polysaccharides.}." Carbohydrate polymers. 222 (2019): 114962. Abstract

The relevance of microalgae biotechnology for producing high-value compounds with biomedical application, such as polysaccharides, has been increasing. Despite this, the knowledge about the composition and structure of microalgae polysaccharides is still scarce. In this work, water-soluble polysaccharides from Nannochloropsis oculata were extracted, fractionated, structurally analysed, and subsequently tested in terms of immunostimulatory activity. A combination of sugar and methylation analysis with interaction data of carbohydrate-binding proteins using carbohydrate microarrays disclosed the complex structural features of the different polysaccharides. These analyses showed that the water-soluble polysaccharides fractions from N. oculata were rich in ($\beta$1→3, $\beta$1→4)-glucans, ($\alpha$1→3)-, ($\alpha$1→4)-mannans, and anionic sulphated heterorhamnans. The immunostimulatory assay highlighted that these fractions could also stimulate murine B-lymphocytes. Thus, the N. oculata water-soluble polysaccharides show potential to be further explored for immune-mediated biomedical applications.

Gao, Tian, Jingyu Yan, Chang-Cheng Liu, Angelina S. Palma, Zhimou Guo, Min Xiao, Xi Chen, Xinmiao Liang, Wengang Chai, and Hongzhi Cao. "{Chemoenzymatic Synthesis of O-Mannose Glycans Containing Sulfated or Nonsulfated HNK-1 Epitope.}." Journal of the American Chemical Society. 141 (2019): 19351-19359. Abstract

The human natural killer-1 (HNK-1) epitope is a unique sulfated trisaccharide sequence presented on O- and N-glycans of various glycoproteins and on glycolipids. It is overexpressed in the nervous system and plays crucial roles in nerve regeneration, synaptic plasticity, and neuronal diseases. However, the investigation of functional roles of HNK-1 in a more complex glycan context at the molecular level remains a big challenge due to lack of access to related structurally well-defined complex glycans. Herein, we describe a highly efficient chemoenzymatic approach for the first collective synthesis of HNK-1-bearing O-mannose glycans with different branching patterns, and for their nonsulfated counterparts. The successful strategy relies on both chemical glycosylation of a trisaccharide lactone donor for the introduction of sulfated HNK-1 branch and substrate promiscuities of bacterial glycosyltransferases that can tolerate sulfated substrates for enzymatic diversification. Glycan microarray analysis with the resulting complex synthetic glycans demonstrated their recognition by two HNK-1-specific antibodies including anti-HNK-1/N-CAM (CD57) and Cat-315, which provided further evidence for the recognition epitopes of these antibodies and the essential roles of the sulfate group for HNK-1 glycan-antibody recognition.

Campanero-Rhodes, María Asunción, Angelina Sa Palma, Margarita Menéndez, and Dolores Solís. "{Microarray Strategies for Exploring Bacterial Surface Glycans and Their Interactions With Glycan-Binding Proteins.}." Frontiers in microbiology. 10 (2019): 2909. Abstract

Bacterial surfaces are decorated with distinct carbohydrate structures that may substantially differ among species and strains. These structures can be recognized by a variety of glycan-binding proteins, playing an important role in the bacteria cross-talk with the host and invading bacteriophages, and also in the formation of bacterial microcolonies and biofilms. In recent years, different microarray approaches for exploring bacterial surface glycans and their recognition by proteins have been developed. A main advantage of the microarray format is the inherent miniaturization of the method, which allows sensitive and high-throughput analyses with very small amounts of sample. Antibody and lectin microarrays have been used for examining bacterial glycosignatures, enabling bacteria identification and differentiation among strains. In addition, microarrays incorporating bacterial carbohydrate structures have served to evaluate their recognition by diverse host/phage/bacterial glycan-binding proteins, such as lectins, effectors of the immune system, or bacterial and phagic cell wall lysins, and to identify antigenic determinants for vaccine development. The list of samples printed in the arrays includes polysaccharides, lipopoly/lipooligosaccharides, (lipo)teichoic acids, and peptidoglycans, as well as sequence-defined oligosaccharide fragments. Moreover, microarrays of cell wall fragments and entire bacterial cells have been developed, which also allow to study bacterial glycosylation patterns. In this review, examples of the different microarray platforms and applications are presented with a view to give the current state-of-the-art and future prospects in this field.

