Vector-borne diseases constitute 17% of all infectious diseases in the world; among the blood-feeding arthropods, ticks transmit the highest number of pathogens. Understanding the interactions between the tick vector, the mammalian host and the pathogens circulating between them is the basis for the successful development of vaccines against ticks or the tick-transmitted pathogens as well as for the development of specific treatments against tick-borne infections. A lot of effort has been put into transcriptomic and proteomic analyses; however, the protein-carbohydrate interactions and the overall glycobiology of ticks and tick-borne pathogens has not been given the importance or priority deserved. Novel (bio)analytical techniques and their availability have immensely increased the possibilities in glycobiology research and thus novel information in the glycobiology of ticks and tick-borne pathogens is being generated at a faster pace each year. This review brings a comprehensive summary of the knowledge on both the glycosylated proteins and the glycan-binding proteins of the ticks as well as the tick-transmitted pathogens, with emphasis on the interactions allowing the infection of both the ticks and the hosts by various bacteria and tick-borne encephalitis virus.

Faculty of Science University of South Bohemia Branišovská 1760 CZ 37005 České Budějovice Czech Republic

Institute of Parasitology Biology Centre Czech Academy of Sciences Branišovská 31 CZ 37005 České Budějovice Czech Republic

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WHO. http://www.who.int/en/. 1948. Accessed 28 Mar 2018.

de la Fuente J, Antunes S, Bonnet S, Cabezas-Cruz A, Domingos AG, Estrada-Pena A, et al. Tick-pathogen interactions and vector competence: identification of molecular drivers for tick-borne diseases. Front Cell Infect Microbiol. 2017;7:114. doi: 10.3389/fcimb.2017.00114. PubMed DOI PMC

Coumou J, Wagemakers A, Trentelman JJ, Nijhof AM, Hovius JW. Vaccination against Bm86 homologues in rabbits does not impair Ixodes ricinus feeding or oviposition. PLoS One. 2014;10:e0123495. doi: 10.1371/journal.pone.0123495. PubMed DOI PMC

Semenza JC, Suk JE. Vector-borne diseases and climate change: a European perspective. FEMS Microbiol Lett. 2018;365:2. doi: 10.1093/femsle/fnx244. PubMed DOI PMC

Dinglasan RR, Jacobs-Lorena M. Insight into a conserved lifestyle: protein-carbohydrate adhesion strategies of vector-borne pathogens. Infect Immun. 2005;73:7797–7807. doi: 10.1128/IAI.73.12.7797-7807.2005. PubMed DOI PMC

Severo MS, Choy A, Stephens KD, Sakhon OS, Chen G, Chung DW, et al. The E3 ubiquitin ligase XIAP restricts Anaplasma phagocytophilum colonization of Ixodes scapularis ticks. J Infect Dis. 2013;208:1830–1840. doi: 10.1093/infdis/jit380. PubMed DOI PMC

Varki ACR, Esko JD, et al. Essentials of Glycobiology. 3. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 2017. PubMed

Ritchie GE, Moffatt BE, Sim RB, Morgan BP, Dwek RA, Rudd PM. Glycosylation and the complement system. Chem Rev. 2002;102:305-20-19. doi: 10.1021/cr990294a. PubMed DOI

Bann JG, Bachinger HP. Glycosylation/hydroxylation-induced stabilization of the collagen triple helix. 4-trans-hydroxyproline in the Xaa position can stabilize the triple helix. J Biol Chem. 2000;275:24466–24469. doi: 10.1074/jbc.M003336200. PubMed DOI

Ault BH, Schmidt BZ, Fowler NL, Kashtan CE, Ahmed AE, Vogt BA, et al. Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism. J Biol Chem. 1997;272:25168–25175. doi: 10.1074/jbc.272.40.25168. PubMed DOI

Dijk M, Holkers J, Voskamp P, Giannetti BM, Waterreus WJ, van Veen HA, et al. How dextran sulfate affects C1-inhibitor activity: a model for polysaccharide potentiation. Structure. 2016;24:2182–2189. doi: 10.1016/j.str.2016.09.013. PubMed DOI

Stavenhagen K, Kayili HM, Holst S, Koeleman C, Engel R, Wouters D, et al. N- and O-glycosylation analysis of human C1-inhibitor reveals extensive mucin-type O-glycosylation. Mol Cell Proteomics. 2017;17:1225–1238. doi: 10.1074/mcp.RA117.000240. PubMed DOI PMC

Minta JO. The role of sialic acid in the functional activity and the hepatic clearance of C1-INH. J Immunol. 1981;126:245–249. PubMed

Novotny MV, Alley WR. Recent trends in analytical and structural glycobiology. Curr Opin Chem Biol. 2013;17:832–840. doi: 10.1016/j.cbpa.2013.05.029. PubMed DOI PMC

Oswald DM, Cobb BA. Emerging glycobiology tools: a Renaissance in accessibility. Cell Immunol. 2018; 10.1016/j.cellimm.2018.04.010. PubMed PMC

Tytgat HL, van Teijlingen NH, Sullan RM, Douillard FP, Rasinkangas P, Messing M, et al. Probiotic gut microbiota isolate interacts with dendritic cells via glycosylated heterotrimeric pili. PLoS One. 2016;11:e0151824. doi: 10.1371/journal.pone.0151824. PubMed DOI PMC

Barbour AG, Hayes SF. Biology of Borrelia species. Microbiol Rev. 1986;50:381–400. PubMed PMC

Coburn J, Fischer JR, Leong JM. Solving a sticky problem: new genetic approaches to host cell adhesion by the Lyme disease spirochete. Mol Microbiol. 2005;57:1182–1195. doi: 10.1111/j.1365-2958.2005.04759.x. PubMed DOI

Berndtson K. Review of evidence for immune evasion and persistent infection in Lyme disease. Int J Gen Med. 2013;6:291–306. doi: 10.2147/IJGM.S44114. PubMed DOI PMC

Cohen M. Notable aspects of glycan-protein interactions. Biomolecules. 2015;5:2056–2072. doi: 10.3390/biom5032056. PubMed DOI PMC

Vancova M, Nebesarova J, Grubhoffer L. Lectin-binding characteristics of a Lyme borreliosis spirochete Borrelia burgdorferi sensu stricto. Folia Microbiol. 2005;50:229–238. doi: 10.1007/BF02931571. PubMed DOI

Stevenson B, Schwan TG, Rosa PA. Temperature-related differential expression of antigens in the Lyme disease spirochete, Borrelia burgdorferi. Infect Immun. 1995;63:4535–4539. PubMed PMC

Pal U, de Silva AM, Montgomery RR, Fish D, Anguita J, Anderson JF, et al. Attachment of Borrelia burgdorferi within Ixodes scapularis mediated by outer surface protein A. J Clin Invest. 2000;106:561–569. doi: 10.1172/JCI9427. PubMed DOI PMC

Schwan TG, Piesman J. Vector interactions and molecular adaptations of Lyme disease and relapsing fever spirochetes associated with transmission by ticks. Emerg Infect Dis. 2002;8:115–121. doi: 10.3201/eid0802.010198. PubMed DOI PMC

Fikrig E, Pal U, Chen M, Anderson JF, Flavell RA. OspB antibody prevents Borrelia burgdorferi colonization of Ixodes scapularis. Infect Immun. 2004;72:1755–1759. doi: 10.1128/IAI.72.3.1755-1759.2004. PubMed DOI PMC

Schwan TG, Piesman J, Golde WT, Dolan MC, Rosa PA. Induction of an outer surface protein on Borrelia burgdorferi during tick feeding. Proc Natl Acad Sci USA. 1995;92:2909–2913. doi: 10.1073/pnas.92.7.2909. PubMed DOI PMC

Ramamoorthi N, Narasimhan S, Pal U, Bao F, Yang XF, Fish D, et al. The Lyme disease agent exploits a tick protein to infect the mammalian host. Nature. 2005;436:573–577. doi: 10.1038/nature03812. PubMed DOI PMC

Simo L, Kazimirova M, Richardson J, Bonnet SI. The essential role of tick salivary glands and saliva in tick feeding and pathogen transmission. Front Cell Infect Microbiol. 2017;7:281. doi: 10.3389/fcimb.2017.00281. PubMed DOI PMC

Anguita J, Ramamoorthi N, Hovius JWR, Das S, Thomas V, Persinski R, et al. Salp15, an Ixodes scapularis salivary protein, inhibits CD4(+) T cell activation. Immunity. 2002;16:849–859. doi: 10.1016/S1074-7613(02)00325-4. PubMed DOI

Kolb P, Vorreiter J, Habicht J, Bentrop D, Wallich R, Nassal M. Soluble cysteine-rich tick saliva proteins Salp15 and Iric-1 from E. coli. FEBS Open Bio. 2015;5:42–55. doi: 10.1016/j.fob.2014.12.002. PubMed DOI PMC

Hovius JW, Schuijt TJ, de Groot KA, Roelofs JJ, Oei GA, Marquart JA, et al. Preferential protection of Borrelia burgdorferi sensu stricto by a Salp15 homologue in Ixodes ricinus saliva. J Infect Dis. 2008;198:1189–1197. doi: 10.1086/591917. PubMed DOI PMC

Hovius JW, de Jong MA, den Dunnen J, Litjens M, Fikrig E, van der Poll T, et al. Salp15 binding to DC-SIGN inhibits cytokine expression by impairing both nucleosome remodeling and mRNA stabilization. PLoS Pathog. 2008;4:e31. doi: 10.1371/journal.ppat.0040031. PubMed DOI PMC

Lam TT, Nguyen TP, Montgomery RR, Kantor FS, Fikrig E, Flavell RA. Outer surface proteins E and F of Borrelia burgdorferi, the agent of Lyme disease. Infect Immun. 1994;62:290–298. PubMed PMC

Casjens S, van Vugt R, Tilly K, Rosa PA, Stevenson B. Homology throughout the multiple 32-kilobase circular plasmids present in Lyme disease spirochetes. J Bacteriol. 1997;179:217–227. doi: 10.1128/jb.179.1.217-227.1997. PubMed DOI PMC

Akins DR, Caimano MJ, Yang X, Cerna F, Norgard MV, Radolf JD. Molecular and evolutionary analysis of Borrelia burgdorferi 297 circular plasmid-encoded lipoproteins with OspE- and OspF-like leader peptides. Infect Immun. 1999;67:1526–1532. PubMed PMC

Sambri V, Stefanelli C, Cevenini R. Detection of glycoproteins in Borrelia burgdorferi. Arch Microbiol. 1992;157:205–208. doi: 10.1007/BF00245150. PubMed DOI

Sterba J, Vancova M, Rudenko N, Golovchenko M, Tremblay TL, Kelly JF, et al. Flagellin and outer surface proteins from Borrelia burgdorferi are not glycosylated. J Bacteriol. 2008;190:2619–2623. doi: 10.1128/JB.01885-07. PubMed DOI PMC

