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Eosinophils, ribonucleases and host defense: Solving the puzzle

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Abstract

The eosinophil ribonucleases eosinophil-derived neurotoxin (EDN/ RNase 2) and eosinophil cationic protein (ECP/RNase 3) are among the major secretory effector proteins of human eosinophilic leukocytes, cells whose role in host defense remains controversial and poorly understood. We have recently described the unusual manner in which this ribonuclease lineage has evolved, with extraordinary diversification observed in primate as well as in rodent EDNs and ECPs. The results of our evolutionary studies suggest that the EDN/ ECP ribonucleases are in the process of being tailored for a specific, ribonuclease-related goal. With this in mind, we have begun to look carefully at some of the intriguing associations that link eosinophils and their ribonucleases to disease caused by the single-stranded RNA viral pathogen, respiratory syncytial virus (RSV). Recent work in our laboratory has demonstrated that eosinophils can mediate a direct, ribonuclease-dependent reduction in infectivity of RSV in vitro, and that EDN can function alone as an independent antiviral agent. The results of this work have led us to consider the possibility that the EDN/ECP ribonucleases represent a heretofore unrecognized element of innate and specific antiviral host defense.

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References

  1. Ehrlich P: On the specific granulations of blood [translation]. Arch Anat Physiol 1897;166.

  2. Rosenberg HF: Eosinophils; in Gallin JI, Snyderman R (eds): Inflammation: basic research and clinical correlates. Philadelphia, PA, Lippincott Williams & Wilkins, 1999, pp. 61–76.

    Google Scholar 

  3. Sher A, Coffman RL, Hieny S, Cheever AW. Ablation of eosinophil and IgE responses with anti-IL-5 or anti-IL-4 antibodies fails to affect immunity againstSchistosoma mansoni in the mouse. J Immunol 1990;145:3911–3916.

    PubMed  CAS  Google Scholar 

  4. Herndon FJ, Kayes SG. Depletion of eosinophils by anti-IL-5 monoclonal antibody treatment of mice infected withTrichinella spiralis does not alter parasite burden or immunologic resistance to reinfection. J Immunol 1992;149:3642–3647.

    PubMed  CAS  Google Scholar 

  5. Freeman GL,Tominaga A, Takatsu K, Secor WE, Colley DG. Elevated innate peripheral blood eosinophilia fails to augment irradiated cercarial vaccine-induced resistance toSchistosoma mansoni in IL-5 transgenic mice. J Parasitai 1995;81:1010–1011.

    Article  Google Scholar 

  6. Kopf M, Brombacher F, Hodgkin PD, Ramsay AJ, Milbourne EA, Dai WJ, Ovington KS, Behm CA Kohler G, Young IG, Matthaei KI. IL-5-deficient mice have a developmental defect in CD5+ B-1 cells and lack eosinophilia but have normal antibody and cytotoxic T cell responses. Immunity 1996; 4:15–24.

    Article  PubMed  CAS  Google Scholar 

  7. Korenaga M, Hitoshi Y, Yamaguchi N, Sato Y, Takatsu K, Tada I. The role of interleukin-5 in protective immunity toStrongyloides venezuelensis infection in mice. Immunology 1991;72:502–507.

    PubMed  CAS  Google Scholar 

  8. Folkard SG, Hogarth PJ, Taylor MJ, Bianco AE: Eosinophils are the major effector cells of immunity to microfilariae in a mouse model of onchocerciasis. Parasitology 1996;112:323–329.

    Article  PubMed  Google Scholar 

  9. Nutten S, Papin JP, Woerly G, Dunne DW, MacGregor J, Trottein F, Capron M. Selectin and Lewis-X are required as co-receptors in antibody-dependent cell-mediated cytotoxicity of human eosinophils toSchistosoma mansoni schistosomula. Eur J Immunol 1999;29:799–808.

    Article  PubMed  CAS  Google Scholar 

  10. Betts CJ, Else KJ: Mast cells, eosinophils and antibody-mediated cellular cytotoxicity are not critical in resistance toTrichuris muris. Parasite Immunol 1999;21:45–52.

