Advertisement

Plant-derived secretory component forms secretory IgA with shiga toxin 1-specific dimeric IgA produced by mouse cells and whole plants

  • Katsuhiro Nakanishi
  • Shota Morikane
  • Nao Hosokawa
  • Yuka Kajihara
  • Kohta Kurohane
  • Yasuo Niwa
  • Hirokazu Kobayashi
  • Yasuyuki Imai
Original Article

Abstract

Key message

A key module, secretory component (SC), was efficiently expressed in Arabidopsis thaliana. The plant-based SC and immunoglobulin A of animal or plant origin formed secretory IgA that maintains antigen-binding activity.

Abstract

Plant expression systems are suitable for scalable and cost-effective production of biologics. Secretory immunoglobulin A (SIgA) will be useful as a therapeutic antibody against mucosal pathogens. SIgA is equipped with a secretory component (SC), which assists the performance of SIgA on the mucosal surface. Here we produced SC using a plant expression system and formed SIgA with dimeric IgAs produced by mouse cells as well as by whole plants. To increase the expression level, an endoplasmic reticulum retention signal peptide, KDEL (Lys-Asp-Glu-Leu), was added to mouse SC (SC-KDEL). The SC-KDEL cDNA was inserted into a binary vector with a translational enhancer and an efficient terminator. The SC-KDEL transgenic Arabidopsis thaliana produced SC-KDEL at the level of 2.7% of total leaf proteins. In vitro reaction of the plant-derived SC-KDEL with mouse dimeric monoclonal IgAs resulted in the formation of SIgA. When reacted with Shiga toxin 1 (Stx1)-specific ones, the antigen-binding activity was maintained. When an A. thaliana plant expressing SC-KDEL was crossed with one expressing dimeric IgA specific for Stx1, the plant-based SIgA exhibited antigen-binding activity. Leaf extracts of the crossbred transgenic plants neutralized Stx1 cytotoxicity against Stx1-sensitive cells. These results suggest that transgenic plants expressing SC-KDEL will provide a versatile means of SIgA production.

Keywords

Transgenic plant Secretory component Secretory immunoglobulin A Plant-based therapeutic antibody 

Notes

Acknowledgements

This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers JP15H04660 and JP25670063 to YI; JP25·10915 to KN as well as by a research grant from the University of Shizuoka. We thank Mr. N.J. Halewood for language editing services.

Compliance with ethical standards

Conflict of interest

The authors declared that they have no conflict of interest.