Eicken C, Sharma V, Klabunde T, Lawrenz MB, Hardham JM, Norris SJ, et al. Crystal structure of Lyme disease variable surface antigen VlsE of Borrelia burgdorferi. J Biol Chem. 2002;277:21691–21696. doi: 10.1074/jbc.M201547200. PubMed DOI

Narasimhan S, Coumou J, Schuijt TJ, Boder E, Hovius JW, Fikrig E. A tick gut protein with fibronectin III domains aids Borrelia burgdorferi congregation to the gut during transmission. PLoS Pathog. 2014;10:e1004278. doi: 10.1371/journal.ppat.1004278. PubMed DOI PMC

Coumou J, Narasimhan S, Trentelman JJ, Wagemakers A, Koetsveld J, Ersoz JI, et al. Ixodes scapularis dystroglycan-like protein promotes Borrelia burgdorferi migration from the gut. J Mol Med (Berl) 2016;94:361–370. doi: 10.1007/s00109-015-1365-0. PubMed DOI PMC

Narasimhan S, Santiago F, Koski RA, Brei B, Anderson JF, Fish D, et al. Examination of the Borrelia burgdorferi transcriptome in Ixodes scapularis during feeding. J Bacteriol. 2002;184:3122–3125. doi: 10.1128/JB.184.11.3122-3125.2002. PubMed DOI PMC

Schuijt Tim J., Coumou Jeroen, Narasimhan Sukanya, Dai Jianfeng, DePonte Kathleen, Wouters Diana, Brouwer Mieke, Oei Anneke, Roelofs Joris J.T.H., van Dam Alje P., van der Poll Tom, van't Veer Cornelis, Hovius Joppe W., Fikrig Erol. A Tick Mannose-Binding Lectin Inhibitor Interferes with the Vertebrate Complement Cascade to Enhance Transmission of the Lyme Disease Agent. Cell Host & Microbe. 2011;10(2):136–146. doi: 10.1016/j.chom.2011.06.010. PubMed DOI PMC

Schuijt TJ, Narasimhan S, Daffre S, DePonte K, Hovius JW, Van't Veer C, et al. Identification and characterization of Ixodes scapularis antigens that elicit tick immunity using yeast surface display. PLoS One. 2011;6:e15926. doi: 10.1371/journal.pone.0015926. PubMed DOI PMC

Coburn J, Leong J, Chaconas G. Illuminating the roles of the Borrelia burgdorferi adhesins. Trends Microbiol. 2013;21:372–379. doi: 10.1016/j.tim.2013.06.005. PubMed DOI PMC

Leong JM, Robbins D, Rosenfeld L, Lahiri B, Parveen N. Structural requirements for glycosaminoglycan recognition by the Lyme disease spirochete, Borrelia burgdorferi. Infect Immun. 1998;66:6045–6048. PubMed PMC

Brissette CA, Gaultney RA. That’s my story, and I’m sticking to it - an update on B. burgdorferi adhesins. Front Cell Infect Microbiol. 2014;4:41. PubMed PMC

Szczepanski A, Furie MB, Benach JL, Lane BP, Fleit HB. Interaction between Borrelia burgdorferi and endothelium in vitro. J Clin Invest. 1990;85:1637–1647. doi: 10.1172/JCI114615. PubMed DOI PMC

Guo BP, Norris SJ, Rosenberg LC, Hook M. Adherence of Borrelia burgdorferi to the proteoglycan decorin. Infect Immun. 1995;63:3467–3472. PubMed PMC

Choi HU, Johnson TL, Pal S, Tang LH, Rosenberg L, Neame PJ. Characterization of the dermatan sulfate proteoglycans, DS-PGI and DS-PGII, from bovine articular cartilage and skin isolated by octyl-sepharose chromatography. J Biol Chem. 1989;264:2876–2884. PubMed

Rosenberg LC, Choi HU, Tang LH, Johnson TL, Pal S, Webber C, et al. Isolation of dermatan sulfate proteoglycans from mature bovine articular cartilages. J Biol Chem. 1985;260:6304–6313. PubMed

Sasaki T, Fassler R, Hohenester E. Laminin: the crux of basement membrane assembly. J Cell Biol. 2004;164:959–963. doi: 10.1083/jcb.200401058. PubMed DOI PMC

Kumar AP, Nandini CD, Salimath PV. Structural characterization of N-linked oligosaccharides of laminin from rat kidney: changes during diabetes and modulation by dietary fiber and butyric acid. FEBS J. 2011;278:143–155. doi: 10.1111/j.1742-4658.2010.07940.x. PubMed DOI

Singh B, Fleury C, Jalalvand F, Riesbeck K. Human pathogens utilize host extracellular matrix proteins laminin and collagen for adhesion and invasion of the host. FEMS Microbiol Rev. 2012;36:1122–1180. doi: 10.1111/j.1574-6976.2012.00340.x. PubMed DOI

Cabello FC, Hulinska D, Godfrey HP. Molecular Biology of Spirochetes. Amsterdam: IOS Press; 2006.

Brissette CA, Verma A, Bowman A, Cooley AE, Stevenson B. The Borrelia burgdorferi outer-surface protein ErpX binds mammalian laminin. Microbiology. 2009;155:863–872. doi: 10.1099/mic.0.024604-0. PubMed DOI PMC

Brissette CA, Cooley AE, Burns LH, Riley SP, Verma A, Woodman ME, et al. Lyme borreliosis spirochete Erp proteins, their known host ligands, and potential roles in mammalian infection. Int J Med Microbiol. 2008;298(Suppl. 1):257–267. doi: 10.1016/j.ijmm.2007.09.004. PubMed DOI PMC

Hynes RO. Integrins: a family of cell surface receptors. Cell. 1987;48:549–554. doi: 10.1016/0092-8674(87)90233-9. PubMed DOI

Cai X, Thinn AMM, Wang Z, Shan H, Zhu J. The importance of N-glycosylation on β3 integrin ligand binding and conformational regulation. Sci Rep. 2017;7:4656. doi: 10.1038/s41598-017-04844-w. PubMed DOI PMC

Coburn J, Magoun L, Bodary SC, Leong JM. Integrins αvβ3 and α5β1 mediate attachment of Lyme disease spirochetes to human cells. Infect Immun. 1998;66:1946–1952. PubMed PMC

Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992;69:11–25. doi: 10.1016/0092-8674(92)90115-S. PubMed DOI

Magoun L, Zuckert WR, Robbins D, Parveen N, Alugupalli KR, Schwan TG, et al. Variable small protein (Vsp)-dependent and Vsp-independent pathways for glycosaminoglycan recognition by relapsing fever spirochaetes. Mol Microbiol. 2000;36:886–897. doi: 10.1046/j.1365-2958.2000.01906.x. PubMed DOI

Porcella SF, Raffel SJ, Anderson DE, Jr, Gilk SD, Bono JL, Schrumpf ME, et al. Variable tick protein in two genomic groups of the relapsing fever spirochete Borrelia hermsii in western North America. Infect Immun. 2005;73:6647–6658. doi: 10.1128/IAI.73.10.6647-6658.2005. PubMed DOI PMC

Probert WS, Johnson BJ. Identification of a 47 kDa fibronectin-binding protein expressed by Borrelia burgdorferi isolate B31. Mol Microbiol. 1998;30:1003–1015. doi: 10.1046/j.1365-2958.1998.01127.x. PubMed DOI

Brissette CA, Bykowski T, Cooley AE, Bowman A, Stevenson B. Borrelia burgdorferi RevA antigen binds host fibronectin. Infect Immun. 2009;77:2802–2812. doi: 10.1128/IAI.00227-09. PubMed DOI PMC

Li X, Liu X, Beck DS, Kantor FS, Fikrig E. Borrelia burgdorferi lacking BBK32, a fibronectin-binding protein, retains full pathogenicity. Infect Immun. 2006;74:3305–3313. doi: 10.1128/IAI.02035-05. PubMed DOI PMC

Hyde JA, Weening EH, Chang M, Trzeciakowski JP, Hook M, Cirillo JD, et al. Bioluminescent imaging of Borrelia burgdorferi in vivo demonstrates that the fibronectin-binding protein BBK32 is required for optimal infectivity. Mol Microbiol. 2011;82:99–113. doi: 10.1111/j.1365-2958.2011.07801.x. PubMed DOI PMC

Niddam AF, Ebady R, Bansal A, Koehler A, Hinz B, Moriarty TJ. Plasma fibronectin stabilizes Borrelia burgdorferi-endothelial interactions under vascular shear stress by a catch-bond mechanism. Proc Natl Acad Sci USA. 2017;114:E3490–E34E8. doi: 10.1073/pnas.1615007114. PubMed DOI PMC

Ebady R, Niddam AF, Boczula AE, Kim YR, Gupta N, Tang TT, et al. Biomechanics of Borrelia burgdorferi vascular interactions. Cell Rep. 2016;16:2593–2604. doi: 10.1016/j.celrep.2016.08.013. PubMed DOI PMC

Lin YP, Chen Q, Ritchie JA, Dufour NP, Fischer JR, Coburn J, et al. Glycosaminoglycan binding by Borrelia burgdorferi adhesin BBK32 specifically and uniquely promotes joint colonization. Cell Microbiol. 2015;17:860–875. doi: 10.1111/cmi.12407. PubMed DOI PMC

Parveen N, Robbins D, Leong JM. Strain variation in glycosaminoglycan recognition influences cell-type-specific binding by Lyme disease spirochetes. Infect Immun. 1999;67:1743–1749. PubMed PMC

Moriarty TJ, Shi M, Lin YP, Ebady R, Zhou H, Odisho T, et al. Vascular binding of a pathogen under shear force through mechanistically distinct sequential interactions with host macromolecules. Mol Microbiol. 2012;86:1116–1131. doi: 10.1111/mmi.12045. PubMed DOI PMC

Garcia BL, Zhi H, Wager B, Hook M, Skare JT. Borrelia burgdorferi BBK32 inhibits the classical pathway by blocking activation of the C1 complement complex. PLoS Pathog. 2016;12:e1005404. doi: 10.1371/journal.ppat.1005404. PubMed DOI PMC

Brissette CA, Rossmann E, Bowman A, Cooley AE, Riley SP, Hunfeld KP, et al. The borrelial fibronectin-binding protein RevA is an early antigen of human Lyme disease. Clin Vaccine Immunol. 2010;17:274–280. doi: 10.1128/CVI.00437-09. PubMed DOI PMC

Shi Y, Xu Q, McShan K, Liang FT. Both decorin-binding proteins A and B are critical for the overall virulence of Borrelia burgdorferi. Infect Immun. 2008;76:1239–1246. doi: 10.1128/IAI.00897-07. PubMed DOI PMC

