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Modeling neutralization of Shiga 2 toxin by A-and B-subunit-specific human monoclonal antibodies

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Abstract

A mathematical model for Shiga 2 toxin neutralization by A-and B-subunit-specific human monoclonal antibodies initially delivered in the extracellular domain is presented, taking into account toxin and antibodies interaction in the extracellular domain, diffusion of toxin, antibodies, and their reaction products toward the cell, the receptor-mediated toxin and complex composed of toxin and antibody to A-subunit internalization from the extracellular into the intracellular medium and excretion of this complex back to the extracellular environment via recycling endosomal carriers. The retrograde transport of the intact toxin to the endoplasmic reticulum and its anterograde movement back to the vicinity of the plasma membrane with its subsequent exocytotic removal to the extracellular space via the secretory vesicle pathway is also taken into account. The model is composed of a set of coupled PDEs. A mathematical model based on a system of ODEs for Shiga 2 toxin neutralization by antibodies in the absence of cell is also studied. Both PDE and ODE systems are solved numerically. Numerical results are illustrated by figures and discussed.

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References

  1. Jeong, K., Chapman-Bonofiglio, S., Singh, P., Lee, J., Tzipori, S.: In vitro and in vivo protective efficacies of antibodies that neutralize the RNA N-glycosidase activity of Shiga toxin 2. BMC Immunol. 11, 16 (2010)

    Article  Google Scholar 

  2. Krautz-Peterson, G., Chapman-Bonofiglio, S., Boisvert, K., Feng, H., Herman, I.M., Tzipori, S.: Intracellular neutralization of Shiga toxin 2 by an A subunit-specific human monoclonal antibody. Infect. Immun. 76, 1931–1939 (2008)

    Article  Google Scholar 

  3. Boerlin, P., McEwen, S.A., Boerlin-Petzold, F., Wilson, J.B., Johnson, R.P., Gyles, C.L.: Associations between virulence factors of Shiga toxin-producing Escherichia coli and disease in humans. J. Clin. Microbiol. 37, 497–503 (1999)

    Google Scholar 

  4. Griffin, P.M., Tauxe, R.V.: The epidemiology of infections caused by Escherichia coli O157:H7, other enterohemorrhagic E. coli, and the associated hemolytic uremic syndrome. Epidemiol. Rev. 13, 60–98 (1991)

    Google Scholar 

  5. Milford, D.V., Taylor, C.M., Guttridge, B., Hall, S.M., Rowe, B., Kleanthous, H.: Haemolytic uraemic syndromes in the British Isles 1985-8: association with verocytotoxin producing Escherichia coli. Part 1. Clinical and epidemiological aspects. Arch. Dis. Child 65, 716–721 (1990)

    Article  Google Scholar 

  6. Ostroff, S.M., Tarr, P.I., Neill, M.A., Lewis, J.H., Hargrett-Bean, N., Kobayashi, J.M.: Toxin genotypes and plasmid profiles as determinants of systemic sequelae in Escherichia coli 0197-H7 infections. J. Infect. Dis. 160, 994–998 (1989)

    Article  Google Scholar 

  7. Lingwood, C.A., Law, H., Richardson, S., Petric, M., Brunton, J.L., De Grandis, S., Karmali, M.: Glycolipid binding of purified and recombinant Escherichia coli produced verotoxin in vitro. J. Biol. Chem. 262, 8834–8839 (1987)

    Google Scholar 

  8. Waddell, T., Head, S., Petric, M., Cohen, A., Lingwood, C.: Globotriosyl ceramide is specifically recognized by the Escherichia coli verocytotoxin 2. Biochem. Biophys. Res. Commun. 152, 674–679 (1988)

    Article  Google Scholar 

  9. Sandvig, K., Van Deurs, B.: Endocytosis, intracellular transport, and cytotoxic action of Shiga toxin and ricin. Physiol. Rev. 76, 949–966 (1996)

    Google Scholar 

  10. Garred, O., Dubinina, E., Holm, P.K., Olsnes, S., van Deurs, B., Kozlov, J.V., Sandvig, K.: Role of processing and intracellular transport for optimal toxicity of Shiga toxin and toxin mutants. Exp. Cell Res. 218, 39–49 (1995)

    Article  Google Scholar 

  11. Endo, Y., Tsurugi, K., Yutsudo, T., Takeda, Y., Ogasawara, T., Igarashi, K.: Site of action of a Vero toxin (VT2) from Escherichia coli O157:H7 and of Shiga toxin on eukaryotic ribosomes. RNA N-glycosidase activity of the toxins. Eur. J. Biochem. 171, 45–50 (1988)

    Article  Google Scholar 

  12. Saxena, S.K., O’Brien, A.D., Ackerman, E.J.: Shiga toxin, Shiga-like toxin II variant, and ricin are all single-site RNA N-glycosidases of 28 S RNA when microinjected into Xenopus oocytes. J. Biol. Chem. 264, 596–601 (1989)