References

  1. Almogren A, Senior BW, Kerr MA (2007) A comparison of the binding of secretory component to immunoglobulin A (IgA) in human colostral S-IgA1 and S-IgA2. Immunology 120:273–280.  https://doi.org/10.1111/j.1365-2567.2006.02498.x CrossRefPubMedPubMedCentralGoogle Scholar
  2. Brandtzaeg P (2013) Secretory IgA: designed for anti-microbial defense. Front Immunol 4:222.  https://doi.org/10.3389/fimmu.2013.00222 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Clough SJ, Bent AF (1998) Floral dip: a simplified method for Agrobacterium-mediated transformation of Arabidopsis thaliana. Plant J 16:735–743.  https://doi.org/10.1046/j.1365-313x.1998.00343.x CrossRefPubMedGoogle Scholar
  4. Corthésy B (2013) Multi-faceted functions of secretory IgA at mucosal surfaces. Front Immunol 4:185.  https://doi.org/10.3389/fimmu.2013.00185 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Crottet P, Corthésy B (1998) Secretory component delays the conversion of secretory IgA into antigen-binding competent F(ab’)2: a possible implication for mucosal defense. J Immunol 161:5445–5453PubMedGoogle Scholar
  6. Crottet P, Cottet S, Corthésy B (1999) Expression, purification and biochemical characterization of recombinant murine secretory component: a novel tool in mucosal immunology. Biochem J 341(Pt 2):299–306.  https://doi.org/10.1042/bj3410299 CrossRefPubMedPubMedCentralGoogle Scholar
  7. da Cunha NB, Vianna GR, da Almeida Lima T, Rech E (2014) Molecular farming of human cytokines and blood products from plants: Challenges in biosynthesis and detection of plant-produced recombinant proteins. Biotechnol J 9:39–50.  https://doi.org/10.1002/biot.201300062 CrossRefPubMedGoogle Scholar
  8. Daniell H, Streatfield SJ, Wycoff K (2001) Medical molecular farming: Production of antibodies, biopharmaceuticals and edible vaccines in plants. Trends Plant Sci 6:219–226.  https://doi.org/10.1016/S1360-1385(01)01922-7 CrossRefPubMedPubMedCentralGoogle Scholar
  9. De Meyer T, Depicker A (2014) Trafficking of endoplasmic reticulum-retained recombinant proteins is unpredictable in Arabidopsis thaliana. Front Plant Sci 5:473.  https://doi.org/10.3389/fpls.2014.00473 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Desai PN, Shrivastava N, Padh H (2010) Production of heterologous proteins in plants: Strategies for optimal expression. Biotechnol Adv 28:427–435.  https://doi.org/10.1016/j.biotechadv.2010.01.005 CrossRefPubMedGoogle Scholar
  11. Fasching CE, Grossman T, Corthesy B, Plaut AG, Weiser JN, Janoff EN (2007) Impact of the Molecular Form of Immunoglobulin A on Functional Activity in Defense against Streptococcus pneumoniae. Infect Immun 75:1801–1810.  https://doi.org/10.1128/IAI.01758-06 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Hirai T, Kurokawa N, Duhita N, Hiwasa-Tanase K, Kato K, Kato K, Ezura H (2011) The HSP terminator of Arabidopsis thaliana induces a high level of miraculin accumulation in transgenic tomatoes. J Agric Food Chem 59:9942–9949.  https://doi.org/10.1021/jf202501e CrossRefPubMedGoogle Scholar
  13. Huang J, Guerrero A, Parker E, Strum JS, Smilowitz JT, German JB, Lebrilla CB (2015) Site-specific glycosylation of secretory immunoglobulin a from human colostrum. J Proteome Res 14:1335–1349.  https://doi.org/10.1021/pr500826q CrossRefPubMedPubMedCentralGoogle Scholar
  14. Imai Y, Nagai R, Ono Y, Ishikawa T, Nakagami H, Tanikawa T, Kurohane K (2004) Production of secretory immunoglobulin a against Shiga toxin-binding subunits in mice by mucosal immunization. Infect Immun 72:889–895.  https://doi.org/10.1128/IAI.72.2.889-895.2004 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Imai Y, Ishikawa T, Tanikawa T, Nakagami H, Maekawa T, Kurohane K (2005) Production of IgA monoclonal antibody against Shiga toxin binding subunits employing nasal-associated lymphoid tissue. J Immunol Methods 302:125–135.  https://doi.org/10.1016/j.jim.2005.05.007 CrossRefPubMedGoogle Scholar
  16. Ito Y, Eiguchi M, Kurata N (2001) KNOX homeobox genes are sufficient in maintaining cultured cells in an undifferentiated state in rice. Genesis 30:231–238.  https://doi.org/10.1002/gene.1069 CrossRefPubMedGoogle Scholar