Salo J, Jaatinen A, Soderstrom M, Viljanen MK, Hytonen J. Decorin binding proteins of Borrelia burgdorferi promote arthritis development and joint specific post-treatment DNA persistence in mice. PLoS One. 2015;10:e0121512. doi: 10.1371/journal.pone.0121512. PubMed DOI PMC

Benoit VM, Fischer JR, Lin YP, Parveen N, Leong JM. Allelic variation of the Lyme disease spirochete adhesin DbpA influences spirochetal binding to decorin, dermatan sulfate, and mammalian cells. Infect Immun. 2011;79:3501–3509. doi: 10.1128/IAI.00163-11. PubMed DOI PMC

Morgan A, Sepuru KM, Feng W, Rajarathnam K, Wang X. Flexible linker modulates glycosaminoglycan affinity of decorin binding protein A. Biochemistry. 2015;54:5113–5119. doi: 10.1021/acs.biochem.5b00253. PubMed DOI PMC

Wang X. Solution structure of decorin-binding protein A from Borrelia burgdorferi. Biochemistry. 2012;51:8353–8362. doi: 10.1021/bi3007093. PubMed DOI PMC

Salo J, Loimaranta V, Lahdenne P, Viljanen MK, Hytonen J. Decorin binding by DbpA and B of Borrelia garinii, Borrelia afzelii, and Borrelia burgdorferi sensu stricto. J Infect Dis. 2011;204:65–73. doi: 10.1093/infdis/jir207. PubMed DOI PMC

Imai DM, Samuels DS, Feng S, Hodzic E, Olsen K, Barthold SW. The early dissemination defect attributed to disruption of decorin-binding proteins is abolished in chronic murine Lyme borreliosis. Infect Immun. 2013;81:1663–1673. doi: 10.1128/IAI.01359-12. PubMed DOI PMC

Schlachter S, Seshu J, Lin T, Norris S, Parveen N. The Borrelia burgdorferi glycosaminoglycan binding protein Bgp in the B31 strain is not essential for infectivity despite facilitating adherence and tissue colonization. Infect Immun. 2018;86:e00667–e00617. PubMed PMC

Verma A, Brissette CA, Bowman A, Stevenson B. Borrelia burgdorferi BmpA is a laminin-binding protein. Infect Immun. 2009;77:4940–4946. doi: 10.1128/IAI.01420-08. PubMed DOI PMC

Antonara S, Ristow L, Coburn J. Adhesion mechanisms of Borrelia burgdorferi. Adv Exp Med Biol. 2011;715:35–49. doi: 10.1007/978-94-007-0940-9_3. PubMed DOI PMC

Pal U, Wang P, Bao F, Yang X, Samanta S, Schoen R, et al. Borrelia burgdorferi basic membrane proteins A and B participate in the genesis of Lyme arthritis. J Exp Med. 2008;205:133–141. doi: 10.1084/jem.20070962. PubMed DOI PMC

Coburn J, Barthold SW, Leong JM. Diverse Lyme disease spirochetes bind integrin αIIbβ3 on human platelets. Infect Immun. 1994;62:5559–5567. PubMed PMC

Alugupalli KR, Michelson AD, Barnard MR, Robbins D, Coburn J, Baker EK, et al. Platelet activation by a relapsing fever spirochaete results in enhanced bacterium-platelet interaction via integrin αIIbβ3 activation. Mol Microbiol. 2001;39:330–340. doi: 10.1046/j.1365-2958.2001.02201.x. PubMed DOI

Coburn J, Chege W, Magoun L, Bodary SC, Leong JM. Characterization of a candidate Borrelia burgdorferi β3-chain integrin ligand identified using a phage display library. Mol Microbiol. 1999;34:926–940. doi: 10.1046/j.1365-2958.1999.01654.x. PubMed DOI

Skare JT, Mirzabekov TA, Shang ES, Blanco DR, Erdjument-Bromage H, Bunikis J, et al. The Oms66 (p66) protein is a Borrelia burgdorferi porin. Infect Immun. 1997;65:3654–3661. PubMed PMC

Barcena-Uribarri I, Thein M, Sacher A, Bunikis I, Bonde M, Bergstrom S, et al. P66 porins are present in both Lyme disease and relapsing fever spirochetes: a comparison of the biophysical properties of P66 porins from six Borrelia species. Biochim Biophys Acta. 1798;2010:1197–1203. PubMed

Kenedy MR, Luthra A, Anand A, Dunn JP, Radolf JD, Akins DR. Structural modeling and physicochemical characterization provide evidence that P66 forms a β-barrel in the Borrelia burgdorferi outer membrane. J Bacteriol. 2014;196:859–872. doi: 10.1128/JB.01236-13. PubMed DOI PMC

Coburn J, Cugini C. Targeted mutation of the outer membrane protein P66 disrupts attachment of the Lyme disease agent, Borrelia burgdorferi, to integrin αVβ3. Proc Natl Acad Sci USA. 2003;100:7301–7306. doi: 10.1073/pnas.1131117100. PubMed DOI PMC

Ristow LC, Bonde M, Lin YP, Sato H, Curtis M, Wesley E, et al. Integrin binding by Borrelia burgdorferi P66 facilitates dissemination but is not required for infectivity. Cell Microbiol. 2015;17:1021–1036. doi: 10.1111/cmi.12418. PubMed DOI PMC

Defoe G, Coburn J. Delineation of Borrelia burgdorferi p66 sequences required for integrin αIIbβ3 recognition. Infect Immun. 2001;69:3455–3459. doi: 10.1128/IAI.69.5.3455-3459.2001. PubMed DOI PMC

Ristow LC, Miller HE, Padmore LJ, Chettri R, Salzman N, Caimano MJ, et al. The β3-integrin ligand of Borrelia burgdorferi is critical for infection of mice but not ticks. Mol Microbiol. 2012;85:1105–1118. doi: 10.1111/j.1365-2958.2012.08160.x. PubMed DOI PMC

Wood E, Tamborero S, Mingarro I, Esteve-Gassent MD. BB0172, a Borrelia burgdorferi outer membrane protein that binds integrin α3β1. J Bacteriol. 2013;195:3320–3330. doi: 10.1128/JB.00187-13. PubMed DOI PMC

Lambris JD, Ricklin D, Geisbrecht BV. Complement evasion by human pathogens. Nat Rev Microbiol. 2008;6:132–142. doi: 10.1038/nrmicro1824. PubMed DOI PMC

Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11:785–797. doi: 10.1038/ni.1923. PubMed DOI PMC

Kraiczy P. Hide and seek: how Lyme disease spirochetes overcome complement attack. Front Immunol. 2016;7:385. PubMed PMC

Rodriguez de Cordoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sanchez-Corral P. The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol. 2004;41:355–367. doi: 10.1016/j.molimm.2004.02.005. PubMed DOI

Fenaille F, Le Mignon M, Groseil C, Ramon C, Riande S, Siret L, et al. Site-specific N-glycan characterization of human complement factor H. Glycobiology. 2007;17:932–944. doi: 10.1093/glycob/cwm060. PubMed DOI

Kraiczy Peter, Wallich Reinhard. The Pathogenic Spirochetes: strategies for evasion of host immunity and persistence. Boston, MA: Springer US; 2012. Borrelial Complement-Binding Proteins; pp. 63–88.

Hellwage J, Kuhn S, Zipfel PF. The human complement regulatory factor-H-like protein 1, which represents a truncated form of factor H, displays cell-attachment activity. Biochem J. 1997;326:321–327. doi: 10.1042/bj3260321. PubMed DOI PMC

Metts MS, McDowell JV, Theisen M, Hansen PR, Marconi RT. Analysis of the OspE determinants involved in binding of factor H and OspE-targeting antibodies elicited during Borrelia burgdorferi infection in mice. Infect Immun. 2003;71:3587–3596. doi: 10.1128/IAI.71.6.3587-3596.2003. PubMed DOI PMC

Wallich R, Pattathu J, Kitiratschky V, Brenner C, Zipfel PF, Brade V, et al. Identification and functional characterization of complement regulator-acquiring surface protein 1 of the Lyme disease spirochetes Borrelia afzelii and Borrelia garinii. Infect Immun. 2005;73:2351–2359. doi: 10.1128/IAI.73.4.2351-2359.2005. PubMed DOI PMC

Kraiczy P, Skerka C, Kirschfink M, Brade V, Zipfel PF. Immune evasion of Borrelia burgdorferi by acquisition of human complement regulators FHL-1/reconectin and Factor H. Eur J Immunol. 2001;31:1674–1684. doi: 10.1002/1521-4141(200106)31:6<1674::AID-IMMU1674>3.0.CO;2-2. PubMed DOI

Kraiczy P, Hellwage J, Skerka C, Becker H, Kirschfink M, Simon MM, et al. Complement resistance of Borrelia burgdorferi correlates with the expression of BbCRASP-1, a novel linear plasmid-encoded surface protein that interacts with human factor H and FHL-1 and is unrelated to Erp proteins. J Biol Chem. 2004;279:2421–2429. doi: 10.1074/jbc.M308343200. PubMed DOI

Haupt K, Kraiczy P, Wallich R, Brade V, Skerka C, Zipfel PF. Binding of human factor H-related protein 1 to serum-resistant Borrelia burgdorferi is mediated by borrelial complement regulator-acquiring surface proteins. J Infect Dis. 2007;196:124–133. doi: 10.1086/518509. PubMed DOI

von Lackum K, Miller JC, Bykowski T, Riley SP, Woodman ME, Brade V, et al. Borrelia burgdorferi regulates expression of complement regulator-acquiring surface protein 1 during the mammal-tick infection cycle. Infect Immun. 2005;73:7398–7405. doi: 10.1128/IAI.73.11.7398-7405.2005. PubMed DOI PMC

Bykowski T., Woodman M. E., Cooley A. E., Brissette C. A., Brade V., Wallich R., Kraiczy P., Stevenson B. Coordinated Expression of Borrelia burgdorferi Complement Regulator-Acquiring Surface Proteins during the Lyme Disease Spirochete's Mammal-Tick Infection Cycle. Infection and Immunity. 2007;75(9):4227–4236. doi: 10.1128/IAI.00604-07. PubMed DOI PMC

Kenedy MR, Vuppala SR, Siegel C, Kraiczy P, Akins DR. CspA-mediated binding of human factor H inhibits complement deposition and confers serum resistance in Borrelia burgdorferi. Infect Immun. 2009;77:2773–2782. doi: 10.1128/IAI.00318-09. PubMed DOI PMC

Hallstrom T, Siegel C, Morgelin M, Kraiczy P, Skerka C, Zipfel PF. CspA from Borrelia burgdorferi inhibits the terminal complement pathway. MBio. 2013;4:e00481-13. PubMed PMC