    Article  PubMed  CAS  Google Scholar 

  11. Wong DTW, Weller PF, Galli SJ, et al: Human eosinophils express transforming growth factor alpha. J Exp Med 1990;172:673–681.

    Article  PubMed  CAS  Google Scholar 

  12. Todd R, Donoff BR, Chiang T, et al: The eosinophil as a cellular source of tranforming growth factor alpha in healing cutaneous wounds. Am J Pathol 1991;138: 1307–1313.

    PubMed  CAS  Google Scholar 

  13. Lucey DR, Nicholson-Weller A, Weller PF: Mature human eosinophils have the capacity to express HLA-DR. Proc Natl Acad Sci USA 1989;86:1348–1351.

    Article  PubMed  CAS  Google Scholar 

  14. Hansel TT, deVries IJ, Carballido JM, Braun RK, Carballido-Perrig N, Rihs S, Blaser K, Walker C. Induction and function of eosinophil intercellular adhesion molecule 1 and HLA-DR. J Immunol 1992;149:2130–2136.

    PubMed  CAS  Google Scholar 

  15. Del Pozo V, De Andres B, Martin E, Cardaba B, Fernandez JC, Gallardo S, Tramon P, Leyva Cobain F, Palomino P, Lahoz C: Eosinophil as antigen-presenting cell: activation of T cell clones and T cell hybridoma by eosinophils after antigen processing. Eur J Immunol 1992;22:1919–1925.

    Article  Google Scholar 

  16. Mawhorter SD, Kazura JW, Boom WH: Human eosinophils as anti-gen presenting cells: relative efficiency for superantigen and antigen induced CD4+ T-cell proliferation. Immunology 1994;81:584–591.

    PubMed  CAS  Google Scholar 

  17. Archer GT, Hirsch JB. Isolation of granules from eosinophil leucocytes and study of their enzyme content. J Exp Med 1963;118:277–284.

    Article  PubMed  CAS  Google Scholar 

  18. Olsson I, Venge P, Sptiznagel JK, Lehrer RI: Arginine-rich cationic proteins of human eosinophil granules. Comparison of theconstitutents of eosinophilic and neutrophilic leukocytes. Lab Invest 1977;36: 493–500.

    PubMed  CAS  Google Scholar 

  19. Olsson I, Persson AM, Winqvist I: Biochemical properties of eosinophil cationic protein and demonstration of its biosynthesisin vitro in marrow cells from patients with eosinophilia. Blood 1986;67: 498–503.

    PubMed  CAS  Google Scholar 

  20. Durack DT, Sumi SM, Klebanoff SJ: Neurotoxicity of human eosinophils. Proc Natl Acad. Sci USA 1979;76:1443–1447.

    Article  PubMed  CAS  Google Scholar 

  21. Durack DT, Ackerman SJ, Loegering DA, Gleich GJ. Purification of human eosinophil-derived neurotoxin. Proc Natl Acad Sci USA 1981;78:5165–5169.

    Article  PubMed  CAS  Google Scholar 

  22. Gleich GJ, Loegering DA, Bell MP, Checkel JL, Ackerman SJ, McKean DJ: Biochemical and functional similarities between human eosinophil-derived neurotoxin and eosinophil cationic protein: homology with ribonuclease. Proc Natl Acad Sci USA 1986;83: 3146–3150.

    Article  PubMed  CAS  Google Scholar 

  23. Rosenberg HF, Tenen DG, Ackerman SJ: Molecular cloning of the human eosinophil-derived neurotoxin: a member of the ribonuclease gene family. Proc Natl Acad Sci USA 1989;86:4460–4464.

    Article  PubMed  CAS  Google Scholar 

  24. Hamann KJ, Barker RL, Loegering DA, Pease LR, Gleich GJ: Sequence of human eosinophilderived neurotoxin cDNA: identity of deduced amino acid sequence with human non-secretory ribonucleases. Gene 1989;83:161–167.