  17. Johansen FE, Braathen R, Brandtzaeg P (2000) Role of J chain in secretory immunoglobulin formation. Scand J Immunol 52:240–248.  https://doi.org/10.1046/j.1365-3083.2000.00790.x CrossRefPubMedGoogle Scholar
  18. Jones RM, Schweikart F, Frutiger S, Jaton JC, Hughes GJ (1998) Thiol-disulfide redox buffers maintain a structure of immunoglobulin A that is essential for optimal in vitro binding to secretory component. Biochim Biophys Acta Protein Struct Mol Enzymol 1429:265–274.  https://doi.org/10.1016/S0167-4838(98)00239-8 CrossRefGoogle Scholar
  19. Juarez P, Huet-Trujillo E, Sarrion-Perdigones A, Falconi EE, Granell A, Orzaez D (2013) Combinatorial analysis of secretory immunoglobulin A (sIgA) expression in plants. Int J Mol Sci 14:6205–6222.  https://doi.org/10.3390/ijms14036205 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Juarez P, Virdi V, Depicker A, Orzaez D (2016) Biomanufacturing of protective antibodies and other therapeutics in edible plant tissues for oral applications. Plant Biotechnol J 14:1791–1799.  https://doi.org/10.1111/pbi.12541 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Lindh E (1975) Increased resistance of immunoglobulin A dimers to proteolytic degradation after binding of secretory component. J Immunol 114:284–286PubMedGoogle Scholar
  22. Longet S, Miled S, Lötscher M, Miescher SM, Zuercher AW, Corthésy B (2013) Human plasma-derived polymeric IgA and IgM antibodies associate with secretory component to yield biologically active secretory-like antibodies. J Biol Chem 288:4085–4094.  https://doi.org/10.1074/jbc.M112.410811 CrossRefPubMedGoogle Scholar
  23. Mantis NJ, Rol N, Corthésy B (2011) Secretory IgA’s complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol 4:603–611.  https://doi.org/10.1038/mi.2011.41 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Mathias A, Corthésy B (2011a) N-glycans on secretory component: mediators of the interaction between secretory IgA and gram-positive commensals sustaining intestinal homeostasis. Gut Microbes 2:287–293.  https://doi.org/10.4161/gmic.2.5.18269 CrossRefPubMedGoogle Scholar
  25. Mathias A, Corthésy B (2011b) Recognition of gram-positive intestinal bacteria by hybridoma- and colostrum-derived secretory immunoglobulin A is mediated by carbohydrates. J Biol Chem 286:17239–17247.  https://doi.org/10.1074/jbc.M110.209015 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Miyashita S, Matsuura Y, Miyamoto D, Suzuki Y, Imai Y (1999) Development of recombinant B subunit of Shiga-like toxin 1 as a probe to detect carbohydrate ligands in immunochemical and flowcytometric application. Glycoconj J 16:697–705.  https://doi.org/10.1023/A:1007107425891 CrossRefPubMedGoogle Scholar
  27. Moldt B, Saye-Francisco K, Schultz N, Burton DR, Hessell AJ (2014) Simplifying the synthesis of SIgA: combination of dIgA and rhSC using affinity chromatography. Methods 65:127–132.  https://doi.org/10.1016/j.ymeth.2013.06.022 CrossRefPubMedGoogle Scholar
  28. Nagaya S, Kawamura K, Shinmyo A, Kato K (2010) The HSP terminator of Arabidopsis thaliana increases gene expression in plant cells. Plant Cell Physiol 51:328–332.  https://doi.org/10.1093/pcp/pcp188 CrossRefPubMedGoogle Scholar
  29. Nakanishi K, Narimatsu S, Ichikawa S, Tobisawa Y, Kurohane K, Niwa Y, Kobayashi H, Imai Y (2013) Production of Hybrid-IgG/IgA plantibodies with neutralizing activity against Shiga toxin 1. PLoS One 8:e80712.  https://doi.org/10.1371/journal.pone.0080712 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Nakanishi K, Morikane S, Ichikawa S, Kurohane K, Niwa Y, Akimoto Y, Matsubara S, Kawakami H, Kobayashi H, Imai Y (2017) Protection of human colon cells from Shiga toxin by plant-based recombinant secretory IgA. Sci Rep 7:45843.  https://doi.org/10.1038/srep45843 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Niwa Y, Goto S, Nakano T, Sakaiya M, Hirano T, Tsukaya H, Komeda Y, Kobayashi H (2006) Arabidopsis mutants by activation tagging in which photosynthesis genes are expressed in dedifferentiated calli. Plant Cell Physiol 47:319–331.  https://doi.org/10.1093/pcp/pci242 CrossRefPubMedGoogle Scholar