Bhide MR, Travnicek M, Levkutova M, Curlik J, Revajova V, Levkut M. Sensitivity of Borrelia genospecies to serum complement from different animals and human: a host-pathogen relationship. FEMS Immunol Med Microbiol. 2005;43:165–172. doi: 10.1016/j.femsim.2004.07.012. PubMed DOI

Herzberger P, Siegel C, Skerka C, Fingerle V, Schulte-Spechtel U, van Dam A, et al. Human pathogenic Borrelia spielmanii sp. nov. resists complement-mediated killing by direct binding of immune regulators factor H and factor H-like protein 1. Infect Immun. 2007;75:4817–4825. doi: 10.1128/IAI.00532-07. PubMed DOI PMC

Hartmann K, Corvey C, Skerka C, Kirschfink M, Karas M, Brade V, et al. Functional characterization of BbCRASP-2, a distinct outer membrane protein of Borrelia burgdorferi that binds host complement regulators factor H and FHL-1. Mol Microbiol. 2006;61:1220–1236. doi: 10.1111/j.1365-2958.2006.05318.x. PubMed DOI

Siegel C, Schreiber J, Haupt K, Skerka C, Brade V, Simon MM, et al. Deciphering the ligand-binding sites in the Borrelia burgdorferi complement regulator-acquiring surface protein 2 required for interactions with the human immune regulators factor H and factor H-like protein 1. J Biol Chem. 2008;283:34855–34863. doi: 10.1074/jbc.M805844200. PubMed DOI PMC

Kraiczy P, Seling A, Brissette CA, Rossmann E, Hunfeld KP, Bykowski T, et al. Borrelia burgdorferi complement regulator-acquiring surface protein 2 (CspZ) as a serological marker of human Lyme disease. Clin Vaccine Immunol. 2008;15:484–491. doi: 10.1128/CVI.00415-07. PubMed DOI PMC

Coleman AS, Yang X, Kumar M, Zhang X, Promnares K, Shroder D, et al. Borrelia burgdorferi complement regulator-acquiring surface protein 2 does not contribute to complement resistance or host infectivity. PLoS One. 2008;3:3010e. doi: 10.1371/journal.pone.0003010. PubMed DOI PMC

Alitalo A, Meri T, Lankinen H, Seppala L, Lahdenne P, Hefty PS, et al. Complement inhibitor factor H binding to Lyme disease spirochetes is mediated by inducible expression of multiple plasmid-encoded outer surface protein E paralogs. J Immunol. 2002;169:3847–3853. doi: 10.4049/jimmunol.169.7.3847. PubMed DOI

Hammerschmidt C, Hallstrom T, Skerka C, Wallich R, Stevenson B, Zipfel PF, et al. Contribution of the infection-associated complement regulator-acquiring surface protein 4 (ErpC) to complement resistance of Borrelia burgdorferi. Clin Dev Immunol. 2012;2012:349657. doi: 10.1155/2012/349657. PubMed DOI PMC

Siegel C, Hallstrom T, Skerka C, Eberhardt H, Uzonyi B, Beckhaus T, et al. Complement factor H-related proteins CFHR2 and CFHR5 represent novel ligands for the infection-associated CRASP proteins of Borrelia burgdorferi. PLoS One. 2010;5:e13519. doi: 10.1371/journal.pone.0013519. PubMed DOI PMC

Hovis KM, Tran E, Sundy CM, Buckles E, McDowell JV, Marconi RT. Selective binding of Borrelia burgdorferi OspE paralogs to factor H and serum proteins from diverse animals: possible expansion of the role of OspE in Lyme disease pathogenesis. Infect Immun. 2006;74:1967–1972. doi: 10.1128/IAI.74.3.1967-1972.2006. PubMed DOI PMC

McDowell JV, Wolfgang J, Tran E, Metts MS, Hamilton D, Marconi RT. Comprehensive analysis of the factor H binding capabilities of Borrelia species associated with Lyme disease: delineation of two distinct classes of factor H binding proteins. Infect Immun. 2003;71:3597–3602. doi: 10.1128/IAI.71.6.3597-3602.2003. PubMed DOI PMC

Stevenson B, Bono JL, Schwan TG, Rosa P. Borrelia burgdorferi erp proteins are immunogenic in mammals infected by tick bite, and their synthesis is inducible in cultured bacteria. Infect Immun. 1998;66:2648–2654. PubMed PMC

Fikrig E, Narasimhan S. Borrelia burgdorferi-traveling incognito? Microbes Infect. 2006;8:1390–1399. doi: 10.1016/j.micinf.2005.12.022. PubMed DOI

Brooks CS, Vuppala SR, Jett AM, Alitalo A, Meri S, Akins DR. Complement regulator-acquiring surface protein 1 imparts resistance to human serum in Borrelia burgdorferi. J Immunol. 2005;175:3299–3308. doi: 10.4049/jimmunol.175.5.3299. PubMed DOI

van Dam AP, Oei A, Jaspars R, Fijen C, Wilske B, Spanjaard L, et al. Complement-mediated serum sensitivity among spirochetes that cause Lyme disease. Infect Immun. 1997;65:1228–1236. PubMed PMC

Sun J, Duffy KE, Ranjith-Kumar CT, Xiong J, Lamb RJ, Santos J, et al. Structural and functional analyses of the human Toll-like receptor 3. Role of glycosylation. J Biol Chem. 2006;281:11144–11151. doi: 10.1074/jbc.M510442200. PubMed DOI

Berende A, Oosting M, Kullberg BJ, Netea MG, Joosten LA. Activation of innate host defense mechanisms by Borrelia. Eur Cytokine Netw. 2010;21:7–18. PubMed

Leifer CA, Medvedev AE. Molecular mechanisms of regulation of Toll-like receptor signaling. J Leukocyte Biol. 2016;100:927–941. doi: 10.1189/jlb.2MR0316-117RR. PubMed DOI PMC

Medzhitov R, Preston-Hurlburt P, Janeway CA., Jr A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388:394–397. doi: 10.1038/41131. PubMed DOI

Muzio M, Bosisio D, Polentarutti N, D’Amico G, Stoppacciaro A, Mancinelli R, et al. Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol. 2000;164:5998–6004. doi: 10.4049/jimmunol.164.11.5998. PubMed DOI

Wooten RM, Ma Y, Yoder RA, Brown JP, Weis JH, Zachary JF, et al. Toll-like receptor 2 is required for innate, but not acquired, host defense to Borrelia burgdorferi. J Immunol. 2002;168:348–355. doi: 10.4049/jimmunol.168.1.348. PubMed DOI

Bernardino AL, Myers TA, Alvarez X, Hasegawa A, Philipp MT. Toll-like receptors: insights into their possible role in the pathogenesis of Lyme neuroborreliosis. Infect Immun. 2008;76:4385–4395. doi: 10.1128/IAI.00394-08. PubMed DOI PMC

Salazar JC, Pope CD, Moore MW, Pope J, Kiely TG, Radolf JD. Lipoprotein-dependent and -independent immune responses to spirochetal infection. Clin Diagn Lab Immunol. 2005;12:949–958. PubMed PMC

Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol. 1999;162:3749–3752. PubMed

Häcker Hans, Mischak Harald, Miethke Thomas, Liptay Susanne, Schmid Roland, Sparwasser Tim, Heeg Klaus, Lipford Grayson B., Wagner Hermann. CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. The EMBO Journal. 1998;17(21):6230–6240. doi: 10.1093/emboj/17.21.6230. PubMed DOI PMC

Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, et al. A Toll-like receptor recognizes bacterial DNA. Nature. 2000;408:740–745. doi: 10.1038/35047123. PubMed DOI

Inohara N, Nunez G. NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol. 2003;3:371–382. doi: 10.1038/nri1086. PubMed DOI

Franchi L, Warner N, Viani K, Nunez G. Function of Nod-like receptors in microbial recognition and host defense. Immunol Rev. 2009;227:106–128. doi: 10.1111/j.1600-065X.2008.00734.x. PubMed DOI PMC

Kanneganti TD, Lamkanfi M, Nunez G. Intracellular NOD-like receptors in host defense and disease. Immunity. 2007;27:549–559. doi: 10.1016/j.immuni.2007.10.002. PubMed DOI

Sterka D, Jr, Marriott I. Characterization of nucleotide-binding oligomerization domain (NOD) protein expression in primary murine microglia. J Neuroimmunol. 2006;179:65–75. doi: 10.1016/j.jneuroim.2006.06.009. PubMed DOI

Sterka D, Jr, Marriott I. Functional expression of NOD2, a novel pattern recognition receptor for bacterial motifs, in primary murine astrocytes. Glia. 2006;53:322–330. doi: 10.1002/glia.20286. PubMed DOI

Petnicki-Ocwieja T, DeFrancesco AS, Chung E, Darcy CT, Bronson RT, Kobayashi KS, et al. Nod2 suppresses Borrelia burgdorferi mediated murine Lyme arthritis and carditis through the induction of tolerance. PLoS One. 2011;6:e17414. doi: 10.1371/journal.pone.0017414. PubMed DOI PMC

Oosting M, Berende A, Sturm P, Ter Hofstede HJ, de Jong DJ, Kanneganti TD, et al. Recognition of Borrelia burgdorferi by NOD2 is central for the induction of an inflammatory reaction. J Infect Dis. 2010;201:1849–1858. doi: 10.1086/652871. PubMed DOI

Stübs Gunthard, Fingerle Volker, Wilske Bettina, Göbel Ulf B., Zähringer Ulrich, Schumann Ralf R., Schröder Nicolas W. J. Acylated Cholesteryl Galactosides Are Specific Antigens ofBorreliaCausing Lyme Disease and Frequently Induce Antibodies in Late Stages of Disease. Journal of Biological Chemistry. 2009;284(20):13326–13334. doi: 10.1074/jbc.M809575200. PubMed DOI PMC

Ben-Menachem G, Kubler-Kielb J, Coxon B, Yergey A, Schneerson R. A newly discovered cholesteryl galactoside from Borrelia burgdorferi. Proc Natl Acad Sci USA. 2003;100:7913–7918. doi: 10.1073/pnas.1232451100. PubMed DOI PMC

Radolf JD, Caimano MJ, Stevenson B, Hu LT. Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes. Nat Rev Microbiol. 2012;10:87–99. doi: 10.1038/nrmicro2714. PubMed DOI PMC

Jones KL, Seward RJ, Ben-Menachem G, Glickstein LJ, Costello CE, Steere AC. Strong IgG antibody responses to Borrelia burgdorferi glycolipids in patients with Lyme arthritis, a late manifestation of the infection. Clin Immunol. 2009;132:93–102. doi: 10.1016/j.clim.2009.03.510. PubMed DOI PMC