    Article  PubMed  CAS  Google Scholar 

  25. Rosenberg HF, Ackerman SJ, Tenen DG. Human eosinophil cationic protein: molecular cloning of a cytotoxin and helminthotoxin with ribonuclease activity. J Exp Med 1989;170:163–176.

    Article  PubMed  CAS  Google Scholar 

  26. Barker RL, Loegering DA, Ten RM, Hamann KJ, Pease LR, Gleich GJ: Eosinophil cationic protein cDNA: comparison with other toxic cationic proteins and ribonucleases. J Immunol 1989; 143: 952–955.

    PubMed  CAS  Google Scholar 

  27. Slifman NR, Loegering DA, McKean DJ, Gleich GJ: Ribonuclease activity associated with human eosinophil-derived neurotoxin and eosinophil cationic protein. J Immunol 1986; 137: 2913–2917.

    PubMed  CAS  Google Scholar 

  28. Gullberg U, Widegren B, Arivason U, Egesten A, Olsson I: The cytotoxic eosinophil cationic protein (ECP) has ribonuclease activity. Biochem Biophys Res Commun 1986;139:1239–1242.

    Article  PubMed  CAS  Google Scholar 

  29. Rosenberg HF: The eosinophil ribonucleases. Cell Mol Life Sci 1998;54:795–803.

    Article  PubMed  CAS  Google Scholar 

  30. Newton DK, Walbridge S, Mikulski SM, Ardelt W, Shogen K, Ackerman SJ, et al: Toxicity of an antitumor ribonuclease to Purkinje neurons. J Neuroxic 1994; 14: 538–544.

    CAS  Google Scholar 

  31. Sorentino S, Glitz, DG, Hamann KJ, Loegering DA, Checkel JL, Gleich GJ: Eosinophil-derived neurotoxin and human liver ribonuclease. Identity of structure and linkage of neurotoxicity to nuclease activity. J Biol Chem 1992;267: 14589–14565.

    Google Scholar 

  32. Wardlaw AJ, Moqbel R, Kay AB: Eosinophils: biology and role in disease. Adv Immunol 1995;60:l 51–266.

    Google Scholar 

  33. Silberstein DS: Eosinophil function in health and disease. Crit Rev Oncol Hematol 1995;19:47–77.

    Article  PubMed  CAS  Google Scholar 

  34. Young JDE, Peterson CGB, Venge P, Cohn ZA: Mechanism of membrane damage mediated by human eosinophil cationic protein. Nature 1986;321:613–616.

    Article  PubMed  CAS  Google Scholar 

  35. Rosenberg HF: Recombinant eosi nophil cationic protein (ECP): ribonuclease activity is not essential for cytotoxicity. J Biol Chem 1995;270:7876–7881.

    Article  PubMed  CAS  Google Scholar 

  36. Molina HA, Kierszenbaum F, Hamann KJ, Gleich GJ: Toxic effects produced or mediated by human eosinphil granule components onTrypanosoma cruzi. Am J Trop Med Hyg 1988;38:327–334.

    PubMed  CAS  Google Scholar 

  37. Rosenberg HF, Dyer KD, Tiffany HL, Gonzalez M: Rapid evolution of a unique family of primate ribonuclease genes. Nature Genetics 1995;10:219–223.

    Article  PubMed  CAS  Google Scholar 

  38. Murphy PM: Molecular mimicry and the generation of host defense protein diversity. Cell 1993;72: 823–826.

    Article  PubMed  CAS  Google Scholar 

  39. Zhang J, Rosenberg HF, Nei M: Positive Darwinian selection after gene duplication in primate ribonuclease genes. Proc Natl Acad Sci USA 1998;95:3708–3713.

    Article  PubMed  CAS  Google Scholar 

  40. Rosenberg HF, Dyer DK: Eosinophil cationic protein and eosinophil-derived neurotoxin: evolution of novel function in a primate ribonuclease gene family. J Biol Chem 1995;270:21,539–21,544.