    Google Scholar 

  13. Mukherjee, J., Chios, K., Fishwild, D., Hudson, D., O’Donnell, S., Rich, S.M., Donohue-Rolfe, A., Tzipori, S.: Human Stx2-specific monoclonal antibodies prevent systemic complications of Escherichia coli O157:H7 infection. Infect. Immun. 70, 612–619 (2002)

    Article  Google Scholar 

  14. Sheoran, A.S., Chapman-Bonofiglio, B.R., Harvey, B.R., Mukherjee, J., Georgiou, G., Donohue-Rolfe, A., Tzipori, S.: Human antibody against Shiga toxin 2 administered to piglets after the onset of diarrhea due to Escherichia coli O157:H7 prevents fatal systemic complications. Infect. Immun. 73, 4607–4613 (2005)

    Article  Google Scholar 

  15. Tzipori, S., Sheoran, A., Akiyoshi, D., Donohue-Rolfe, A., Trachtman, H.: Antibody therapy in the management of Shiga toxin-induced hemolytic uremic syndrome. Clin. Microbiol. Rev. 17, 926–941 (2004)

    Article  Google Scholar 

  16. Sandvig, K., van Deurs, B.: Transport of protein toxins into cells: pathways used by ricin, cholera toxin, and Shiga toxin. FEBS Lett. 529, 49–53 (2002)

    Article  Google Scholar 

  17. Skakauskas, V., Katauskis, P.: Modelling of toxin-antibody interaction and toxin transport toward the endoplasmic reticulum. J. Biol. Phys. 42, 83–97 (2016)

    Article  Google Scholar 

  18. Smith, D.A., Simmons, R.M.: Models of motor-assisted transport of intracellular particles. Biophys. J. 80, 45–68 (2001)

    Article  ADS  Google Scholar 

  19. Friedman, A., Cracium, G.: A model of intracellular transport of particles in an axon. J. Math. Biol. 51, 217–246 (2005)

    Article  MathSciNet  MATH  Google Scholar 

  20. Grant, B.D., Donaldson, J.G.: Pathways and mechanisms of endocytic recycling. Nat. Rev. Mol. Cell Biol. 10, 597–608 (2009)

    Article  Google Scholar 

  21. Vale, R.D., Reese, T.S., Sheetz, M.P.: Identification of a novel force-generating protein, kinesin, involved in microtubule-based motility. Cell 42, 39–50 (1985)

    Article  Google Scholar 

  22. Vale, R.D., Schnapp, B.J., Reese, T.S., Sheetz, M.P.: Movement of organelles along filaments dissociated from the axoplasm of the squid giant axon. Cell 40, 449–454 (1985)

    Article  Google Scholar 

  23. Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K., Watson, J.D.: : Molecular Biology of the Cell, 3rd edn. Garland Publishing, New York (1994)

    Google Scholar 

  24. Wang, S., Hsu, S.C.: The molecular mechanisms of the mammalian exocyst complex in exocytosis. Biochem. Soc. Trans. 34, 687–690 (2006)

    Article  Google Scholar 

  25. Press, W.H., Teukolsky, S.A., Vetterling, W.T., Flannery, B.P.: : Numerical Recipes: The Art of Scientific Computing, 3rd edn. Cambridge University Press, Cambridge, UK (2007)

    MATH  Google Scholar 

  26. Shampine, L.F., Gladwell, I., Thompson, S., Beardah, C.: Solving ODEs with MATLAB. Cambridge University Press, Cambridge, UK (2003)

    Book  MATH  Google Scholar 

  27. Samarskii, A.A.: The Theory of Difference Schemes. Marcel Dekker, New York (2001)

    Book  MATH  Google Scholar 

  28. Truskey, G.A., Yuan, F., Katz, D.F.: Transport Phenomena in Biological Systems, 2nd edn. Pearson Prentice Hall Bioengineering (2009)

  29. Lord, J.M., Spooner, R.A.: Ricin trafficking in plant and mammalian cells. Toxins 3, 787–801 (2011)

    Article  Google Scholar 

  30. Van Deurs, B., Sandvig, K., Peterson, O.W., Olsnes, S., Simons, K., Griffiths, G.: Estimation of the amount of internalized ricin that reaches the trans-Golgi network. J. Cell Biol. 106, 253–267 (1988)

    Article  Google Scholar 

  31. Nakajima, H., Kiyokawa, N., Katagiri, Y.U., Taguchi, T., Suzuki, T., Sekino, T., Mimori, K., Ebata, T., Saito, M., Nakao, H., Takeda, T., Fujimoto, J.: Kinetic analysis of binding between Shiga toxin and receptor glycolipid Gb3Cer by surface plasmon resonance. J. Biol. Chem. 276, 42915–42921 (2001)

    Article  Google Scholar 

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Correspondence to Vladas Skakauskas.

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Skakauskas, V., Katauskis, P. Modeling neutralization of Shiga 2 toxin by A-and B-subunit-specific human monoclonal antibodies. J Biol Phys 42, 435–452 (2016). https://doi.org/10.1007/s10867-016-9416-5

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  • DOI: https://doi.org/10.1007/s10867-016-9416-5

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