Comstock LE, Fikrig E, Shoberg RJ, Flavell RA, Thomas DD. A monoclonal antibody to OspA inhibits association of Borrelia burgdorferi with human endothelial cells. Infect Immun. 1993;61:423–431. PubMed PMC

Wang J, Li Y, Kinjo Y, Mac TT, Gibson D, Painter GF, et al. Lipid binding orientation within CD1d affects recognition of Borrelia burgorferi antigens by NKT cells. Proc Natl Acad Sci USA. 2010;107:1535–1540. doi: 10.1073/pnas.0909479107. PubMed DOI PMC

Garcia Monco JC, Wheeler CM, Benach JL, Furie RA, Lukehart SA, Stanek G, et al. Reactivity of neuroborreliosis patients (Lyme disease) to cardiolipin and gangliosides. J Neurol Sci. 1993;117:206–214. doi: 10.1016/0022-510X(93)90175-X. PubMed DOI

Garcia-Monco JC, Seidman RJ, Benach JL. Experimental immunization with Borrelia burgdorferi induces development of antibodies to gangliosides. Infect Immun. 1995;63:4130–4137. PubMed PMC

Weller M, Stevens A, Sommer N, Dichgans J, Kappler B, Wietholter H. Ganglioside antibodies: a lack of diagnostic specificity and clinical utility? J Neurol. 1992;239:455–459. doi: 10.1007/BF00856811. PubMed DOI

Venkataswamy MM, Porcelli SA. Lipid and glycolipid antigens of CD1d-restricted natural killer T cells. Semin Immunol. 2010;22:68–78. doi: 10.1016/j.smim.2009.10.003. PubMed DOI PMC

Hossain H, Wellensiek HJ, Geyer R, Lochnit G. Structural analysis of glycolipids from Borrelia burgdorferi. Biochimie. 2001;83:683–692. doi: 10.1016/S0300-9084(01)01296-2. PubMed DOI

Smith DG, Williams SJ. Immune sensing of microbial glycolipids and related conjugates by T cells and the pattern recognition receptors MCL and Mincle. Carbohydr Res. 2016;420:32–45. doi: 10.1016/j.carres.2015.11.009. PubMed DOI

Garcia Monco JC, Fernandez Villar B, Rogers RC, Szczepanski A, Wheeler CM, Benach JL. Borrelia burgdorferi and other related spirochetes bind to galactocerebroside. Neurology. 1992;42:1341–1348. doi: 10.1212/WNL.42.7.1341. PubMed DOI

Backenson PB, Coleman JL, Benach JL. Borrelia burgdorferi shows specificity of binding to glycosphingolipids. Infect Immun. 1995;63:2811–2817. PubMed PMC

Kaneda K, Masuzawa T, Yasugami K, Suzuki T, Suzuki Y, Yanagihara Y. Glycosphingolipid-binding protein of Borrelia burgdorferi sensu lato. Infect Immun. 1997;65:3180–3185. PubMed PMC

Hajnicka V, Kocakova P, Slavikova M, Slovak M, Gasperik J, Fuchsberger N, et al. Anti-interleukin-8 activity of tick salivary gland extracts. Parasite Immunol. 2001;23:483–489. doi: 10.1046/j.1365-3024.2001.00403.x. PubMed DOI

Frauenschuh A, Power CA, Deruaz M, Ferreira BR, Silva JS, Teixeira MM, et al. Molecular cloning and characterization of a highly selective chemokine-binding protein from the tick Rhipicephalus sanguineus. J Biol Chem. 2007;282:27250–27258. doi: 10.1074/jbc.M704706200. PubMed DOI

Eaton James R. O., Alenazi Yara, Singh Kamayani, Davies Graham, Geis-Asteggiante Lucia, Kessler Benedikt, Robinson Carol V., Kawamura Akane, Bhattacharya Shoumo. The N-terminal domain of a tick evasin is critical for chemokine binding and neutralization and confers specific binding activity to other evasins. Journal of Biological Chemistry. 2018;293(16):6134–6146. doi: 10.1074/jbc.RA117.000487. PubMed DOI PMC

Uhlir J, Grubhoffer L, Borsky I, Dusbabek F. Antigens and glycoproteins of larvae, nymphs and adults of the tick Ixodes ricinus. Med Vet Entomol. 1994;8:141–150. doi: 10.1111/j.1365-2915.1994.tb00154.x. PubMed DOI

Mulenga A, Kim T, Ibelli AM. Amblyomma americanum tick saliva serine protease inhibitor 6 is a cross-class inhibitor of serine proteases and papain-like cysteine proteases that delays plasma clotting and inhibits platelet aggregation. Insect Mol Biol. 2013;22:306–319. doi: 10.1111/imb.12024. PubMed DOI PMC

Tirloni L, Kim TK, Coutinho ML, Ali A, Seixas A, Termignoni C, et al. The putative role of Rhipicephalus microplus salivary serpins in the tick-host relationship. Insect Biochem Mol Biol. 2016;71:12–28. doi: 10.1016/j.ibmb.2016.01.004. PubMed DOI PMC

Deruaz M, Frauenschuh A, Alessandri AL, Dias JM, Coelho FM, Russo RC, et al. Ticks produce highly selective chemokine binding proteins with antiinflammatory activity. J Exp Med. 2008;205:2019–2031. doi: 10.1084/jem.20072689. PubMed DOI PMC

Pratt CW, Church FC. Heparin binding to protein C inhibitor. J Biol Chem. 1992;267:8789–8794. PubMed

Rein CM, Desai UR, Church FC. Serpin-glycosaminoglycan interactions. Methods Enzymol. 2011;501:105–137. doi: 10.1016/B978-0-12-385950-1.00007-9. PubMed DOI

Tollefsen DM. Heparin Cofactor II. In: Church FC, Cunningham DD, Ginsburg D, Hoffman M, Stone SR, Tollefsen DM, editors. Chemistry and Biology of Serpins (Advances in Experimental Medicine and Biology, Vol. 425). New York: Springer Science+Business Media; 1997.

Radulovic ZM, Mulenga A. Heparan sulfate/heparin glycosaminoglycan binding alters inhibitory profile and enhances anticoagulant function of conserved Amblyomma americanum tick saliva serpin 19. Insect Biochem Mol Biol. 2017;80:1–10. doi: 10.1016/j.ibmb.2016.11.002. PubMed DOI PMC

Koh CY, Kazimirova M, Trimnell A, Takac P, Labuda M, Nuttall PA, et al. Variegin, a novel fast and tight binding thrombin inhibitor from the tropical bont tick. J Biol Chem. 2007;282:29101–29113. doi: 10.1074/jbc.M705600200. PubMed DOI

Shabareesh PRV, Kumar A, Salunke DM, Kaur KJ. Structural and functional studies of differentially O-glycosylated analogs of a thrombin inhibitory peptide - variegin. J Pept Sci. 2017;23:880–888. doi: 10.1002/psc.3052. PubMed DOI

Stuen S, Bergstrom K, Palmer E. Reduced weight gain due to subclinical Anaplasma phagocytophilum (formerly Ehrlichia phagocytophila) infection. Exp Appl Acarol. 2002;28:209–215. doi: 10.1023/A:1025350517733. PubMed DOI

Splitter EJ, Twiehaus MJ, Castro ER. Anaplasmosis in sheep in the United States. J Am Vet Med Assoc. 1955;127:244–245. PubMed

Melendez RD. Future perspectives on veterinary hemoparasite research in the tropics at the start of this century. Ann N Y Acad Sci. 2000;916:253–258. doi: 10.1111/j.1749-6632.2000.tb05297.x. PubMed DOI

Dumler JS, Bakken JS. Human ehrlichioses: newly recognized infections transmitted by ticks. Annu Rev Med. 1998;49:201–213. doi: 10.1146/annurev.med.49.1.201. PubMed DOI

Keesing F, Hersh MH, Tibbetts M, McHenry DJ, Duerr S, Brunner J, et al. Reservoir competence of vertebrate hosts for Anaplasma phagocytophilum. Emerg Infect Dis. 2012;18:2013–2016. doi: 10.3201/eid1812.120919. PubMed DOI PMC

Parola P, Raoult D. Ticks and tickborne bacterial diseases in humans: an emerging infectious threat. Clin Infect Dis. 2001;32:897–928. doi: 10.1086/319347. PubMed DOI

Stafford KC, Station CAE. Tick management handbook: an integrated guide for homeowners, pest control operators, and public health officials for the prevention of tick-associated disease. New Haven: Connecticut Agricultural Experiment Station; 2007.

Seidman D, Hebert KS, Truchan HK, Miller DP, Tegels BK, Marconi RT, et al. Essential domains of Anaplasma phagocytophilum invasins utilized to infect mammalian host cells. PLoS Pathog. 2015;11:e1004669. doi: 10.1371/journal.ppat.1004669. PubMed DOI PMC

Ojogun N, Kahlon A, Ragland SA, Troese MJ, Mastronunzio JE, Walker NJ, et al. Anaplasma phagocytophilum outer membrane protein A interacts with sialylated glycoproteins to promote infection of mammalian host cells. Infect Immun. 2012;80:3748–3760. doi: 10.1128/IAI.00654-12. PubMed DOI PMC

Hebert KS, Seidman D, Oki AT, Izac J, Emani S, Oliver LD Jr, et al. Anaplasma marginale outer membrane protein A is an adhesin that recognizes sialylated and fucosylated glycans and functionally depends on an essential binding domain. Infect Immun. 2017;85:e00968-16. PubMed PMC

Barbet AF, Allred DR. The msp1β multigene family of Anaplasma marginale: nucleotide sequence analysis of an expressed copy. Infect Immun. 1991;59:971–976. PubMed PMC

McGarey DJ, Allred DR. Characterization of hemagglutinating components on the Anaplasma marginale initial body surface and identification of possible adhesins. Infect Immun. 1994;62:4587–4593. PubMed PMC

de la Fuente J, Garcia-Garcia JC, Blouin EF, Kocan KM. Differential adhesion of major surface proteins 1a and 1b of the ehrlichial cattle pathogen Anaplasma marginale to bovine erythrocytes and tick cells. Int J Parasitol. 2001;31:145–153. doi: 10.1016/S0020-7519(00)00162-4. PubMed DOI

McGarey DJ, Barbet AF, Palmer GH, McGuire TC, Allred DR. Putative adhesins of Anaplasma marginale: major surface polypeptides 1a and 1b. Infect Immun. 1994;62:4594–4601. PubMed PMC

Contreras M, Alberdi P, Mateos-Hernandez L, Fernandez de Mera IG, Garcia-Perez AL, Vancova M, et al. Anaplasma phagocytophilum MSP4 and HSP70 proteins are involved in interactions with host cells during pathogen infection. Front Cell Infect Microbiol. 2017;7:307. doi: 10.3389/fcimb.2017.00307. PubMed DOI PMC