    Article  CAS  Google Scholar 

  41. Rosenberg HF, Dyer KD: Diversity among the primate eosinophil-derived neurotoxin genes: a specific carboxy-terminal sequence is necessary for enhanced ribonuclease activity. Nucleic Acids Res 1997;35:3532–3536.

    Article  Google Scholar 

  42. Rosenberg HF, Dyer KD: Molecular cloning and characterization of a novel human ribonuclease (RNase k6): increasing diversity in the enlarging ribonuclease gene family. Nucleic Acids Res 1996;24:3507–3513.

    Article  PubMed  CAS  Google Scholar 

  43. Deming MS, Dyer KD, Bankier AT, Piper MB, Dear PH, Rosenberg HF: Ribonuclease k6: chromosomal localization and divergen rates of evolution in the RNase A superfamily. Genome Res 1998;8: 599–607.

    PubMed  CAS  Google Scholar 

  44. Larson KA, Olson EA, Maden BJ, Gleich GJ, Lee NA, Lee JJ: Two highyly homologous ribonuclease genes expressed in mouse eoisnophils identify a larger subgroup of the mammalian ribonuclease superfamily. Proc Natl Acad Sci USA 1996;93:12,370–12,375.

    CAS  Google Scholar 

  45. Batten D, Dyer KD, Domachowske JB, Rosenberg HF: Molecular cloning of four novel murine ribonuclease genes: unusual expansion within the Ribonuclease A gene family. Nucleic Acids Res 1997;25:4235–4239.

    Article  PubMed  CAS  Google Scholar 

  46. Singhania NA, Dyer KD, Zhang J, Deming MS, Bonville CA, Domachowske JB, Rosenberg HF: Rapid evolution of the RNase A superfamily: adaptive expansion of inde-pendent gene clusters in rats and mice. J Mol Evol 1999;49:721–728.

    Article  PubMed  CAS  Google Scholar 

  47. Collins PL, Mclntosh K, Chanock RM: Respiratory syncytial virus, Fields BN, Knipe DM, Howley PM, eds. Fields Virology, 2nd ed. Lippincott-Raven Publishers, Philadelpha PA; 1996; pp. 1313–1351.

    Google Scholar 

  48. Prober CG, Wang EEL: Reducing the morbidity of lower respiratory tract infectious caused by respiratory syncytial virus: still no answer. Pediatrics 1997;99:472–475.

    Article  PubMed  CAS  Google Scholar 

  49. Domachowske JB, Rosenberg HF: Respiratory syncytial virus infection: immune response, immunopathogenesis and treatment. Clin Microbiol Rev 1999;12:298–309.

    PubMed  CAS  Google Scholar 

  50. Garofalo R, Kimpen JLL, Welliver RC, Ogra PL: Eosinophil degranulation in the respiratory tract during naturally acquired respiratory syncytial virus infection. J Pediatrics 1992;120:28–32.

    Article  CAS  Google Scholar 

  51. Kimpen JL, Garofalo R, Welliver RC, Ogra PL: Activation of human eosinophils by respiratory syncytial virus. Pediatric Res 1992;32: 160–164.

    Article  CAS  Google Scholar 

  52. Arnold RB, Humbert H, Werchau H, Gallati H, Konig W: Interleukin-8, interleukin-6 and soluble tumor necrosis factor receptor type-1 release from a human pulmonary epithelial cell line (A549) exposed to respiratory syncytial virus. Immunology 1994;8:20–27.

    Google Scholar 

  53. Fiedler MA, Wernke-Dollries K, Stark JM: Respiratory syncytial virus increases IL-8 gene expression and protein release in A549 cells. Am J Phyisol 1995;269: L865-L872.

    CAS  Google Scholar 

  54. Becker S, Reed W, Henderson RW, Noah TL: RSV infection of airway epithelial cells causes production of the beta-chemokine RANTES. Am J Physiol 1997; 272:L512-L520.

    PubMed  CAS  Google Scholar 

  55. Saito T, Deskin RW, Casola A, Haeberle H, Olszewska B, Ernst PB, Alam R, Ogra P, Garofalo R: Respiratory syncytial virus induced selective production of the chemokine RANTES by upper airway epithelial cells. J Infect Dis 1997;175:497–504.