Rudkin, Fiona M., Ingrida Raziunaite, Hillary Workman, Sosthene Essono, Rodrigo Belmonte, Donna M. MacCallum, Elizabeth M. Johnson, Lisete M. Silva, Angelina S. Palma, Ten Feizi, Allan Jensen, Lars P. Erwig, and Neil A. R. Gow. "Single human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis." Nature communications. 9 (2018): 5288. Abstract

The high global burden of over one million annual lethal fungal infections reflects a lack of protective vaccines, late diagnosis and inadequate chemotherapy. Here, we have generated a unique set of fully human anti-Candida monoclonal antibodies (mAbs) with diagnostic and therapeutic potential by expressing recombinant antibodies from genes cloned from the B cells of patients suffering from candidiasis. Single class switched memory B cells isolated from donors serum-positive for anti-Candida IgG were differentiated in vitro and screened against recombinant Candida albicans Hyr1 cell wall protein and whole fungal cell wall preparations. Antibody genes from Candida-reactive B cell cultures were cloned and expressed in Expi293F human embryonic kidney cells to generate a panel of human recombinant anti-Candida mAbs that demonstrate morphology-specific, high avidity binding to the cell wall. The species-specific and pan-Candida mAbs generated through this technology display favourable properties for diagnostics, strong opsono-phagocytic activity of macrophages in vitro, and protection in a murine model of disseminated candidiasis.