NCBI. 1988. https://www.ncbi.nlm.nih.gov/. Accessed 30 Nov 2017.

de la Fuente J, Garcia-Garcia JC, Blouin EF, Kocan KM. Characterization of the functional domain of major surface protein 1a involved in adhesion of the rickettsia Anaplasma marginale to host cells. Vet Microbiol. 2003;91:265–283. doi: 10.1016/S0378-1135(02)00309-7. PubMed DOI

Garcia-Garcia JC, de la Fuente J, Bell-Eunice G, Blouin EF, Kocan KM. Glycosylation of Anaplasma marginale major surface protein 1a and its putative role in adhesion to tick cells. Infect Immun. 2004;72:3022–3030. doi: 10.1128/IAI.72.5.3022-3030.2004. PubMed DOI PMC

Park J, Choi KS, Dumler JS. Major surface protein 2 of Anaplasma phagocytophilum facilitates adherence to granulocytes. Infect Immun. 2003;71:4018–4025. doi: 10.1128/IAI.71.7.4018-4025.2003. PubMed DOI PMC

Rejmanek D, Foley P, Barbet A, Foley J. Antigen variability in Anaplasma phagocytophilum during chronic infection of a reservoir host. Microbiology. 2012;158:2632–2641. doi: 10.1099/mic.0.059808-0. PubMed DOI PMC

Rejmanek D, Foley P, Barbet A, Foley J. Evolution of antigen variation in the tick-borne pathogen Anaplasma phagocytophilum. Mol Biol Evol. 2012;29:391–400. doi: 10.1093/molbev/msr229. PubMed DOI PMC

Ge Y, Rikihisa Y. Identification of novel surface proteins of Anaplasma phagocytophilum by affinity purification and proteomics. J Bacteriol. 2007;189:7819–7828. doi: 10.1128/JB.00866-07. PubMed DOI PMC

Mastronunzio JE, Kurscheid S, Fikrig E. Postgenomic analyses reveal development of infectious Anaplasma phagocytophilum during transmission from ticks to mice. J Bacteriol. 2012;194:2238–2247. doi: 10.1128/JB.06791-11. PubMed DOI PMC

Troese MJ, Kahlon A, Ragland SA, Ottens AK, Ojogun N, Nelson KT, et al. Proteomic analysis of Anaplasma phagocytophilum during infection of human myeloid cells identifies a protein that is pronouncedly upregulated on the infectious dense-cored cell. Infect Immun. 2011;79:4696–4707. doi: 10.1128/IAI.05658-11. PubMed DOI PMC

Goodman JL, Nelson CM, Klein MB, Hayes SF, Weston BW. Leukocyte infection by the granulocytic ehrlichiosis agent is linked to expression of a selectin ligand. J Clin Invest. 1999;103:407–412. doi: 10.1172/JCI4230. PubMed DOI PMC

Ojogun N, Barnstein B, Huang B, Oskeritzian CA, Homeister JW, Miller D, et al. Anaplasma phagocytophilum infects mast cells via α1,3-fucosylated but not sialylated glycans and inhibits IgE-mediated cytokine production and histamine release. Infect Immun. 2011;79:2717–2726. doi: 10.1128/IAI.00181-11. PubMed DOI PMC

Carlyon JA, Akkoyunlu M, Xia L, Yago T, Wang T, Cummings RD, et al. Murine neutrophils require α1,3-fucosylation but not PSGL-1 for productive infection with Anaplasma phagocytophilum. Blood. 2003;102:3387–3395. doi: 10.1182/blood-2003-02-0621. PubMed DOI

McEver RP, Cummings RD. Role of PSGL-1 binding to selectins in leukocyte recruitment. J Clin Invest. 1997;100(Suppl. 11):S97–103. PubMed

Yago T, Leppanen A, Carlyon JA, Akkoyunlu M, Karmakar S, Fikrig E, et al. Structurally distinct requirements for binding of P-selectin glycoprotein ligand-1 and sialyl Lewis x to Anaplasma phagocytophilum and P-selectin. J Biol Chem. 2003;278:37987–37997. doi: 10.1074/jbc.M305778200. PubMed DOI

Herron MJ, Nelson CM, Larson J, Snapp KR, Kansas GS, Goodman JL. Intracellular parasitism by the human granulocytic ehrlichiosis bacterium through the P-selectin ligand, PSGL-1. Science. 2000;288:1653–1656. doi: 10.1126/science.288.5471.1653. PubMed DOI

Pedra JH, Narasimhan S, Rendic D, DePonte K, Bell-Sakyi L, Wilson IB, et al. Fucosylation enhances colonization of ticks by Anaplasma phagocytophilum. Cell Microbiol. 2010;12:1222–1234. doi: 10.1111/j.1462-5822.2010.01464.x. PubMed DOI PMC

Kariu T, Smith A, Yang X, Pal U. A chitin deacetylase-like protein is a predominant constituent of tick peritrophic membrane that influences the persistence of Lyme disease pathogens within the vector. PLoS One. 2013;8:e78376. doi: 10.1371/journal.pone.0078376. PubMed DOI PMC

Abraham NM, Liu L, Jutras BL, Yadav AK, Narasimhan S, Gopalakrishnan V, et al. Pathogen-mediated manipulation of arthropod microbiota to promote infection. Proc Natl Acad Sci USA. 2017;114:E781–EE90. doi: 10.1073/pnas.1613422114. PubMed DOI PMC

Heisig M, Abraham NM, Liu L, Neelakanta G, Mattessich S, Sultana H, et al. Antivirulence properties of an antifreeze protein. Cell Rep. 2014;9:417–424. doi: 10.1016/j.celrep.2014.09.034. PubMed DOI PMC

Neelakanta G, Sultana H, Fish D, Anderson JF, Fikrig E. Anaplasma phagocytophilum induces Ixodes scapularis ticks to express an antifreeze glycoprotein gene that enhances their survival in the cold. J Clin Invest. 2010;120:3179–3190. doi: 10.1172/JCI42868. PubMed DOI PMC

Ip WK, Takahashi K, Ezekowitz RA, Stuart LM. Mannose-binding lectin and innate immunity. Immunol Rev. 2009;230:9–21. doi: 10.1111/j.1600-065X.2009.00789.x. PubMed DOI

Matsushita M. Ficolins: complement-activating lectins involved in innate immunity. J Innate Immun. 2010;2:24–32. doi: 10.1159/000228160. PubMed DOI

Krarup A, Thiel S, Hansen A, Fujita T, Jensenius JC. L-ficolin is a pattern recognition molecule specific for acetyl groups. J Biol Chem. 2004;279:47513–47519. doi: 10.1074/jbc.M407161200. PubMed DOI

Kairies N, Beisel HG, Fuentes-Prior P, Tsuda R, Muta T, Iwanaga S, et al. The 2.0-A crystal structure of tachylectin 5A provides evidence for the common origin of the innate immunity and the blood coagulation systems. Proc Natl Acad Sci USA. 2001;98:13519–13524. doi: 10.1073/pnas.201523798. PubMed DOI PMC

Hanington PC, Zhang SM. The primary role of fibrinogen-related proteins in invertebrates is defense, not coagulation. J Innate Immun. 2011;3:17–27. doi: 10.1159/000321882. PubMed DOI PMC

Kopacek P, Hajdusek O, Buresova V. Tick as a model for the study of a primitive complement system. Adv Exp Med Biol. 2012;710:83–93. doi: 10.1007/978-1-4419-5638-5_9. PubMed DOI

Kovar V, Kopacek P, Grubhoffer L. Isolation and characterization of Dorin M, a lectin from plasma of the soft tick Ornithodoros moubata. Insect Biochem Mol Biol. 2000;30:195–205. doi: 10.1016/S0965-1748(99)00107-1. PubMed DOI

Rego ROM, Hajdusek O, Kovar V, Kopacek P, Grubhoffer L, Hypsa V. Molecular cloning and comparative analysis of fibrinogen-related proteins from the soft tick Ornithodoros moubata and the hard tick Ixodes ricinus. Insect Biochem Mol Biol. 2005;35:991–1004. doi: 10.1016/j.ibmb.2005.04.001. PubMed DOI

Rego ROM, Kovar V, Kopacek P, Weise C, Man P, Sauman I, et al. The tick plasma lectin, Dorin M, is a fibrinogen-related molecule. Insect Biochem Mol Biol. 2006;36:291–299. doi: 10.1016/j.ibmb.2006.01.008. PubMed DOI

Man P, Kovar V, Sterba J, Strohalm M, Kavan D, Kopacek P, et al. Deciphering Dorin M glycosylation by mass spectrometry. Eur J Mass Spectrom. 2008;14:345–354. doi: 10.1255/ejms.979. PubMed DOI

Sterba J, Dupejova J, Fiser M, Vancova M, Grubhoffer L. Fibrinogen-related proteins in ixodid ticks. Parasit Vectors. 2011;4:127. doi: 10.1186/1756-3305-4-127. PubMed DOI PMC

Honig Mondekova H, Sima R, Urbanova V, Kovar V, Rego ROM, Grubhoffer L, et al. Characterization of Ixodes ricinus fibrinogen-related proteins (Ixoderins) discloses their function in the tick innate immunity. Front Cell Infect Microbiol. 2017;7:509. doi: 10.3389/fcimb.2017.00509. PubMed DOI PMC

Dupejova J, Sterba J, Vancova M, Grubhoffer L. Hemelipoglycoprotein from the ornate sheep tick, Dermacentor marginatus: structural and functional characterization. Parasit Vectors. 2011;4:4. doi: 10.1186/1756-3305-4-4. PubMed DOI PMC

Huang X, Tsuji N, Miyoshi T, Nakamura-Tsuruta S, Hirabayashi J, Fujisaki K. Molecular characterization and oligosaccharide-binding properties of a galectin from the argasid tick Ornithodoros moubata. Glycobiology. 2007;17:313–323. doi: 10.1093/glycob/cwl070. PubMed DOI

Vasta GR, Ahmed H, Nita-Lazar M, Banerjee A, Pasek M, Shridhar S, et al. Galectins as self/non-self recognition receptors in innate and adaptive immunity: an unresolved paradox. Front Immunol. 2012;3:199. doi: 10.3389/fimmu.2012.00199. PubMed DOI PMC

Maeda H, Miyata T, Kusakisako K, Galay RL, Talactac MR, Umemiya-Shirafuji R, et al. A novel C-type lectin with triple carbohydrate recognition domains has critical roles for the hard tick Haemaphysalis longicornis against Gram-negative bacteria. Dev Comp Immunol. 2016;57:38–47. doi: 10.1016/j.dci.2015.12.015. PubMed DOI