    PubMed  CAS  Google Scholar 

  56. Harrison AM, Bonville CA, Rosenberg HF, Domachowske JB: Respiratory syncytial virus infection induces expression of macrophage inflammatory protein 1 -alpha (MIP1-alpha) in the human lower respiratory tract in vivo: association with eosinophil recruitment and degranulation. Am J Resp Dis Crit Care Med 1999;159:1918–1924.

    CAS  Google Scholar 

  57. Stark JM, Godding V, Sedgewick JB, Busse WW: Respiratory syncytial virus infection enhances neutrophil and eosinophil adhesion to cultured respiratory epithelial cells. J Immunol 1996; 156: 4774–4782.

    PubMed  CAS  Google Scholar 

  58. Schwarze J, Cieslewicz G, Hamelmann E, Joetham A, Schultz LD, Lamers MC, Gelfand EW: IL-5 and eosinophils are essential for the development of airway hyperresponsiveness following acute respiratory syncytial virus infection. J Immunol 1999;162:2997–3004.

    PubMed  CAS  Google Scholar 

  59. Schwarze J, Cieslewicz G, Joetham A, Ikemura T, Hamelmann E, Gelfand EW: CD8 T cells are essential in the development of respiratory syncytial virus-induced lung eosinophilia and airway hyperresponsiveness. J Immunol 1999;162:4207–4211.

    PubMed  CAS  Google Scholar 

  60. Domachowske JB, Dyer KD, Bonville CA, Rosenberg HF: Recombinant human eosinophil-derived neurotoxin / RNase 2 functions as an effective antiviral agent against respiratory syncytial virus. J Infect Dis 1998;177:1458–1464.

    PubMed  CAS  Google Scholar 

  61. Domachowske JB, Dyer KD, Adams AG, Leto TL, Rosenberg HF: Eosinophil cationic protein (ECP / RNase 3): another eosinophil ribonuclease with direct antiviral activity. Nucleic Acids Res 1998;26:3358–3363.

    Article  PubMed  CAS  Google Scholar 

  62. Domachowske JB, Bonville CA, Dyer KD, Rosenberg HF: Evolution of antiviral activity in the Ribonuclease A gene superfamily: evidence for a specific interaction between eosinophil-derived neurotoxin (EDN / RNase 2) and respiratory syncytial virus. Nucleic Acids Res 1998;26:5327–5332.

    Article  PubMed  CAS  Google Scholar 

  63. Motojima S, Frigas E, Loegering DA, Gleich GJ: Toxicity of eosinophil cationic proteins for guinea pic tracheal epithelia in vitro. Am Rev Respir Dis 1989;139: 801–805.

    PubMed  CAS  Google Scholar 

  64. Vasandani VM, Wu YN, Mikulski SM, Youle RJ, Sung C: Molecular determinants in the plasma clearance and tissue distribution of ribonucleases of the ribonuclease A superfamily. Cancer Res 1996; 56:4180–4186.

    PubMed  CAS  Google Scholar 

  65. Kimura M: A simple method for estimating evolutionary rate of base substitution through comparative studies of nucleotide sequences. J Mol Evol 1980;16: 111–120.

    Article  PubMed  CAS  Google Scholar 

  66. Kumar S, Tamura K, Nei M: Molecular Evolutionary Genetics Analysis, version 1.02, Institute of Molecular Evolutionary Genetics, The Pennsylvania State University, PA.

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Authors and Affiliations

  1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 20892, Bethesda, Maryland

    Helene F. Rosenberg MD

  2. Department of Pediatrics, State University of New York Health Science Center at Syracuse, 13210, Syracuse, New York

    Joseph B. Domachowske

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  1. Helene F. Rosenberg MD
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Correspondence to Helene F. Rosenberg MD.

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Rosenberg, H.F., Domachowske, J.B. Eosinophils, ribonucleases and host defense: Solving the puzzle. Immunol Res 20, 261–274 (1999). https://doi.org/10.1007/BF02790409

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