  32. Parr EL, Bozzola JJ, Parr MB (1995) Purification and measurement of secretory IgA in mouse milk. J Immunol Methods 180:147–157.  https://doi.org/10.1016/0022-1759(94)00310-S CrossRefPubMedGoogle Scholar
  33. Phalipon A, Cardona A, Kraehenbuhl JP, Edelman L, Sansonetti PJ, Corthésy B (2002) Secretory component: a new role in secretory IgA-mediated immune exclusion in vivo. Immunity 17:107–115.  https://doi.org/10.1016/S1074-7613(02)00341-2 CrossRefPubMedGoogle Scholar
  34. Reinhart D, Kunert R (2014) Upstream and downstream processing of recombinant IgA. Biotechnol Lett 37:241–251.  https://doi.org/10.1007/s10529-014-1686-z CrossRefPubMedGoogle Scholar
  35. Schouten A, Roosien J, van Engelen FA, de Jong GA, Borst-Vrenssen AW, Zilverentant JF, Bosch D, Stiekema WJ, Gommers FJ, Schots A, Bakker J (1996) The C-terminal KDEL sequence increases the expression level of a single-chain antibody designed to be targeted to both the cytosol and the secretory pathway in transgenic tobacco. Plant Mol Biol 30:781–793.  https://doi.org/10.1007/BF00019011 CrossRefPubMedGoogle Scholar
  36. Segawa K, Kurata S, Yanagihashi Y, Brummelkamp TR, Matsuda F, Nagata S (2014) Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344:1164–1168.  https://doi.org/10.1126/science.1252809 CrossRefPubMedGoogle Scholar
  37. Shoji K, Takahashi T, Kurohane K, Iwata K, Matsuoka T, Tsuruta S, Sugino T, Miyake M, Suzuki T, Imai Y (2015) Recombinant immunoglobulin A specific for influenza A virus hemagglutinin: production, functional analysis, and formation of secretory immunoglobulin A. Viral Immunol 28:170–178.  https://doi.org/10.1089/vim.2014.0098 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Streatfield SJ, Kushnir N, Yusibov V (2015) Plant-produced candidate countermeasures against emerging and reemerging infections and bioterror agents. Plant Biotechnol J 13:1136–1159.  https://doi.org/10.1111/pbi.12475 CrossRefPubMedGoogle Scholar
  39. Sugio T, Satoh J, Matsuura H, Shinmyo A, Kato K (2008) The 5′-untranslated region of the Oryza sativa alcohol dehydrogenase gene functions as a translational enhancer in monocotyledonous plant cells. J Biosci Bioeng 105:300–302.  https://doi.org/10.1263/jbb.105.300 CrossRefPubMedGoogle Scholar
  40. Tanikawa T, Ishikawa T, Maekawa T, Kuronane K, Imai Y (2008) Characterization of monoclonal immunoglobulin A and G against Shiga toxin binding subunits produced by intranasal immunization. Scand J Immunol 68:414–422.  https://doi.org/10.1111/j.1365-3083.2008.02153.x CrossRefPubMedGoogle Scholar
  41. Tesh VL (2010) Induction of apoptosis by Shiga toxins. Future Microbiol 5:431–453.  https://doi.org/10.2217/fmb.10.4 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Tobisawa Y, Maruyama T, Tanikawa T, Nakanishi K, Kurohane K, Imai Y (2011) Establishment of recombinant hybrid-IgG/IgA immunoglobulin specific for Shiga toxin. Scand J Immunol 74:574–584.  https://doi.org/10.1111/j.1365-3083.2011.02617.x CrossRefPubMedGoogle Scholar
  43. Twyman RM, Schillberg S, Fischer R (2013) Optimizing the yield of recombinant pharmaceutical proteins in plants. Curr Pharm Des 19:5486–5494.  https://doi.org/10.2174/1381612811319310004 CrossRefPubMedGoogle Scholar
  44. Virdi V, Juarez P, Boudolf V, Depicker A (2016) Recombinant IgA production for mucosal passive immunization, advancing beyond the hurdles. Cell Mol Life Sci 73:535–545.  https://doi.org/10.1007/s00018-015-2074-0 CrossRefPubMedGoogle Scholar
  45. Woof JM, Kerr MA (2006) The function of immunoglobulin A in immunity. J Pathol 208:270–282.  https://doi.org/10.1002/path.1877 CrossRefPubMedGoogle Scholar
  46. Yamasaki S, Sanada Y, Imase R, Matsuura H, Ueno D, Demura T, Kato K (2018) Arabidopsis thaliana cold-regulated 47 gene 5′-untranslated region enables stable high-level expression of transgenes. J Biosci Bioeng 125:124–130.  https://doi.org/10.1016/j.jbiosc.2017.08.007 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Laboratory of Microbiology and Immunology, School of Pharmaceutical SciencesUniversity of ShizuokaShizuoka CityJapan
  2. 2.Laboratory of Plant Molecular Improvement, Graduate Division of Nutritional and Environmental SciencesUniversity of ShizuokaShizuoka CityJapan

Personalised recommendations