Smith AA, Pal U. Immunity-related genes in Ixodes scapularis - perspectives from genome information. Front Cell Infect Microbiol. 2014;4:116. PubMed PMC

Pang X, Xiao X, Liu Y, Zhang R, Liu J, Liu Q, et al. Mosquito C-type lectins maintain gut microbiome homeostasis. Nat Microbiol. 2016;1:16023. doi: 10.1038/nmicrobiol.2016.23. PubMed DOI

Cheng G, Cox J, Wang P, Krishnan MN, Dai J, Qian F, et al. A C-type lectin collaborates with a CD45 phosphatase homolog to facilitate West Nile virus infection of mosquitoes. Cell. 2010;142:714–725. doi: 10.1016/j.cell.2010.07.038. PubMed DOI PMC

Neelakanta G, Sultana H. Viral receptors of the gut: vector-borne viruses of medical importance. Curr Opin Insect Sci. 2016;16:44–50. doi: 10.1016/j.cois.2016.04.015. PubMed DOI

Alarcon-Chaidez F, Ryan R, Wikel S, Dardick K, Lawler C, Foppa IM, et al. Confirmation of tick bite by detection of antibody to Ixodes calreticulin salivary protein. Clin Vaccine Immunol. 2006;13:1217–1222. doi: 10.1128/CVI.00201-06. PubMed DOI PMC

Schroeder H, Skelly PJ, Zipfel PF, Losson B, Vanderplasschen A. Subversion of complement by hematophagous parasites. Dev Comp Immunol. 2009;33:5–13. doi: 10.1016/j.dci.2008.07.010. PubMed DOI PMC

Eggleton P, Lieu TS, Zappi EG, Sastry K, Coburn J, Zaner KS, et al. Calreticulin is released from activated neutrophils and binds to C1q and mannan-binding protein. Clin Immunol Immunopathol. 1994;72:405–409. doi: 10.1006/clin.1994.1160. PubMed DOI

Kim TK, Ibelli AM, Mulenga A. Amblyomma americanum tick calreticulin binds C1q but does not inhibit activation of the classical complement cascade. Ticks Tick Borne Dis. 2015;6:91–101. doi: 10.1016/j.ttbdis.2014.10.002. PubMed DOI PMC

Uhlir J, Grubhoffer L, Volf P. Novel agglutinin in the midgut of the tick Ixodes ricinus. Folia Parasitol (Praha) 1996;43:233–239. PubMed

Grubhoffer L, Kovar V, Rudenko N. Tick lectins: structural and functional properties. Parasitology. 2004;129:S113–SS25. doi: 10.1017/S0031182004004858. PubMed DOI

Kamwendo SP, Ingram GA, Musisi FL, Molyneux DH. Haemagglutinin activity in tick (Rhipicephalus appendiculatus) haemolymph and extracts of gut and salivary gland. Ann Trop Med Parasitol. 1993;87:303–305. doi: 10.1080/00034983.1993.11812771. PubMed DOI

Kamwendo SP, Ingram GA, Musisi FL, Trees AJ, Molyneux DH. Characteristics of tick, Rhipicephalus appendiculatus, glands distinguished by surface lectin binding. Ann Trop Med Parasitol. 1993;87:525–535. doi: 10.1080/00034983.1993.11812805. PubMed DOI

Pal U, Li X, Wang T, Montgomery RR, Ramamoorthi N, Desilva AM, et al. TROSPA, an Ixodes scapularis receptor for Borrelia burgdorferi. Cell. 2004;119:457–468. doi: 10.1016/j.cell.2004.10.027. PubMed DOI

Grubhoffer L, Dusbabek F. Lectin binding analysis of Argas polonicus tissue glycoproteins. Vet Parasitol. 1991;38:235–247. doi: 10.1016/0304-4017(91)90133-G. PubMed DOI

Vancova M, Zacharovova K, Grubhoffer L, Nebesarova J. Ultrastructure and lectin characterization of granular salivary cells from Ixodes ricinus females. J Parasitol. 2006;92:431–440. doi: 10.1645/GE-648R.1. PubMed DOI

Grubhoffer L, Hajdusek O, Vancova M, Sterba J, Rudenko N. Glycobiochemistry of ticks, vectors of infectious diseases: carbohydrate-binding proteins and glycans. FEBS J. 2009;276:141.

Vancova M, Sterba J, Dupejova J, Simonova Z, Nebesarova J, Novotny MV, et al. Uptake and incorporation of sialic acid by the tick Ixodes ricinus. J Insect Physiol. 2012;58:1277–1287. doi: 10.1016/j.jinsphys.2012.06.016. PubMed DOI

Thall A, Galili U. Distribution of Galα1-3Galβ1-4GlcNAc residues on secreted mammalian glycoproteins (thyroglobulin, fibrinogen, and immunoglobulin G) as measured by a sensitive solid-phase radioimmunoassay. Biochemistry. 1990;29:3959–3965. doi: 10.1021/bi00468a024. PubMed DOI

Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-α-1,3-galactose. N Engl J Med. 2008;358:1109–1117. doi: 10.1056/NEJMoa074943. PubMed DOI PMC

Commins SP, James HR, Kelly LA, Pochan SL, Workman LJ, Perzanowski MS, et al. The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose. J Allergy Clin Immunol. 2011;127:1286–93.e6. doi: 10.1016/j.jaci.2011.02.019. PubMed DOI PMC

Van Nunen SA, O'Connor KS, Clarke LR, Boyle RX, Fernando SL. An association between tick bite reactions and red meat allergy in humans. Med J Aust. 2009;190:510–511. PubMed

Chinuki Y, Ishiwata K, Yamaji K, Takahashi H, Morita E. Haemaphysalis longicornis tick bites are a possible cause of red meat allergy in Japan. Allergy. 2016;71:421–425. doi: 10.1111/all.12804. PubMed DOI

Hamsten C, Starkhammar M, Tran TA, Johansson M, Bengtsson U, Ahlen G, et al. Identification of galactose-α-1,3-galactose in the gastrointestinal tract of the tick Ixodes ricinus; possible relationship with red meat allergy. Allergy. 2013;68:549–552. doi: 10.1111/all.12128. PubMed DOI

Wang H, Nuttall PA. Excretion of host immunoglobulin in tick saliva and detection of IgG-binding proteins in tick haemolymph and salivary glands. Parasitology. 1994;109:525–530. doi: 10.1017/S0031182000080781. PubMed DOI

Valenzuela JG, Francischetti IMB, Pham VM, Garfield MK, Mather TN, Ribeiro JMC. Exploring the sialome of the tick Ixodes scapularis. J Exp Biol. 2002;205:2843–2864. PubMed

Araujo RN, Franco PF, Rodrigues H, Santos LCB, McKay CS, Sanhueza CA, et al. Amblyomma sculptum tick saliva: α-Gal identification, antibody response and possible association with red meat allergy in Brazil. Int J Parasitol. 2016;46:213–220. doi: 10.1016/j.ijpara.2015.12.005. PubMed DOI PMC

Altmann F. The role of protein glycosylation in allergy. Int Arch Allergy Immunol. 2007;142:99–115. doi: 10.1159/000096114. PubMed DOI

van Die I, Gomord V, Kooyman FN, van den Berg TK, Cummings RD, Vervelde L. Core α1->3-fucose is a common modification of N-glycans in parasitic helminths and constitutes an important epitope for IgE from Haemonchus contortus infected sheep. FEBS Lett. 1999;463:189–193. doi: 10.1016/S0014-5793(99)01508-2. PubMed DOI

Altmann F. Coping with cross-reactive carbohydrate determinants in allergy diagnosis. Allergo J Int. 2016;25:98–105. doi: 10.1007/s40629-016-0115-3. PubMed DOI PMC

Vancova M, Nebesarova J. Correlative fluorescence and scanning electron microscopy of labelled core fucosylated glycans using cryosections mounted on carbon-patterned glass slides. PLoS One. 2015;10:e0145034. doi: 10.1371/journal.pone.0145034. PubMed DOI PMC

Bencurova M, Hemmer W, Focke-Tejkl M, Wilson IB, Altmann F. Specificity of IgG and IgE antibodies against plant and insect glycoprotein glycans determined with artificial glycoforms of human transferrin. Glycobiology. 2004;14:457–466. doi: 10.1093/glycob/cwh058. PubMed DOI

North SJ, Koles K, Hembd C, Morris HR, Dell A, Panin VM, et al. Glycomic studies of Drosophila melanogaster embryos. Glycoconjugate J. 2006;23:345–354. doi: 10.1007/s10719-006-6693-4. PubMed DOI

Koles K, Irvine KD, Panin VM. Functional characterization of Drosophila sialyltransferase. J Biol Chem. 2004;279:4346–4357. doi: 10.1074/jbc.M309912200. PubMed DOI

Repnikova E, Koles K, Nakamura M, Pitts J, Li H, Ambavane A, et al. Sialyltransferase regulates nervous system function in Drosophila. J Neurosci. 2010;30:6466–6476. doi: 10.1523/JNEUROSCI.5253-09.2010. PubMed DOI PMC

Sterba J, Vancova M, Sterbova J, Bell-Sakyi L, Grubhoffer L. The majority of sialylated glycoproteins in adult Ixodes ricinus ticks originate in the host, not the tick. Carbohydr Res. 2014;389:93–99. doi: 10.1016/j.carres.2014.02.017. PubMed DOI

Gritsun TS, Lashkevich VA, Gould EA. Tick-borne encephalitis. Antiviral Res. 2003;57:129–146. doi: 10.1016/S0166-3542(02)00206-1. PubMed DOI

Welsch S, Miller S, Romero-Brey I, Merz A, Bleck CK, Walther P, et al. Composition and three-dimensional architecture of the dengue virus replication and assembly sites. Cell Host Microbe. 2009;5:365–375. doi: 10.1016/j.chom.2009.03.007. PubMed DOI PMC

Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010;84:10438–10447. doi: 10.1128/JVI.00986-10. PubMed DOI PMC

Offerdahl DK, Dorward DW, Hansen BT, Bloom ME. A three-dimensional comparison of tick-borne flavivirus infection in mammalian and tick cell lines. PLoS One. 2012;7:e47912. doi: 10.1371/journal.pone.0047912. PubMed DOI PMC

Miorin L, Romero-Brey I, Maiuri P, Hoppe S, Krijnse-Locker J, Bartenschlager R, et al. Three-dimensional architecture of tick-borne encephalitis virus replication sites and trafficking of the replicated RNA. J Virol. 2013;87:6469–6481. doi: 10.1128/JVI.03456-12. PubMed DOI PMC

Yu L, Takeda K, Gao Y. Characterization of virus-specific vesicles assembled by West Nile virus non-structural proteins. Virology. 2017;506:130–140. doi: 10.1016/j.virol.2017.03.016. PubMed DOI