Liu, Y., A. S. Palma, T. Feizi, and W. Chai. "Insights Into Glucan Polysaccharide Recognition Using Glucooligosaccharide Microarrays With Oxime-Linked Neoglycolipid Probes." Methods Enzymol.. 598 (2018): 139-167.
Loureiro, LR, DP Sousa, D. Ferreira, W. Chai, L. Lima, C. Pereira, CB Lopes, VG Correia, LM Silva, C. Li, LL Santos, JA Ferreira, A. Barbas, A. S. Palma, C. Novo, and PA Videira. "Novel Monoclonal Antibody L2A5 Specifically Targeting sialyl-Tn and Short Glycans Terminated by alpha-2-6 Sialic Acids." Sci Rep.. 8.1 (2018): 12196.
Li, Z., C. Gao, Y. Zhang, A. S. Palma, and et al. "O-Glycome Beam Search Arrays for Carbohydrate Ligand Discovery." Mol Cell Proteomics. 17.1 (2018): 121-133.
Zhang, H., A. S. Palma, Y. Zhang, R. A. Childs, Y. Liu, D. A. Mitchell, L. S. Guidolin, W. Weigel, B. Mulloy, A. E. Ciocchini, T. Feizi, and W. Chai. "Generation and characterization of β1,2-gluco-oligosaccharide probes from Brucella abortus cyclic β-glucan and their recognition by C-type lectins of the immune system." Glycobiology (2016). AbstractWebsite
Silva, Lisete, Robert A. Childs, Angelina S. Palma, Wengang Chai, Ten Feizi, and Yan Liu. "Influence of carrier lipid composition on glycan recognition in NGL-based microarrays." Glycobiology. 25 (2015): 1260. Abstract
Palma, Angelina S., Yan Liu, Hongtao Zhang, Yibing Zhang, Barry V. McCleary, Guangli Yu, Qilin Huang, Leticia S. Guidolin, Andres E. Ciocchini, Antonella Torosantucci, Denong Wang, Ana Luisa Carvalho, Carlos M. G. A. Fontes, Barbara Mulloy, Robert A. Childs, Ten Feizi, and Wengang Chai. "Unravelling Glucan Recognition Systems by Glycome Microarrays Using the Designer Approach and Mass Spectrometry." Molecular & Cellular Proteomics. 14 (2015): 974-988. Abstract
Gao, Chao, Yan Liu, Hongtao Zhang, Yibing Zhang, Michiko N. Fukuda, Angelina S. Palma, Radoslaw P. Kozak, Robert A. Childs, Motohiro Nonaka, Zhen Li, Don L. Siegel, Peter Hanfland, Donna M. Peehl, Wengang Chai, Mark I. Greene, and Ten Feizi. "Carbohydrate Sequence of the Prostate Cancer-associated Antigen F77 Assigned by a Mucin O-Glycome Designer Array." Journal of Biological Chemistry. 289 (2014): 16462-16477. Abstract
Palma, Angelina S., Ten Feizi, Robert A. Childs, Wengang Chai, and Yan Liu. "The neoglycolipid (NGL)-based oligosaccharide microarray system poised to decipher the meta-glycome." Current Opinion in Chemical Biology. 18 (2014): 87-94. Abstract
Crusat, Martin, Junfeng Liu, Angelina S. Palma, Robert A. Childs, Yan Liu, Stephen A. Wharton, Yi Pu Lin, Peter J. Coombs, Stephen R. Martin, Mikhail Matrosovich, Zi Chen, David J. Stevens, Vo Minh Hien, Tran Tan Thanh, Le Nguyen Truc Nhu, Lam Anh Nguyet, Do Quang Ha, Rogier H. van Doorn, Tran Tinh Hien, Harald S. Conradt, Makoto Kiso, Steve J. Gamblin, Wengang Chai, John J. Skehel, Alan J. Hay, Jeremy Farrar, Menno D. de Jong, and Ten Feizi. "Changes in the hemagglutinin of H5N1 viruses during human infection - Influence on receptor binding." Virology. 447 (2013): 326-337. Abstract
Palma, Angelina S., Benedita Pinheiro, Yan Liu, Yoichi Takeda, Wengang Chai, Yukishige Ito, Maria Joao Romao, Ana Luisa Carvalho, and Ten Feizi. "The Structural Basis of the Recognition of Di-glucosylated N-glycans by the ER Lectin Malectin." Glycobiology. 23 (2013): 1368-1369. Abstract
Neu, Ursula, Stacy-Ann A. Allen, Barbel S. Blaum, Yan Liu, Martin Frank, Angelina S. Palma, Luisa J. Stroh, Ten Feizi, Thomas Peters, Walter J. Atwood, and Thilo Stehle. "A Structure-Guided Mutation in the Major Capsid Protein Retargets BK Polyomavirus." PLoS pathogens. 9 (2013): e1003688. Abstract
Neu, Ursula, Zaigham Mahmood Khan, Benjamin Schuch, Angelina S. Palma, Yan Liu, Michael Pawlita, Ten Feizi, and Thilo Stehle. "Structures of B-Lymphotropic Polyomavirus VP1 in Complex with Oligosaccharide Ligands." PLoS pathogens. 9 (2013): e1003714. Abstract
Graham, Lisa M., Vandana Gupta, Georgia Schafer, Delyth M. Reid, Matti Kimberg, Kevin M. Dennehy, William G. Hornsell, Reto Guler, Maria A. Campanero-Rhodes, Angelina S. Palma, Ten Feizi, Stella K. Kim, Peter Sobieszczuk, Janet A. Willment, and Gordon D. Brown. "The C-type Lectin Receptor CLECSF8 (CLEC4D) Is Expressed by Myeloid Cells and Triggers Cellular Activation through Syk Kinase." Journal of Biological Chemistry. 287 (2012): 25964-25974. Abstract
Palma, Angelina S., Yan Liu, Yibing Zhang, Hongtao Zhang, Ana S. Luis, Ana Luisa Carvalho, Harry J. Gilbert, Alisdair Boraston, Carlos M. G. A. Fontes, Wengang Chai, and Ten Feizi. "Designer-oligosaccharide microarrays to decipher ligands in mammalian and prokaryotic glucan-recognition systems." Glycobiology. 22 (2012): 1612-1613. Abstract
Palma, Angelina S., Yibing Zhang, Robert A. Childs, Maria A. Campanero-Rhodes, Yan Liu, Ten Feizi, and Wengang Chai. "Neoglycolipid-based "designer" oligosaccharide microarrays to define beta-glucan ligands for Dectin-1." Methods in molecular biology (Clifton, N.J.). 808 (2012): 337-59. Abstract
Liu, Yan, Robert A. Childs, Angelina S. Palma, Maria A. Campanero-Rhodes, Mark S. Stoll, Wengang Chai, and Ten Feizi. "Neoglycolipid-based oligosaccharide microarray system: preparation of NGLs and their noncovalent immobilization on nitrocellulose-coated glass slides for microarray analyses." Methods in molecular biology (Clifton, N.J.). 808 (2012): 117-36. Abstract