Best SM, Morris KL, Shannon JG, Robertson SJ, Mitzel DN, Park GS, et al. Inhibition of interferon-stimulated JAK-STAT signaling by a tick-borne flavivirus and identification of NS5 as an interferon antagonist. J Virol. 2005;79:12828–12839. doi: 10.1128/JVI.79.20.12828-12839.2005. PubMed DOI PMC

Lindenbach BD, Rice CM. Molecular biology of flaviviruses. Adv Virus Res. 2003;59:23–61. doi: 10.1016/S0065-3527(03)59002-9. PubMed DOI

Lorenz IC, Allison SL, Heinz FX, Helenius A. Folding and dimerization of tick-borne encephalitis virus envelope proteins prM and E in the endoplasmic reticulum. J Virol. 2002;76:5480–5491. doi: 10.1128/JVI.76.11.5480-5491.2002. PubMed DOI PMC

Mackenzie JM, Westaway EG. Assembly and maturation of the flavivirus Kunjin virus appear to occur in the rough endoplasmic reticulum and along the secretory pathway, respectively. J Virol. 2001;75:10787–10799. doi: 10.1128/JVI.75.22.10787-10799.2001. PubMed DOI PMC

Stadler K, Allison SL, Schalich J, Heinz FX. Proteolytic activation of tick-borne encephalitis virus by furin. J Virol. 1997;71:8475–8481. PubMed PMC

Mandl CW. Steps of the tick-borne encephalitis virus replication cycle that affect neuropathogenesis. Virus Res. 2005;111:161–174. doi: 10.1016/j.virusres.2005.04.007. PubMed DOI

Heinz FX, Allison SL. Flavivirus structure and membrane fusion. Adv Virus Res. 2003;59:63–97. doi: 10.1016/S0065-3527(03)59003-0. PubMed DOI

Hammond C, Braakman I, Helenius A. Role of N-linked oligosaccharide recognition, glucose trimming, and calnexin in glycoprotein folding and quality control. Proc Natl Acad Sci USA. 1994;91:913–917. doi: 10.1073/pnas.91.3.913. PubMed DOI PMC

Yoshii K, Yanagihara N, Ishizuka M, Sakai M, Kariwa H. N-linked glycan in tick-borne encephalitis virus envelope protein affects viral secretion in mammalian cells, but not in tick cells. J Gen Virol. 2013;94:2249–2258. doi: 10.1099/vir.0.055269-0. PubMed DOI

Winkler G, Heinz FX, Kunz C. Studies on the glycosylation of flavivirus E proteins and the role of carbohydrate in antigenic structure. Virology. 1987;159:237–243. doi: 10.1016/0042-6822(87)90460-0. PubMed DOI

Rey FA, Heinz FX, Mandl C, Kunz C, Harrison SC. The envelope glycoprotein from tick-borne encephalitis virus at 2 A resolution. Nature. 1995;375:291–298. doi: 10.1038/375291a0. PubMed DOI

Lorenz IC, Kartenbeck J, Mezzacasa A, Allison SL, Heinz FX, Helenius A. Intracellular assembly and secretion of recombinant subviral particles from tick-borne encephalitis virus. J Virol. 2003;77:4370–4382. doi: 10.1128/JVI.77.7.4370-4382.2003. PubMed DOI PMC

Grubhoffer L, Guirakhoo F, Heinz F, Kunz C. Lectins: Biology, Biochemistry and Clinical Biochemistry. St Louis: Sigma Chemical Company; 1990. Interaction of tick-borne encephalitis virus protein E with labelled lectins; pp. 313–319.

Fuzik T, Formanova P, Ruzek D, Yoshii K, Niedrig M, Plevka P. Structure of tick-borne encephalitis virus and its neutralization by a monoclonal antibody. Nat Commun. 2018;9:436. doi: 10.1038/s41467-018-02882-0. PubMed DOI PMC

Goto A, Yoshii K, Obara M, Ueki T, Mizutani T, Kariwa H, et al. Role of the N-linked glycans of the prM and E envelope proteins in tick-borne encephalitis virus particle secretion. Vaccine. 2005;23:3043–3052. doi: 10.1016/j.vaccine.2004.11.068. PubMed DOI

Putnak JR, Charles PC, Padmanabhan R, Irie K, Hoke CH, Burke DS. Functional and antigenic domains of the dengue-2 virus nonstructural glycoprotein NS-1. Virology. 1988;163:93–103. doi: 10.1016/0042-6822(88)90236-X. PubMed DOI

Chambers TJ, Hahn CS, Galler R, Rice CM. Flavivirus genome organization, expression, and replication. Annu Rev Microbiol. 1990;44:649–688. doi: 10.1146/annurev.mi.44.100190.003245. PubMed DOI

Heinz FX, Allison SL. Structures and mechanisms in flavivirus fusion. Adv Virus Res. 2000;55:231–269. doi: 10.1016/S0065-3527(00)55005-2. PubMed DOI PMC

Hanna SL, Pierson TC, Sanchez MD, Ahmed AA, Murtadha MM, Doms RW. N-linked glycosylation of west nile virus envelope proteins influences particle assembly and infectivity. J Virol. 2005;79:13262–13274. doi: 10.1128/JVI.79.21.13262-13274.2005. PubMed DOI PMC

Bryant JE, Calvert AE, Mesesan K, Crabtree MB, Volpe KE, Silengo S, et al. Glycosylation of the dengue 2 virus E protein at N67 is critical for virus growth in vitro but not for growth in intrathoracically inoculated Aedes aegypti mosquitoes. Virology. 2007;366:415–423. doi: 10.1016/j.virol.2007.05.007. PubMed DOI

Mondotte JA, Lozach PY, Amara A, Gamarnik AV. Essential role of dengue virus envelope protein N-glycosylation at asparagine-67 during viral propagation. J Virol. 2007;81:7136–7148. doi: 10.1128/JVI.00116-07. PubMed DOI PMC

Moudy RM, Zhang B, Shi PY, Kramer LD. West Nile virus envelope protein glycosylation is required for efficient viral transmission by Culex vectors. Virology. 2009;387:222–228. doi: 10.1016/j.virol.2009.01.038. PubMed DOI PMC

Murata R, Eshita Y, Maeda A, Maeda J, Akita S, Tanaka T, et al. Glycosylation of the West Nile virus envelope protein increases in vivo and in vitro viral multiplication in birds. Am J Trop Med Hyg. 2010;82:696–704. doi: 10.4269/ajtmh.2010.09-0262. PubMed DOI PMC

Hyde JA. Borrelia burgdorferi keeps moving and carries on: a review of borrelial dissemination and invasion. Front Immunol. 2017;8:114. doi: 10.3389/fimmu.2017.00114. PubMed DOI PMC

Hooper LV, Gordon JI. Glycans as legislators of host-microbial interactions: spanning the spectrum from symbiosis to pathogenicity. Glycobiology. 2001;11:1R–10R. doi: 10.1093/glycob/11.2.1R. PubMed DOI

Nizet V, Esko JD, et al. Bacterial and viral infections. In: Varki A, Cummings RD, Esko JD, Freeze HH, Stanley P, Bertozzi CR, et al., editors. Essentials of Glycobiology. 2. Cold Spring Harbor: Cold Spring Harbour Laboratory Press; 2009. PubMed

de la Fuente J, Canales M, Kocan KM. The importance of protein glycosylation in development of novel tick vaccine strategies. Parasite Immunol. 2006;28:687–688. doi: 10.1111/j.1365-3024.2006.00902.x. PubMed DOI

Sprong H, Trentelman J, Seemann I, Grubhoffer L, Rego RO, Hajdusek O, et al. ANTIDotE: anti-tick vaccines to prevent tick-borne diseases in Europe. Parasit Vectors. 2014;7:77. doi: 10.1186/1756-3305-7-77. PubMed DOI PMC

Boysen A, Palmisano G, Krogh TJ, Duggin IG, Larsen MR, Moller-Jensen J. A novel mass spectrometric strategy “BEMAP” reveals extensive O-linked protein glycosylation in enterotoxigenic Escherichia coli. Sci Rep. 2016;6:32016. doi: 10.1038/srep32016. PubMed DOI PMC

Parveen N, Leong JM. Identification of a candidate glycosaminoglycan-binding adhesin of the Lyme disease spirochete Borrelia burgdorferi. Mol Microbiol. 2000;35:1220–1234. doi: 10.1046/j.1365-2958.2000.01792.x. PubMed DOI

Guo BP, Brown EL, Dorward DW, Rosenberg LC, Hook M. Decorin-binding adhesins from Borrelia burgdorferi. Mol Microbiol. 1998;30:711–723. doi: 10.1046/j.1365-2958.1998.01103.x. PubMed DOI

Fuchs H, Wallich R, Simon MM, Kramer MD. The outer surface protein A of the spirochete Borrelia burgdorferi is a plasmin(ogen) receptor. Proc Natl Acad Sci USA. 1994;91:12594–12598. doi: 10.1073/pnas.91.26.12594. PubMed DOI PMC

Lagal V, Portnoi D, Faure G, Postic D, Baranton G. Borrelia burgdorferi sensu stricto invasiveness is correlated with OspC-plasminogen affinity. Microbes Infect. 2006;8:645–652. doi: 10.1016/j.micinf.2005.08.017. PubMed DOI

Onder O, Humphrey PT, McOmber B, Korobova F, Francella N, Greenbaum DC, et al. OspC is potent plasminogen receptor on surface of Borrelia burgdorferi. J Biol Chem. 2012;2870:16860–16868. doi: 10.1074/jbc.M111.290775. PubMed DOI PMC

Floden AM, Watt JA, Brissette CA. Borrelia burgdorferi enolase is a surface-exposed plasminogen binding protein. PLoS One. 2011;6:e27502. doi: 10.1371/journal.pone.0027502. PubMed DOI PMC

Cinco M, Cini B, Murgia R, Presani G, Prodan M, Perticarari S. Evidence of involvement of the mannose receptor in adhesion of Borrelia burgdorferi to monocyte/macrophages. Infect Immun. 2001;69:2743–2747. doi: 10.1128/IAI.69.4.2743-2747.2001. PubMed DOI PMC

Guo BP, Teneberg S, Munch R, Terunuma D, Hatano K, Matsuoka K, et al. Relapsing fever Borrelia binds to neolacto glycans and mediates rosetting of human erythrocytes. Proc Natl Acad Sci USA. 2009;106:19280–19285. doi: 10.1073/pnas.0905470106. PubMed DOI PMC

Kuismanen E, Hedman K, Saraste J, Pettersson RF. Uukuniemi virus maturation: accumulation of virus particles and viral antigens in the Golgi complex. Mol Cell Biol. 1982;2:1444–1458. doi: 10.1128/MCB.2.11.1444. PubMed DOI PMC

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